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Role of nitric oxide in the physiopathology of pain

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      Abstract

      Many painful disorders, including joint dysfunctions such as rheumatoid arthritis (RA) or temporomandibular joint disorders (TMD), are associated with hyperthermia of the overlying skin. The same is true of certain intractable chronic pain conditions, such as chronic orofacial pain, which may be associated with TMD. We suggest that this skin hyperthermia, caused by regional vasodilation, is induced by extravascular nitric oxide (NO). Extravascular NO can be produced in the affected joint by osteoblasts, chondrocytes, and macrophages, by mechanical stimulation of endothelial cells, or by stimulated neurons. In view of a strong correlation between pain and skin hyperthermia in these disorders, and the evidence that NO enhances the sensitivity of peripheral nociceptors, we also suggest that at least this kind of pain is associated with excessive local level of NO. This hypothesis can be verified by dynamic area telethermometry, assessing the effect of NO on the sympathetic nervous function. This mechanism, which is in line with the general role of NO as a mediator between different organ systems, also may be relevant to any pain associated with enhanced immune response. Clinical implications of the proposed mechanism are discussed.

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      References

        • McNeill C.
        Temporomandibular disorders.
        in: McNeill C. American Academy of Orofacial Pain Guidelines for classification, assessment and management. Quintessence, Chicago1993: 11-13
        • McNeill C.
        Temporomandibular disorders.
        in: McNeill C. American Academy of Orofacial Pain Guidelines for classification, assessment and management. Quintessence, Chicago1993: 29
        • McNeill C.
        Temporomandibular disorders.
        in: McNeill C. American Academy of Orofacial Pain Guidelines for classification, assessment and management. Quintessence, Chicago1993: 40-53
        • McNeill C.
        Temporomandibular disorders.
        in: McNeill C. American Academy of Orofacial Pain Guidelines for classification, assessment and management. Quintessence, Chicago1993: 122
        • Carlsson G.E.
        • LeResche L.
        Epidemiology of temporomandibular disorders.
        in: Temporomandibular disorders and related pain, progress in pain research and management. vol 4. IASP Press, Seattle1995: 211-226
        • Von Korff M.
        • Dworkin S.F.
        • LeResche L.
        • Kruger A.
        An epidemiologic comparison of pain complaints.
        Pain. 1988; 32: 173-183
        • Lipton J.A.
        • Ship J.A.
        • Larach-Robinson D.
        Estimated prevalence and distribution of reported orofacial pain in the United States.
        J Am Dent Assoc. 1993; 124: 115-121
        • Von Korff M.
        Health services research and temporomandibular pain.
        in: Temporomandibular disorders and related pain, progress in pain research and management. vol 4. IASP Press, Seattle1995: 227-236
        • Gratt B.M.
        • Sickles E.A.
        Electronic facial thermography: an analysis of asymptomatic adult subjects.
        J Orofacial Pain. 1995; 9: 255-265
        • Gratt B.M.
        • Sickles E.A.
        Thermographic characterization of the asymptomatic temporomandibular joint.
        J Orofacial Pain. 1993; 7: 7-14
        • Uematsu S.
        Thermographic imaging of cutaneous sensory segment in patients with peripherral nerve injury. Skin temperature stability between sides of the body.
        J Neurosurg. 1985; 62: 716-720
        • Gratt B.M.
        • Sickles E.A.
        • Ross J.B.
        • et al.
        Thermographic assessment of craniomandibular disorders: diagnostic interpretation versus temperature measurement analysis.
        J Orofacial Pain. 1994; 8: 278-288
        • Gratt B.M.
        • Sickles E.A.
        • Wexler C.E.
        • Ross J.B.
        Thermographic characterization of an internal derangement of the temporomandibular joint.
        J Orofacial Pain. 1994; 8: 197-206
        • Gratt B.M.
        • Sickles E.A.
        • Wexler C.E.
        Thermographic characterization of osteorthrosis of the temporomandibular joint.
        J Orofacial Pain. 1993; 7: 345-353
        • Canavan D.
        • Gratt B.M.
        Electronic thermography for the assessment of mild and moderate TMJ dysfunction.
        Oral Surg Oral Med Oral Pathol. 1995; 79: 778-786
        • McBeth S.A.
        • Gratt B.M.
        A cross-sectional thermographic assessment of TMJ problems in orthodontic patients.
        Am J Orthod Dentofacial Orthop. 1996; 109: 481-488
        • Ketelaer M.-C.
        Thermographic changes seen in traumatic neuraligia following a double-blind somatosensory block.
        in: MSc thesis in oral biology. UCLA School of Dentistry, 1995
        • Ignarro L.J.
        Nitric oxide as a communication signal in vascular and neuronal cells.
        in: Lancaster Jr., J. Nitric oxide, principles and actions. Academic, San Diego1996: 111-138
        • Whittle B.J.
        Nitric oxide in physiology and pathology.
        Histochem J. 1995; 27: 727-737
        • Wink D.A.
        • Hanbauer I.
        • Grisham M.B.
        • et al.
        Chemical biology of nitric oxide: regulation and protective and toxic mechanisms.
        Curr Top Cell Regul. 1996; 34: 159-187
        • McDonald L.J.
        • Murad F.
        Nitric oxide and cyclic GMP signaling.
        in: Proc Soc Exp Biol Med. 211. 1996: 1-6
        • Lincoln T.M.
        Cyclic GMP receptor proteins: role in nervous system and other tissues.
        in: Vincent S. Nitric oxide in the nervous system. Academic, San Diego1995: 51-82
        • Murphy S.
        • Grybicki D.M.
        • Simmons M.L.
        Glial cells as nitric oxide sources and targets.
        in: Vincent S. Nitric oxide in the nervous system. Academic, San Diego1995: 163-190
        • Rand M.J.
        • Li G.G.
        Nitric oxide in the autonomic and enteric nervous systems.
        in: Vincent S. Nitric oxide in the nervous system. Academic, San Diego1995: 227-280
        • Schuman E.M.
        Nitric oxide signalling, long term potentiation and long term depression.
        in: Vincent S. Nitric oxide in the nervous system. Academic, San Diego1995: 125-150
        • Lancaster J.
        • Stuehr D.J.
        The intracellular reactions of nitric oxide in the immune system and its enzymatic synthesis.
        in: Lancaster Jr., J. Nitric oxide, principles and actions. Academic, San Diego1996: 139-176
        • Levi R.
        • Park K.H.
        • Imamura M.
        • et al.
        Nitric oxide and adrenergic neuromodulation.
        Adv Pharmacol. 1995; 34: 399-414
        • Anbar M.
        Nitric oxide: a synchronizing chemical messenger.
        Experientia. 1995; 51: 545-550
        • Ignarro L.J.
        Nitric oxide-mediated vasorelaxation.
        Thromb Haemost. 1993; 70: 148-151
        • Wang Y.
        • Mardsen P.A.
        Nitric oxide synthases: gene structure and regulation.
        Adv Pharmacol. 1995; 34: 71-90
        • Fukuto J.M.
        • Mayer B.
        The enzymology of nitric oxide synthase.
        in: Feelisch M. Stamler J.S. Methods in nitric oxide research. John Wiley and Sons, Chichester1996: 147-160
        • Michel T.
        • Xie Q.W.
        • Nathan C.
        Molecular biological analysis of nitric oxide synthases.
        in: Feelisch M. Stamler J.S. Methods in nitric oxide research. John Wiley and Sons, Chichester1996: 161-175
        • Lewis D.A.
        • Rud K.S.
        • Miller V.M.
        Cofactors of constitutive nitric oxide synthase and endothelium-dependent relaxations in canine femoral veins.
        J Cardiovasc Pharmacol. 1993; 22: 443-448
        • Gao Y.
        • Chou H.
        • aj J.U.
        Endothelium-derived nitric oxide plays a larger role in pulmonary veins than in arteries of newborn lambs.
        Circ Res. 1995; 76: 559-565
        • Buga G.M.
        • gnarro L.J.
        Electrical field stimulation causes endothelium-dependent and nitric oxide-mediated relaxation of pulmonary artery.
        Am J Physiol. 1992; 262: H973-H979
        • Uchiyama Y.
        • Morita K.
        • Kitayama S.
        • et al.
        Possible involvement of nitric oxide in acetylcholine-induced increase of intracellular Ca2+ concentration and catecholamine release in bovine adrenal chromaffin cells.
        Jpn J Pharmacol. 1994; 65: 73-77
        • Buga G.M.
        • Griscavage J.M.
        • Rogers N.E.
        • Ignarro L.J.
        Negative feedback regulation of endothelial cell function by nitric oxide.
        Circ Res. 1993; 73: 808-812
        • Griscavage J.M.
        • Hobbs A.J.
        • Ignarro L.J.
        Negative modulation of nitric oxide synthase by nitric oxide and nitroso compounds.
        Adv Pharmacol. 1995; 34: 215-234
        • Persechini A.
        • McMillan K.
        • Leakey P.
        Activation of myosin light chain kinase and nitric oxide synthase activities by calmodulin fragments.
        J Biol Chem. 1994; 269: 16148-16154
        • Bredt D.S.
        Targeting nitric oxide to its targets.
        in: Proc Soc Exp Biol Med. 211. 1996: 41-48
        • Albina J.E.
        • Reichner J.S.
        Nitric oxide in inflammation and immunity.
        New Horitz. 1995; 3: 46-64
        • Szabo C.
        • Thiemermann C.
        Regulation of the expression of the inducible isoform of nitric oxide synthase.
        Adv Pharmacol. 1995; 34: 113-154
        • Wong J.M.
        • Billiar T.R.
        Regulation and function of inducible nitric oxide synthase during sepsis and acute inflammation.
        Adv Pharmacol. 1995; 34: 155-170
        • Forstermann U.
        • Kleinert H.
        Nitric oxide synthase: expression and expressional control of the three isoforms.
        Naunyn Schmiederbergs Arch Pharmacol. 1995; 352: 351-364
        • Murrell G.A.C.
        • Dolan M.M.
        • Jang D.
        • et al.
        Nitric oxide—an important articular free radical.
        J Bone Joint Surg. 1996; 78A: 265-274
        • Salzman A.L.
        • Menconi M.J.
        • Unno N.
        • et al.
        Nitric oxide dilates tight junctions and depletes ATP in cultured Caco-2BBe intestinal epithelial monolayers.
        Am J Physiol. 1995; 268: G361-G373
        • Stadler J.
        • Schmalix W.A.
        • Doehmer J.
        Inhibition of biotransformation by nitric oxide (NO) overproduction and toxic consequences.
        Toxicol Lett. 1995; 82–83: 215-219
        • Anbar M.
        Hyperthermia of the cancerous breast—analysis of mechanism.
        Cancer Lett. 1994; 84: 23-29
        • Anbar M.
        Thermological implication of vasodilation mediated by nitric oxide.
        Thermologie Osterreich. 1995; 5: 15-27
        • Chenitz J.E.
        Rheumatoid arthritis and its implications in temporomandibular disorders.
        Cranic. 1992; 10: 59-69
        • Farrell A.J.
        • Blake D.R.
        • Palmer R.M.
        • Moncada S.
        Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic disease.
        Ann Rheum Dis. 1992; 51: 1219-1222
        • Ralston S.H.
        • Todd D.
        • Helfrich M.
        • et al.
        Human osteoblast-like cells produce nitric oxide and express inducible nitric oxide synthase.
        Endocrinology. 1994; 135: 330-336
        • Kaur H.
        • Halliwell B.
        Evidence for nitric oxide-mediated oxidative damage in chronic inflammation. Nitrotyrosine in serum and synovial fluid from rheumatoid patients.
        FEBS Lett. 1994; 350: 9-12
        • Connor J.R.
        • Manning P.T.
        • Settle S.L.
        • et al.
        Suppression of adjuvant-induced arthritis by selective inhibition of inducible nitric oxide synthase.
        Eur J Pharmacol. 1995; 273: 15-24
        • Houri J.M.
        • O'Sullivan F.X.
        Animal models in rheumatoid arthritis.
        Curr Opin Rheumatol. 1995; 7: 201-205
        • Grabowski P.S.
        • England A.J.
        • Dykhuizen R.
        • et al.
        Elevated nitric oxide production in rheumatoid arthritis—detection using the fasting urinary nitrate/creatinine ratio.
        Arthritis Rheum. 1996; 39: 643-647
        • Grabowski P.S.
        • Macpherson H.
        • Ralston S.H.
        Nitric oxide production in cells derived from the human joint.
        Br J Rheumatol. 1996; 35: 207-212
        • Ueki Y.
        • Miyake S.
        • Tominaga Y.
        • Eguchi K.
        Increased nitric oxide levels in patients with rheumatoid arthritis.
        J Rheumatol. 1996; 23: 230-236
        • Scher D.M.
        • Stolerman E.
        • DiCesare P.E.
        Biologic markers of arthritis.
        Am J Orthoped. 1996; 25: 263-272
        • Cosh J.A.
        • Ring E.F.J.
        Techniques of heat detection used in the assessment of rheumatic diseases.
        J Radiol Electrol Med Nucl. 1967; 18: 84-89
        • Collins A.J.
        • Ring F.
        • Bacon P.A.
        • Brookshaw J.D.
        Thermography and radiology complimentary methods for the study of inflammatory diseases.
        Clin Radiol. 1976; 27: 237-243
        • Devereaux M.D.
        • Parr G.R.
        • Thomas D.P.
        • Hazleman B.L.
        Disease activity indexes in rheumatoid arthritis; a prospective, comparative study with thermography.
        Ann Rheum Dis. 1985; 44: 434-437
        • Schattenkirchner M.
        Diagnostic methods for evaluation of activity in inflammatory rheumatic diseases.
        Scand J Rheumatol. 1987; 65 (suppl): 63-70
        • Fioravanti A.
        • Franci A.
        • Gelli R.
        • et al.
        Evaluation of the efficacy of intra-articular administration of somatostatin in rheumatoid arthritis.
        Clin Ter. 1993; 142: 453-457
        • Devereaux M.D.
        • Parr G.R.
        • Lachmann S.M.
        • et al.
        Thermographic diagnosis in athletes with patellofemoral arthralgia.
        J Bone Joint Surg. 1986; 68: 42-44
        • Anbar M.
        Dynamic area telethermometry—a new field in clinical thermology. Part I.
        Med Electron. 1994; 146: 62-73
        • Anbar M.
        Dynamic area telethermometry—a new field in clinical thermology. Part II.
        Med Electron. 1994; 147: 73-85
        • Black C.M.
        • Clark R.P.
        • Darton K.
        • et al.
        A pyroelectric thermal imaging system for use in medical diagnosis.
        J Biomed Eng. 1990; 12: 281-286
        • Biundo Jr., J.J.
        • Torres-Ramos F.M.
        Rehabilitation and biomechanics.
        Curr Opin Rheumatol. 1991; 3: 291-299
        • Will R.K.
        • Ring E.F.
        • Clarke A.K.
        • Maddison P.J.
        Infrared thermography: what is its place in rheumatology in the 1990s?.
        Br J Rheumatol. 1992; 31: 337-344
        • Hall J.
        • Clarke A.K.
        • Elvins D.M.
        • Ring E.F.
        Low level laser therapy is ineffective in the management of rheumatoid arthritic finger joints.
        Br J Rheumatol. 1994; 33: 142-147
        • Fioravanti A.
        • Govoni M.
        • La Montagna G.
        • et al.
        Somatostatin 14 and joint inflammation: evidence for intraarticular efficacy of prolonged administration in rheumatoid arthritis.
        Drugs Exp Clin Res. 1995; 21: 97-103
        • Palmer R.M.
        • Hickery M.S.
        • Charles I.G.
        • et al.
        Induction of nitric oxide synthase in human chondrocytes.
        Biochem Biophys Res Commun. 1993; 193: 398-405
        • Beckmann J.S.
        • Ye Y.Z.
        • Anderson P.G.
        • et al.
        Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry.
        Biol Chem. 1994; 375: 81-88
        • Crow J.P.
        • Beckman J.S.
        Reactions between nitric oxide, superoxide, and peroxynitrate: Footprints of peroxynitrate in vivo.
        Adv Pharmacol. 1995; 34: 17-43
        • Ischiropoulos H.
        • al-Mehdi A.B.
        Peroxynitrite-mediated oxidative protein modifications.
        FEBS Lett. 1995; 364: 279-282
        • Stichtenoth D.O.
        • Fauler J.
        • Zeidler H.
        • Frolich J.C.
        Urinary nitrate excretion is increased in patients with rheumatoid arthritis and reduced by prediosolone.
        Ann Rheum Dis. 1995; 54: 820-824
        • Renoux M.
        • Hilliquin P.
        • Galoppin L.
        • et al.
        Cellular activation products in osteoarthritis synovial fluid.
        Int J Clin Pharmacol Res. 1995; 15: 135-138
        • Schellhas K.P.
        • Piper M.A.
        • Omlie M.R.
        Facial skeleton remodeling due to temporomandibular joint degeneration: an imaging study of 100 patients.
        Cranio. 1992; 10: 248-259
        • Luder H.U.
        • Schroeder H.E.
        Light and electron microscopic morphology of the temporomandibular joint in growing and mature crab-eating monkeys (Macaca fascicularis): the condylar calcified cartilage.
        Anat Embryology. 1992; 185: 189-199
        • Piette E.
        Anatomy of the human temporomandibular joint. An updated comprehensive review.
        Acta Stomatol Belg. 1993; 90: 103-127
        • Sato H.
        • Fujii T.
        • Yamada N.
        • Kitamori H.
        Temporomandibular joint osteoarthritis: a comparative clinical and tomograpphic study pre- and post-treatment.
        J Oral Rehabil. 1994; 21: 383-395
        • Kang J.D.
        • Georgescu H.J.
        • Mcintyrelarkin L.
        • et al.
        Herniated cervical intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2.
        Spine. 1995; 20: 2373-2378
        • Kang J.D.
        • Georgescu H.I.
        • Mcintyrelarkin L.
        • et al.
        Herniated cervical intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2.
        Spine. 1996; 21: 271-277
        • Asahara H.
        • Yokoi I.
        • Tamada T.
        • et al.
        Increased cerebrospinal fluid nitrite and nitrate levels in patients with lumbar spondylosis.
        Res Commun Mol Pathol Pharmacol. 1996; 91: 77-83
        • Evans D.M.
        • Ralston S.H.
        Nitric oxide and bone.
        J Bone Miner Res. 1996; 11: 300-305
        • Zaidi M.
        • Alam A.S.
        • Bax B.E.
        • et al.
        Role of the endothelial cell in osteoclast control: new perspectives.
        Bone. 1993; 14: 97-102
        • Sunyer T.
        • Rothe L.
        • Jiang X.S.
        • et al.
        Proinflammatory agents, IL-8 and IL-10, upregulate inducible nitric oxide synthase expression and nitric oxide production in avian osteoclast-like cells.
        J Cell Biochem. 1996; 60: 469-483
        • MacIntyre I.
        • Zaidi M.
        • Alam A.S.
        • et al.
        Osteoclastic inhibition: an action of nitric oxide not mediated by cyclic GMP.
        in: Proc Natl Acad Sci USA. 88. 1991: 2936-2940
        • Hukkanen M.
        • Hughes F.J.
        • Buttery L.D.K.
        • et al.
        Cytokine-stimulated expression of inducible nitric oxide synthase by mouse, rat, and human osteoblast-like cells and its functional role in osteoblast metabolic activity.
        Endocrinology. 1995; 136: 5445-5453
        • De Grooth R.
        • Mieremet R.H.
        • Kawilarang-De Haas E.W.
        • Nijweide P.J.
        Murine macrophage precursor cell lines are unable to differentiate into osteoclasts: a possible implication for osteoclast ontogeny.
        Int J Exp Pathol. 1994; 75: 265-275
        • Martin T.J.
        • Ng K.W.
        Mechanisms by which cells of the osteoblast lineage control osteoclast formation and activity.
        J Cell Biochem. 1994; 56: 357-366
        • Horowitz S.M.
        • Rapuano B.P.
        • Lane J.M.
        • Burstein A.H.
        The interaction of the macrophage and the osteoblast in the pathophysiology of aseptic loosening of joint replacements.
        Calcif Tissue Int. 1994; 54: 320-324
        • Takaishi T.
        • Matsui T.
        • Tsukamoto T.
        • et al.
        TGF-beta-induced macrophage colony-stimulating factor gene expression in various mesenchymal cell lines.
        Am J Physiol. 1994; 267: C25-C31
        • Weinberg J.B.
        • Misukonis M.A.
        • Shami P.J.
        • et al.
        Human mononuclear phagocyte inducible nitric oxide synthase (iNOS)—analysis of inos mrna, inos protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages.
        Blood. 1995; 86: 1184-1195
        • Schoedon G.
        • Schneemann M.
        • Walter R.
        • et al.
        Nitric oxide and infection: another view.
        Clin Infect Dis. 1995; 21: S152-S157
        • Merryman P.F.
        • Clancy R.M.
        • He X.Y.
        • Abramson S.B.
        Modulation of human T cell responses by nitric oxide and its derivative, S-nitrosoglutathione.
        Arthritis Rheum. 1993; 36: 1414-1422
        • Hoffman R.A.
        • Langrehr J.M.
        • Simmons R.L.
        Role of nitric oxide in allograph rejection.
        in: Lancaster Jr., J. Nitric oxide, principles and actions. Academic, San Diego1996: 237-257
        • Denham S.
        • Rowland I.J.
        Inhibition of the reactive proliferation of lymphocytes by activated macrophages: the role of nitric oxide.
        Clin Exp Immunol. 1992; 87: 157-162
        • Blackburn W.D.
        Management of osteoarthritis and rheumatoid arthritis—prospects and possibilities.
        Am J Med. 1996; 100: S24-S30
        • Watkins L.R.
        • Maier S.F.
        • Goehler L.E.
        Immune activation—the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states.
        Pain. 1995; 63: 289-302
        • Sharma J.N.
        • Buchanan W.W.
        Pathogenic responses of bradykinin system in chronic inflammatory rheumatoid disease.
        Exp Tox Pathol. 1994; 46: 421-433
        • Walker K.
        • Perkins M.
        • Dray A.
        Kinins and kinin receptors in the nervous system.
        Neurochem Int. 1995; 26: 1-16
        • Ferreira S.H.
        The role of interleukins and nitric oxide in the mediation of inflammatory pain and its control by peripheral analgesics.
        Drugs. 1993; 46: 1-9
        • Bauer M.B.
        • Murphy S.
        • Gebhart G.F.
        Stimulation of cyclic GMP production via a nitrosyl factor in sensory neuronal cultures by algesic or inflammatory agents.
        J Neurochem. 1995; 65: 363-372
        • Marianipedroso S.B.
        • Bizeto L.
        • Gutunes E.
        • et al.
        Dissimilarity between prostaglandin E(1) and nitric oxide donors as potentiations of plasma exudation in the rabbit skin in vivo.
        Prostaglandins Leukot Essent Fatty Acids. 1995; 52: 399-402
        • Oyanagui Y.
        • Sato S.
        Opposite effect of superoxide dismutase, L-arginine analogues, methylene blue and desferal: suppression of histamine-induced and stimulation of serotonin-induced paw edema in mice.
        Biol Signals. 1993; 2: 37-44
        • Holzer P.
        • Jocic M.
        • Peskar B.A.
        Mediation by prostaglandins of the nitric oxide-induced neurogenic vasodilatation in rat skin.
        Br J Pharmacol. 1995; 116: 2365-2370
        • Muhl H.
        • Pfeilschifter J.
        Tetrahydrobiopterin is a limiting factor of nitric oxide generation in interleukin 1 beta-stimulated rat glomerular mesangial cells.
        Kidney Int. 1994; 46: 1302-1306
        • Vandijk A.P.M.
        • Keuskamp Z.J.
        • Wilson J.H.P.
        • Zijlstra G.J.
        Sequential release of cytokines, lipid mediators and nitric oxide in experimental colitis.
        Mediators Inflamm. 1995; 4: 186-190
        • Kolios G.
        • Brown Z.
        • Robson R.L.
        • et al.
        Inductible nitric oxide synthase activity and expression in a human colonic epithelial cell line, HT-29.
        Br J Pharmacol. 1995; 116: 2866-2872
        • Kitade H.
        • Sakitani K.
        • Inoue K.
        • et al.
        Interleukin 1-beta markedly stimulates nitric oxide formation in the abscence of other cytokines or lipopolysaccharide in primary cultured rat hepatocytes but not in Kupffer cells.
        Hepatology. 1996; 23: 797-802
        • Eberhardt W.
        • Kunz D.
        • Hummel R.
        • Pfeilschifter J.
        Molecular cloning of the rat inducible nitric oxide synthase gene promoter.
        Biochem Biophys Res Commun. 1996; 223: 752-756
        • Tetsuka T.
        • Baier L.D.
        • Morrison A.R.
        Antioxidants inhibit interleukin-1-induced cyclooxygenase and nitrix-oxide synthase expression in rat mesangial cells. Evidence for post-transcriptional regulation.
        J Biol Chem. 1996; 271: 11689-11693
        • Brunetti L.
        • Volpe A.R.
        • Ragazzoni E.
        • et al.
        Interleukin-1 beta specifically stimulates nitric oxide production in the hypothalamus.
        Life Sci. 1996; 58: PL373-PL377
        • Ikeda U.
        • Kanbe T.
        • Shimada K.
        Adrenomedullin increases inducible nitric oxide synthase in rat vascular smooth muscle cells stimulated with interleukin-1.
        Hypertension. 1996; 27: 1240-1244
        • Dinarello C.A.
        Biologic basis for interleukin-1 in disease.
        Blood. 1996; 87: 2095-2147
        • Farivar R.S.
        • Chobanian A.V.
        • Brecher P.
        Salicylate or aspirin inhibits the induction of the inducible nitric oxide synthase in rat cardiac fibroblasts.
        Circ Res. 1996; 78: 759-768
        • Sirsjo A.
        • Karlsson M.
        • Gidlof A.
        • et al.
        Increased expression of inducible nitric oxide synthase in psoriatic skin and cytokine-stimulated cultured keratinocytes.
        Br J Dermatol. 1996; 134: 643-648
        • Kalyada A.Y.
        • Savikovsky N.
        • Madias N.E.
        Transcriptional regulation of the human iNOS gene in vascular-smooth-muscle cells and macrophages: evidence for tissue specificity.
        Biochem Biophys Res Commun. 1996; 220: 600-605
        • Durante W.
        • Liao L.
        • Ifukhar I.
        • et al.
        Differential regulation of l-arginine transport and nitric oxide production by vascular smooth muscle and endothelium.
        Circ Res. 1996; 78: 1075-1082
        • Rivier C.
        Blockade of nitric oxide formation augments adrenocorticotropin released by blood-borne interleukin-1 beta: role of vasopressin, prostaglandins, and alpha l-adrenergic receptors.
        Endocrinology. 1995; 136: 3597-3603
        • Palmgren T.
        • Gronblad M.
        • Virri J.
        • et al.
        Immunohistochemical demonstration of sensory and autonomic nerve terminals in heyniated lumbar disc tissue.
        Spine. 1996; 21: 1301-1303
        • Zhang R.X.
        • Mi Z.P.
        • Qiao J.T.
        Changes of spinal substance P, calcitonin gene-related peptide, somatostatin, Met-enkephalin and neurotensin in rats in response to formalin-induced pain.
        Regul Pept. 1994; 51: 25-32
        • Duggan A.W.
        • Furmidge L.J.
        Probing the brain and spinal cord with neuropeptides in pathways related to pain and other functions.
        Front Neuroendocrinol. 1994; 15: 275-300
        • Abbadie C.
        • Brown J.L.
        • Mantyh P.W.
        • Basbaum A.I.
        Spinal cord substance P receptor immunoreactivity increases in both inflammatory and nerve injury models of persistent pain.
        Neuroscience. 1996; 70: 201-209
        • Deal C.L.
        • Schnitzer T.J.
        • Lipstein E.
        • et al.
        Treatment of arthritis with topical capsaicin: a double-blind trial.
        Clin Ther. 1991; 13: 383-395
        • Menkes C.J.
        • Renoux M.
        • Laoussadi S.
        • et al.
        Substance P levels in the synovium and synovial fluid from patients with rheumatoid-arthritis and osteoarthritis.
        J Rheumatol. 1993; 20: 714-717
        • Watkins L.R.
        • Wiertelak E.P.
        • Furness L.E.
        • Maier S.F.
        Illness-induced hyperalgesia is mediated by spinal neuropeptides and excitatory amino acids.
        Brain Res. 1994; 664: 17-24
        • Moore A.R.
        • Willoughby D.A.
        Hyaluronan as a drug delivery system for diclofenac—a hypothesis for mode of action.
        Int J Tissue React. 1995; 17: 153-156
        • Bjorkman R.
        • Hallman K.M.
        • Hedner J.
        • et al.
        Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P.
        Pain. 1994; 57: 259-264
        • Coderre T.J.
        • Yashpal K.
        Intracellular messengers contributing to persistent nociception and hyperalgesia induced by L-glutamate and substance P in the rat formalin pain model.
        Eur J Neurosci. 1994; 6: 1328-1334
        • Ralevic V.
        • Khalil Z.
        • Helme R.D.
        • Dusting G.J.
        Role of nitric oxide in the actions of substance P and other mediators of inflammation in rat skin microvasculature.
        Eur J Pharmacol. 1995; 284: 231-239
        • Radhakrishnan V.
        • Yashpal K.
        • Hui-Chan C.W.
        • Henry J.L.
        Implication of a nitric oxide synthase mechanism in the action of substanceP: L-NAME blocks thermal hyperalgesia induced by endogenous and exogenous substance P in the rat.
        Eur J Neurosci. 1995; 7: 1920-1925
        • Harris E.D.
        The rationale for combination therapy of rheumatoid arthritis based on pathophysiology.
        J Rheumatol. 1996; 23: 2-4
        • Mauel J.
        • Ransijn A.
        • Corradin S.B.
        • Buchmullerrouiller Y.
        Effect of PGE(2) and of agents that raise camp levels on macrophage activation induced by IFN-gamma and TNF-alpha.
        J Leukoc Biol. 1995; 58: 217-224
        • Whittle B.J.R.
        The modulation of IL-6 and TNF alpha release by nitric oxide following stimulation of J774 cells with LPS and IFN-gamma.
        Cytokine. 1995; 7: 408-416
        • Harbrecht B.G.
        • Mcclure E.A.
        • Simmons R.I.
        • Billiar T.R.
        Prostanoids inhibit kupffer cell nitric oxide synthesis.
        J Surg Res. 1995; 58: 625-629
        • Sautebin L.
        • Ialenti A.
        • Ianaro A.
        • Di Rosa M.
        Endogenous nitric oxide increases prostaglandin biosynthesis in carrageenin rat paw oedema.
        Eur J Pharmacol. 1995; 286: 219-222
        • Mollace V.
        • Colasanti M.
        • Rodino P.
        • et al.
        NMDA-dependent prostaglandin E(2) release by human cultured astroglial cells is driven by nitric oxide.
        Biochem Biophys Res Commun. 1995; 215: 793-799
        • Molinaholgado F.
        • Lledo A.
        • Guaza C.
        Evidence for cyclooxygenase activation by nitric oxide in astrocytes.
        Glia. 1995; 5: 167-172
        • Wilson K.T.
        • Vaandrager A.B.
        • De Vente J.
        • et al.
        Production and localization of cGMP and PGE2 in nitroprusside-stimulated rat colonic ion transport.
        Am J Physiol. 1996; 270: C832-C840
        • Dong Y.L.
        • Yallampalli C.
        Interaction between nitric oxide and prostaglandin E2 pathways in pregnant rat uteri.
        Am J Physiol. 1996; 270: E471-E476
        • Goldsmith P.C.
        • Leslie T.A.
        • Hayes N.A.
        • et al.
        Inhibitors of nitric oxide synthase in human skin.
        J Invest Dermatol. 1996; 106: 113-118
        • Yeh J.L.
        • Whitney E.G.
        • Lamb S.
        • Brophy C.M.
        Nitric oxide is an autocrine feedback inhibitor of vascular smooth muscle contraction.
        Surgery. 1996; 119: 104-109
        • Gaboury J.P.
        • Niu X.F.
        • Kubes P.
        Nitric oxide inhibits numerous features of mast cell-induced inflammation.
        Circulation. 1996; 93: 318-326
        • Oyanagui Y.
        • Sato S.
        Histamine paw edema of mice was increased and became H2-antagonist sensitive by co-injection of nitric oxide forming agents, but serotonin paw edema was decreased.
        Life Sci. 1993; 52: 159-164
        • Francischi J.N.
        • Dias M.F.
        • Rocha O.A.
        • et al.
        Pharmacological characterization of Sephadex-induced oedema in rat paws: predominant role of serotonin and platelet-activating factor.
        Int Arch Allergy Appl Immunol. 1996; 109: 398-406
        • Bruning T.A.
        • van Zwieten P.A.
        • Blauw G.J.
        • Chang P.C.
        No functional involvement of 5-hydroxytryptamine1A receptors in nitric oxide-dependent dilatation caused by serotonin in the human forearm vascular bed.
        J Cardiovasc Pharmacol. 1994; 24: 454-461
        • Stroes E.S.G.
        • Koomans H.A.
        • Debruin T.W.A.
        • Rabelink T.J.
        Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication.
        Lancet. 1995; 346: 467-471
        • Stroes E.S.
        • Joles J.A.
        • Chang P.C.
        • et al.
        Impaired endothelial function in patients with nephrotic range proteinuria.
        Kidney Int. 1995; 48: 544-550
        • Ramadan N.M.
        • Gilkey S.J.
        • Mitchell M.
        • et al.
        Post-angiography headache.
        Headache. 1995; 35: 21-24
        • Briejer M.R.
        • Akkermans L.M.
        • Schuurkes J.A.
        Interactions of serotonin with multiple receptors and neurotransmitters in the guinea-pig isolated colon.
        Arch Int Pharmacodyn Ther. 1995; 329: 121-133
        • Kuhn D.M.
        • Arthur Jr., R.E.
        Inactivation of brain tryptophan hydroxylase by nitric oxide.
        J Neurochem. 1996; 67: 1072-1077
        • Winther K.
        • Oxholm P.
        • Sengelov H.
        Effect of auronofin on human platelet aggregation, release of serotonin, and cyclic-AMP formation.
        Inflammation. 1988; 12: 107-112
        • Endresen G.K.
        Evidence for activation of platelets in the synuvial fluid from patients with rheumatoid arthritis.
        Rheumatol Int. 1989; 9: 19-24
        • Iversen H.K.
        Experimental headache in humans.
        Cephalalgia. 1995; 15: 281-287
        • Lassen L.H.
        • Thomsen L.L.
        • Olesen J.
        Histamine induces migraine via the H-1-receptorsupport for the NO hypothesis of migraine.
        Neuroreport. 1995; 6: 1475-1479
        • Dear J.W.
        • Scadding G.K.
        • Foreman J.C.
        Reduction by N-G-nitro-l-arginine methyl ester (l-NAME) of antigen-induced nasal airway plasma extravasation in human subjects in vivo.
        Br J Pharmacol. 1995; 116: 1720-1722
        • Meijer F.
        • Ruitjer J.M.
        • Vandelft J.L.
        • Vanhaerngen N.J.
        Nitric oxide induces vascylar permeability changes in the guinea pig conjunctiva.
        Eur J Pharmacol. 1995; 284: 61-67
        • Feldman M.J.
        • Morris G.P.
        • Dinda P.K.
        • Paterson W.G.
        Mast cells mediate acid-induced augmentation of opossum esophageal blood flow via histamine and nitric oxide.
        Gastroenterology. 1996; 110: 121-128
        • Izumi H.
        • Makino Y.
        • Shirakawa K.
        • Garfield R.E.
        Role of nitric oxide on vasorelaxation in human umbilical artery.
        Am J Obstet Gynecol. 1995; 172: 1477-1484
        • Kawai Y.
        • Ohhashi T.
        Histamine H-2 receptor-mediated endothelium-dependent relaxation in canine spinal artery.
        Jpn J Physiol. 1995; 45: 607-618
        • Nakahara T.
        • Ishii K.
        • Iwamoto K.I.
        • Nakayama K.
        Differential significance of nitric oxide in hypotensive mechanisms of acetylcholine and histamine in dogs.
        Res Commun Mol Pathol Pharmacol. 1995; 89: 77-84
        • Laight D.W.
        • Woodward B.
        • Waterfall J.F.
        Renal vasodilation to histamine in vitro: roles of nitric oxide, cyclo-oxygenase products and H2 receptors.
        Inflam Res. 1995; 44: 116-120
        • Zygmunt P.M.
        • Ryman T.
        • Hogestatt E.D.
        Regional differences in endothelium-dependent relaxation in the rat: contribution of nitric oxide and nitric oxide-dependent mechanisms.
        Acta Physiol Scand. 1995; 155: 257-266
        • Beyak M.
        • Vanner S.
        Histamine H1 and H3 vasodilator mechanisms in the guinea pig ileum.
        Gastroenterology. 1995; 108: 712-718
        • Oyanagui Y.
        • Sato S.
        Histamine paw edema of mice was increased and became H2-antagonist sensitive by co-injection of nitric oxide forming agents, but serotonin paw edema was decreased.
        Life Sci. 1993; 52: PL159-PL164
        • Noel A.A.
        • Fallek S.R.
        • Hobson R.W.
        • Duran W.N.
        Inhibition of nitric oxide synthase attenuates primed microvascular permeability in the in vivo microcirculation.
        J Vasc Surg. 1995; 22: 661-670
        • Ziganshina L.E.
        • Ziganshin A.U.
        • Hoyle C.H.V.
        • Burnstock G.
        Acute paw oedema formation induced by ATP—re-evaluation of the mechanisms involved.
        Inflam Res. 1996; 45: 96-102
        • Manfredi A.A.
        • Rovere P.
        • Ferrarini M.
        • et al.
        Tuberculosis, sarcoidosis and Hodgkins disease—theme with variations.
        Fund Clin Immunol. 1995; 3: 147-152
        • Preiser J.C.
        • Reper P.
        • Vlasselaer K.
        • et al.
        Nitric oxide production is increased in patients after burn injury.
        J Trauma Inj Infect Crit Care. 1996; 40: 368-371
        • Benvenuti C.
        • Bories P.N.
        • Loisance D.
        Increased serum nitrate concentration in cardiac transplant patients—a marker for acute allograft cellular rejection.
        Transplantation. 1996; 61: 745-749
        • Eisenstein T.K.
        • Huang D.
        • Meissler Jr., J.J.
        • al-Ramadi B.
        Macrophage nitric oxide mediates immunosuppression in infectious inflammation.
        Immunobiol. 1994; 191: 493-502
        • Green S.J.
        • Scheller L.F.
        • Marletta M.A.
        • et al.
        Nitric oxide: cytokine-regulation of nitric oxide in host resistance to intracellular pathogens.
        Immunol Lett. 1994; 43: 87-94
        • Nicholson S.
        • Bonecinialmeida M.D.G.
        • Silva J.R.L.
        • et al.
        Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis.
        J Exp Med. 1996; 183: 2293-2302
        • Tomioka H.
        • Sato K.
        • Maw W.W.
        • Saito H.
        The role of tumor necrosis factor, interferon-gamma, transforming growth factor-beta, and nitric oxide in the expression of immunosuppressive functions of splenic macrophages induced by mycobacterium avium complex infection.
        J Leukoc Biol. 1995; 58: 704-712
        • Shapiro K.B.
        • Hotchkiss J.H.
        Induction of nitric oxide synthesis in murine macrophages by helicobacter pylori.
        Cancer Lett. 1996; 102: 49-56
        • Sirsjo A.
        • Karlsson M.
        • Gidlof A.
        • et al.
        Increased expression of inducible nitric oxide synthase in psoriatic skin and cytoiine-stimulated cultured keratinocytes.
        Br J Dermatol. 1996; 134: 643-648
        • Ippolito F.
        • Di Carlo A.
        • Carducci M.
        • et al.
        Cyclosporin A and psoriasis: a thermographic study.
        Acta Derm Venereol Suppl (Stockh). 1989; 146: 155-158
        • Goldman D.
        • Cho Y.
        • Zhao M.L.
        • et al.
        Expression of inducible nitric oxide synthase in rat pulmonary cryptococcus neoformans granulomas.
        Am J Pathol. 1996; 148: 1275-1282
        • Kaplan S.S.
        • Lancaster J.R.
        • Basford R.E.
        • Simmons R.L.
        Effect of nitric oxide on staphylococcal killing and interactive effect with superoxide.
        Infect Immun. 1996; 64: 69-76
        • James S.L.
        Role of nitric oxide in parasitic infections.
        Microbiol Rev. 1995; 59: 533-581
        • Stenger S.
        • Donhauser N.
        • Thuring H.
        • et al.
        Reactivation of latent leishmaniasis by inhibition of inducible nitric oxide synthase.
        J Exp Med. 1996; 183: 1501-1514
        • Silva J.S.
        • Vespa G.N.R.
        • Cardoso M.A.G.
        • et al.
        Tumor necrosis factor alpha mediates resistance to typanosoma cruzi infection in mice by inducing nitric oxide production in infected gamma interferon-activated macrophages.
        Infect Immun. 1995; 63: 4862-4867
        • Jacobs P.
        • Radzioch D.
        • Stevenson M.M.
        In vivo regulation of nitric oxide production by tumor necrosis factor alpha and gamma interferon, but not by interleukin-4, during blood stage malaria in mice.
        Infect Immun. 1996; 64: 44-49
        • Igietseme J.U.
        The molecular mechanism of T-cell control of chlamydia in mice—role of nitric oxide.
        Immunology. 1996; 87: 1-8
        • Igietseme J.U.
        Molecular mechanism of T-cell control of chlamydia in mice—role of nitric oxide in vivo.
        Immunology. 1996; 88: 1-5
        • Degroote M.A.
        • Testerman T.
        • Xu Y.S.
        • et al.
        Homocysteine antagonism of nitric oxide-related cytostasis in salmonella typhimurium.
        Science. 1996; 272: 414-417
        • Shellito J.E.
        • Kolls J.K.
        • Olariu R.
        • Beck J.M.
        Nitric oxide and host defense against pneumocystis carinii infection in a mouse model.
        J Infect Dis. 1996; 173: 432-439
        • Bevan J.A.
        Flow regulation of vascular tone. Its sensitivity to changes in sodium and calcium.
        Hypertension. 1993; 22: 273-281
        • Korenaga R.
        • Ando J.
        • Tsuboi H.
        • et al.
        Laminar flow stimulates ATP- and shear stress-dependent nitric oxide production in cultured bovine endothelial cells.
        Biochem Biophys Res Commun. 1994; 198: 213-219
        • Awolesi M.A.
        • Widmann M.D.
        • Sessa W.C.
        • Sumpio B.E.
        Cyclic strain increases endothelilal nitric oxide synthase activity.
        Surgery. 1994; 116: 439-444
        • Noris M.
        • Morigi M.
        • Donadelli R.
        • et al.
        Nitric oxide synthesis by cultured endothelial cells is modulated by flow conditions.
        Circ Res. 1995; 76: 536-543
        • Hishikawa K.
        • Nakaki T.
        • Marumo T.
        • et al.
        Pressure enhances endothelin-1 release from cultured human endothelial cells.
        Hypertension. 1995; 25: 449-452
        • Rubin C.T.
        • Donahue H.J.
        • Rubin J.E.
        • McLeod K.J.
        Optimization of electric field parameters for the control of bone remodling: exploitation of an indigenous mechanism for the prevention of osteopenia.
        J Bone Miner Res. 1993; 8: S573-S581
        • Fleming I.
        • Busse R.
        Control and consequences of endothelial nitric oxide formation.
        Adv Pharmacol. 1995; 34: 187-207
        • Abu-Soud H.M.
        • Feldman P.I.
        • Clark P.
        • Stuehr D.J.
        Electron: transfer in the nitric-oxide synthases. Characterization of L-arginine analogs that block heme iron reduction.
        J Biol Chem. 1994; 269: 32318-32326
        • Campos K.L.
        • Giovanelli J.
        • Kaufman S.
        Characteristics of the nitric oxide synthase-catalyzed conversion of arginine to N-hydroxyarginine, the first oxygenation step in the enzymic synthesis of nitric oxide.
        J Biol Chem. 1995; 270: 1721-1728
        • Hernandez M.
        • Prieto D.
        • Orensanz L.M.
        • et al.
        Nitric oxide is involved in the non-adrenergic, non-cholinergic inhibitory neurotransmission of the pig intravesical ureter.
        Neurosci Lett. 1993; 186: 33-36
        • Jing L.
        • Inoue R.
        • Tashiro K.
        • et al.
        Role of nitric oxide in non-adrenergic, non-cholinergic relaxation and modulation of excitatory neuroeffector transmission in the cat airway.
        J Physiol. 1995; 483: 225-237
        • Lippe I.T.
        • Stabentheiner A.
        • Holzer P.
        Participation of nitric oxide in the mustard oil-induced neurogenic inflammation of the rat paw skin.
        Eur J Pharmacol. 1993; 232: 113-120
        • Mathison R.
        • Davison J.S.
        Regulation of jejunal arterioles by capsicin-sensitive nerves in Nippostrongylus brasiliensis-sensitized rats.
        J Pharmacol Exp Ther. 1995; 273: 337-343
        • Amin A.R.
        • DiCesare P.E.
        • Vyas P.
        • et al.
        The expression and regulation of nitric oxide synthase in human osteoarthtitus-affected chondrocytes: evidence for up-regulated neuronal nitric oxide synthase.
        J Exp Med. 1995; 182: 2097-2102
        • Saumet J.L.
        • Degoute C.S.
        • Saumet M.
        • Abraham P.
        The effect of nerve blockade on forearm and finger skin blood flow during body heating and cooling.
        Int J Microcirc Clin Exp. 1992; 11: 231-240
        • Varner P.D.
        • Beckman J.S.
        Nitric oxide toxicity in neuronal injury and degradation.
        in: Vincent S. Nitric oxide in the nervous system. San Diego Academic, 1995: 191-206
        • Oyanagui Y.
        Immunosuppressants and TGF-beta 1 accelerated and prolonged the nitric oxide/oxyradicals-dependent suppression by dexamethasone in paw edema of mice.
        Life Sci. 1996; 58: PL287-PL294
        • Moilanen E.
        • Vapaatalo H.
        Nitric oxide in inflammation and immune response.
        Ann Med. 1995; 27: 359-367
        • Liew F.Y.
        Nitric oxide in infections and autoimmune diseases.
        in: Ciba Found Symp. 495. 1995: 234-244
        • Lyons C.R.
        The role of nitric oxide in inflammation.
        Adv Immunol. 1995; 60: 323-371
        • Clancy R.M.
        • Abramson S.B.
        Nitric oxide: a novel mediator of inflammation.
        in: Proc Soc Exp Biol Med. 210. 1995: 93-101
        • Cattell V.
        • Jansen A.
        Inducible nitric oxide synthase in inflammation.
        Histochem J. 1995; 27: 777-784
        • Michaelis M.
        • Habler H.J.
        • Janig W.
        Silent afferents—a separate class of primary afferents.
        Clin Exp Pharmacol Physiol. 1996; 23: 99-105
        • Qian Y.
        • Chao D.S.
        • Santillano D.R.
        • et al.
        cGMP-dependent protein kinase in dorsal root ganglion: relationship with nitric oxide synthase and nociceptive neurons.
        J Neurosci. 1996; 16: 3130-3138
        • Onaka M.
        • Minami T.
        • Nishihara I.
        • Ito S.
        Involvement of glutamate receptors in strychniae- and bicuculline-induced allodynia in conscious mice.
        Anesthesiology. 1996; 84: 1215-1222
        • Kakizaki H.
        • de Groat W.C.
        Role of spinal nitric oxide in the facilitation of the micturition reflex by bladder irritation.
        J Urol. 1996; 155: 355-360
        • Neugebauer V.
        • Rumenapp P.
        • Schaible H.G.
        The role of spinal neurokinin-2 receptors in the processing of nociceptive information from the joint and in the generation and maintenance of inflammation-evoked hyperexcitability of dorsal horn neurons in the rat.
        Eur J Neurosci. 1996; 8: 249-260
        • Sakurada T.
        • Sugiyama A.
        • Sakurada C.
        • et al.
        Effect of spinal nitric oxide inhibition on capsaicin-induced nociceptive response.
        Life Sci. 1996; 59: 921-930
        • Cuevas P.
        • Prieto R.
        • Detejada I.S.
        • Gimenezgallego G.
        Analgesic effects of fibroblast growth factor in the rat.
        Neurosci Lett. 1996; 207: 175-178
        • Karatinos J.
        • Rosse R.B.
        • Deutsch S.I.
        The nitric oxide pathway—potential implications for treatment of neuropsychiatric disorders.
        Clin Neuropharmacol. 1995; 18: 482-499
        • Dickenson A.H.
        Central acute pain mechanisms.
        Ann Med. 1995; 27: 223-227
        • Shibura S.
        • Mashimoto T.
        • Ohara A.
        • et al.
        Intracerebroventricular administration of a nitric oxide-releasing compound, NOC-18, produces thermal hyperalgesia in rats.
        Neurosci Lett. 1995; 187: 103-106
        • Gordh T.
        • Karlsten R.
        • Kristensen J.
        Intervention with spinal NMDA, adenosine, and NO systems for pain modulation.
        Ann Med. 1995; 27: 229-234
        • Ren K.
        • Ruda M.A.
        Nitric oxide synthase-containing neurons in sensory ganglia of the rat are susceptible to capsaicin-induced cytotoxicity.
        Neuroscience. 1995; 65: 505-511
        • Rice A.S.
        Topical spinal administration of a nitric oxide synthase inhibitor prevents the hypereflexia associated with a rat model of persistent visceral pain.
        Neurosci Lett. 1995; 187: 111-114
        • Niedbala I.
        • Sanchez A.
        • Feria M.
        Nitric oxide mediates neuropathic pain behavior in peripherally denervated rats.
        Neurosci Lett. 1995; 188: 57-60
        • Morris R.
        • Southam E.
        • Gittins S.R.
        • et al.
        The NO-cGMP pathway in neonatal rat dorsal horn.
        Eur J Neurosci. 1994; 6: 876-879
        • Kumar A.
        • Raghubir R.
        • Dhawan B.N.
        Possible involvement of nitric oxide in red nucleus stimulation-induced analgesia in the rat.
        Eur J Pharmacol. 1995; 279: 1-5
        • Xu J.Y.
        • Tseng L.F.
        Nitric oxide/cyclic guanosine monophosphate system in the spinal cord differentially modulates intracerebroventricularly administered morphine- and beta-endorphin-induced antinociception in the mouse.
        J Pharmacol Exp Ther. 1995; 274: 8-16
        • Rawal N.
        Spinal antinociception: clinical aspects.
        Ann Med. 1995; 27: 263-268
        • Wiertelak E.P.
        • Furness L.E.
        • Horan R.
        • et al.
        Subcutaneous formalin produces centrifugal hyperalgesia at a non-injected site via the NMDA-nitric oxide cascade.
        Brain Res. 1994; 649: 19-26
        • Steel J.H.
        • Terenghi G.
        • Chung J.M.
        • et al.
        Increased nitric oxide synthase immunoreactivity in rat dorsal root ganglia in a neuropathic pain model.
        Neurosci Lett. 1994; 169: 81-84
        • Dray A.
        Inflammatory mediators of pain.
        Br J Anaesth. 1995; 75: 125-131
        • Palmgren T.
        • Gronblad M.
        • Virri J.
        • et al.
        Immunohistochemical demonstration of sensory and autonomic nerve terminals in herniated lumbar disc tissue.
        Spine. 1996; 21: 1301-1306
        • Oddis C.V.
        New perspectives on osteoarthritis.
        Am J Med. 1996; 100: 10S-15S
        • Carotti M.
        • Salaffi F.
        • Ferraccioli G.F.
        • et al.
        Soluble interleukin-2 receptor in sera and synovial fluids of rheumatoid patients: correlations with disease activity.
        Rheumatol Int. 1994; 14: 47-52
        • Bull H.A.
        • Hothersall J.
        • Chowdhury N.
        • et al.
        Neuropeptides induce release of nitric oxide from human dermal microvascular endothelial cells.
        J Invest Dermatol. 1996; 106: 655-660
        • Kilbourn R.G.
        • Fonseca G.A.
        • Grifith G.W.
        • et al.
        NG-methyl-L-arginine: an inhibitor of nitric oxide synthase, reverses interleukin-2-induced hypotension.
        Crit Care Med. 1995; 23: 1018-1024
        • Orucevic A.
        • Lala P.K.
        NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis ameliorates interleukin-2-induced capillary syndrome in healthy mice.
        J Immunother Tumor Immunol. 1995; 18: 210-220
        • Crucevic A.
        • Lala P.K.
        Effects of N(g)-methyl-L-arginine, an inhibitor of nitric oxide synthesis, on interleukin-2-induced capillary leakage and antitumor responses in healthy and tumor-bearing mice.
        Cancer Immunol Immunother. 1996; 42: 38-46
        • Orucevic A.
        • Lala P.K.
        NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin-2-induced capillary leakage and reduces tumour growth in adenocarcinoma-bearing mice.
        Br J Cancer. 1996; 73: 189-196
        • Cifone M.G.
        • Festuccia C.
        • Cironi L.
        • et al.
        Induction of the nitric oxide-synthesizing pathway in fresh and interleukin 2-cultured rat natural killer cells.
        Cell Immunol. 1994; 157: 181-194
        • Juretic A.
        • Spagnoli G.C.
        • Horig H.
        • et al.
        Tyrosine kinase-dependent and -independent events induced by interleukin-2 stimulation: interleukin-2-mediated NO production required for the induction of lymphokine-activated killer cell activity in rat splenocytes is tyrosine kinase independent.
        Immunology. 1995; 85: 325-330
        • Meller S.T.
        • Cummings C.P.
        • Traub R.J.
        • Gebhart G.F.
        The role of nitric oxide in the development and maintenance of the hyperalgesia produced by intraplantar injection of carrageenan in the rat.
        Neuroscience. 1994; 60: 367-374
        • Babbedge R.C.
        • Wallace P.
        • Gaffen Z.A.
        • et al.
        L-NG-nitro arginine p-nitroanilide (L-NAPNA) is anti-nociceptive in the mouse.
        Neuroreport. 1993; 4: 307-310
        • Moore P.K.
        • Babbedge R.C.
        • Wallace P.
        • et al.
        7-Nitro indazole, an inhibitor of nitric oxide synthase, exhibits anti-nociceptive activity in the mouse without increasing blood pressure.
        Br J Pharmacol. 1993; 108: 296-297
        • Babbedge R.C.
        • Bland-Ward P.A.
        • Hart S.L.
        • Moore P.K.
        Inhibition of rat cerebellar nitric oxide synthase by 7-nitro indazole and related substituted indazole.
        Br J Pharmacol. 1993; 110: 225-228
        • Semba J.
        • Sakai M.
        • Miyoshi R.
        • Kito S.
        NG-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, increases extracellular GABA in the striatum of the freely moving rat.
        Neuroreport. 1995; 6: 1426-1428
        • Kamisaki Y.
        • Wada K.
        • Nakamoto K.
        • Itoh T.
        Nitric oxide inhibition of the depolarization-evoked glutamate release from synaptosomes of rat cerebellum.
        Neurosci Lett. 1995; 194: 5-8
        • Meller S.T.
        • Dykstra C.
        • Grzybycki D.
        • et al.
        The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat.
        Neuropharmacology. 1994; 33: 1471-1478
        • Iwamoto E.T.
        • Marion L.
        Pharmacological evidence that nitric oxide mediates the antinociception produced by muscarinic agonists in the rostral ventral medulla of rats.
        J Pharmacol Exp Ther. 1994; 269: 699-708
        • Iwamoto E.T.
        • Marion L.
        Pharmacologic evidence that spinal muscarinic analgesia is mediated by an L-arginine/nitric oxide/cyclic GMP cascade in rats.
        J Pharmacol Exp Ther. 1994; 271: 601-608
        • Malmberg A.B.
        • Yaksh T.L.
        Spinal nitric oxide synthesis inhibition blocks NMDA-induced thermal hyperalgesia and produces antinociception in the formalin tests in rats.
        Pain. 1993; 54: 291-300
        • Bjorkman R.
        Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paraceta-mol—experimental studies in the rat.
        Acta Anaesthesiol Scand. 1995; 39: 3-44
        • Henderson S.A.
        • Lee P.H.
        • Aeberhard F.E.
        • et al.
        Nitrix oxide reduces early growth response-1 gene expression in rat lung macrophages treated with interferon-gamma and lipopolysaccharide.
        J Biol Chem. 1994; 269: 25239-25242
        • Ignarro L.J.
        • Aeberhard E.E.
        • Henderson S.A.
        Nonsteroidal anti-inflammatory drugs (NSAIDs) prevent transcriptional expression of the inducible NO synthase gene in macrophages by interference with NF-kB activation.
        in: Moncada S. Stamler J. Gross S. Higgs E.A. The biology of nitric oxide. Portland, London1996: 5 (part 5)
        • Aeberhard E.E.
        • Henderson S.A.
        • Arabolos N.S.
        • et al.
        Nonsteroidal anti-inflammatory drugs inhibit expression of the inducible nitric oxide synthase gene.
        Biochem Biophys Res Commun. 1995; 208: 1053-1059
        • Amin A.R.
        • Vyas P.
        • Attur M.
        • et al.
        The mode of action of aspirin-like drugs: effect on inducible nitric oxide synthase.
        in: Proc Nat Acad Sci USA. 92. 1995: 7926-7930
        • Xu J.Y.
        • Tseng L.F.
        Nitric oxide/cyclic guanosine monophosphate system in the spinal cord differentially modulates intracerebroventricularly administered morphine- and beta-endorphin-induced antinociception in the mouse.
        J Pharmacol Exp Ther. 1995; 274: 8-16
        • Mao J.R.
        • Price D.D.
        • Mayer D.J.
        Experimental mononeuropathy reduces the antinociceptive effects of morphine—implications for common intracellular mechanisms involved in morphine tolerance and neuropathic pain.
        Pain. 1995; 61: 353-364
        • Mao J.R.
        • Price D.D.
        • Mayer D.J.
        Mechanisms of hyperalgesia and morphine tolerance—a current view of their possible interactions.
        Pain. 1995; 62: 259-274
        • Granadossoto V.
        • Floresmurrieta F.J.
        • Castaneda-Hernandez G.
        • Lopezmunoz F.J.
        Evidence for the involvement of nitric oxide in the antinociceptive effect of ketorolac.
        Eur J Pharmacol. 1995; 277: 281-284
        • Minami T.
        • Onaka M.
        • Okudaashitaka E.
        • et al.
        L-name, an inhibitor of nitric oxide synthase, blocks the established allodynia induced by intrathecal administration of prostaglandin E(2).
        Neurosci Lett. 1995; 201: 239-242
        • Semos M.L.
        • Headley P.M.
        The role of nitric oxide in spinal nociceptive reflexes in rats with neurogenic and non-neurogenic peripheral inflammation.
        Neuropharmacol. 1994; 33: 1487-1497
        • Holthusen H.
        • Arndt J.O.
        Nitric oxide evokes pain at nociceptors of the paravascular tissue and veins in humans.
        J Physiol. 1995; 487: 253-258
        • Kindgenmilles D.
        • Arndt J.O.
        Nitric oxide as a chemical link in the generation of pain from veins in humans.
        Pain. 1996; 64: 139-142
        • Kawabata A.
        • Manabe S.
        • Manabe Y.
        • Takagi H.
        Effect of topical administration of L-arginine on formalin-induced nociception in the mouse: a dual role of peripherally formed NO in pain modulation.
        Br J Pharmacol. 1994; 112: 547-550
        • Meyer P.
        • Flammer J.
        • Luscher T.F.
        Local anesthetic drugs reduce endothelium-dependent relaxations of porcine ciliary arteries.
        Invest Ophthalmol Vis Sci. 1993; 34: 2730-2736
        • Koltzenburg M.
        • Handwerker H.O.
        Differential ability of human cutaneous nociceptors to signal mechanical pain and to produce vasodilatation.
        J Neurosci. 1994; 14 (3 Pt 2): 1756-1765
        • Lang E.
        • Claus D.
        • Neundorfer B.
        • Handwerker H.O.
        Parameters of thick and thin nerve-fiber functions as predictors of pain in carpal tunnel syndrome.
        Pain. 1995; 60: 295-302
        • Hersch E.V.
        • Pertes R.A.
        • Ochs H.A.
        Topical capsaicin-pharmacology and potential role in the treatment of temporomandibular pain.
        J Clin Dent. 1994; 5: 54-59
        • Handwerker H.O.
        Assessment of the effect of ibuprofen and other non-steroidal anti-rheumatic drugs in experimental algesimetry.
        Z Rheumatol. 1991; 50: 15-18
        • Tosussi C.R.
        • Ferreira S.H.
        Mechanism of diclofenac analgesia: direct blockade of inflammatory sensitization.
        Eur J Pharmacol. 1994; 251: 173-179
        • Aeberhard E.E.
        • Henderson S.A.
        • Arabolos N.S.
        • et al.
        Nonsteroidal anti-inflammatory drugs inhibit expression of the inducible nitric oxide synthase gene.
        Biochem Biophys Res Commun. 1995; 208: 1053-1059
        • Olesen J.
        • Thomsen L.L.
        • Lassen L.H.
        • Olesen I.J.
        The nitric oxide hypothesis of migraine and other vascular headaches.
        Cephalalgia. 1995; 15: 94-100
        • Thomsen L.I.
        • Olesen J.
        The autonomic nervous system and the regulation of arterial tone in migraine.
        Clin Autonom Res. 1995; 5: 243-250
        • Iversen H.K.
        • Olesen J.
        Nitroglycerin-induced headache is not dependent on histamine release: support for a direct nociceptive action of nitric oxide.
        Cephalalgia. 1994; 14: 437-442
        • Berrazueta J.R.
        • Fleitas M.
        • Salas E.
        • et al.
        Local transdermal glyceryl trinitrate has an antiinflammatory action on thrombophlebitis induced by sclerosis of leg varicose veins.
        Angiology. 1994; 45: 347-351
        • Gorfine S.R.
        Treatment of benign anal disease with topical nitroglycerin.
        Dis Colon Rectum. 1995; 38: 453-456
        • Imamura M.
        • Poli F.
        • Omoniyi A.T.
        • Levi R.
        Unmasking of histamine H3 receptorsin myocardia ischemia: their role as regulators of exocytotic norepinephrine release.
        J Pharmacol Exp Ther. 1994; 271: 1259-1266
        • Levi R.
        • Park K.H.
        • Imamura M.
        • et al.
        Nitric oxide and peripheral adrenergic neuromodulation.
        Adv Pharmacol. 1995; 34: 399-413
        • de Silva M.
        • Kyle V.
        • Hazleman B.
        • et al.
        Assessment of inflammation in the rheumatoid knee joint: correlation between clinical, radioisotopic, and thermographic methods.
        Ann Rheum Dis. 1986; 45: 277-280
        • Fraser S.
        • Land D.
        • Sturrock R.D.
        Microwave thermography—an index of inflammatory joint disease.
        Br J Rheumatol. 1987; 26: 37-39
        • Inoue K.
        • Nishioka J.
        • Kohori T.
        • et al.
        The use of thermography in the assessment of the rheumatoid knee—the thermographic index and the heat distribution index.
        Ryumachi. 1990; 30: 356-361
        • MacDonald A.G.
        • Land D.V.
        • Sturrock R.D.
        Microwave thermography as a noninvasive assessment of disease activity in inflammatory arthritis.
        Clin Rheumatol. 1994; 13: 589-592
        • Ilowite N.T.
        • Walco G.A.
        • Pochaczevsky R.
        Assessment of pain in patients with juvenile rheumatoid arthritis: relation between pain intensity and degree of joint inflammation.
        Ann Rheum Dis. 1992; 51: 343-346
        • Jolliffe V.A.
        • Anand P.
        • Kidd B.L.
        Assessment of cutaneous sensory and autonomic axon reflexes in rheumatoid arthritis.
        Ann Rheum Dis. 1995; 54: 251-255
        • Bani D.
        • Masini E.
        • Bello M.G.
        • et al.
        Relaxin activates the L-arginine-nitric oxide pathway in human breast cancer cells.
        Cancer Res. 1995; 55: 5272-5275
        • Thomsen L.L.
        • Miles D.W.
        • Happerfield L.
        • et al.
        Nitric oxide synthase activity in human breast cancer.
        Br J Cancer. 1995; 72: 41-44
        • Spinella M.
        • Bodnar R.J.
        Nitric oxide synthase inhibition selectively potentiates swim stress anti-niciception in rats.
        Pharmacol Biochem Behav. 1994; 47: 727-733
        • Gold M.S.
        • Reichling D.B.
        • Shuster M.J.
        • Levine J.D.
        Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors.
        in: Proc Nat Acad Sci USA. 93. 1996: 1108-1112
        • Minami T.
        • Nishihara I.
        • Ito S.
        • et al.
        Nitric oxide mediates allodynia induced by intrathecal administration of prostaglandin E2 or prostaglandin F2 alpha in conscious mice.
        Pain. 1995; 61: 285-290
        • McMahon S.B.
        NGF as a mediator of inflammatory pain.
        Phil Trans R Soc Lind (Biol). 1996; 351: 431-440
        • Pennova N.
        • Enikolopov G.
        Nitric oxide triggers a switch to growth arrest during differentiation of neuronal cells.
        Nature. 1995; 375: 68-73
        • Pieretti S.
        • Di Giannuario A.
        • Capasso A.
        • et al.
        Effects induced by cysteamine on chemically-induced nociception in mice.
        Life Sci. 1994; 54: 1091-1099
        • Silveri F.
        • Morosini P.
        • Brecciaroli D.
        • Cervini C.
        Intra-articular injection of somatostatin in knee osteoarthritis: clinical results and IGF-1 serum levels.
        Int J Clin Pharmacol Res. 1994; 14: 79-85
        • Taddese A.
        • Nah S.Y.
        • McCleskey E.W.
        Selective opioid inhibition of small nociceptive neurons.
        Science. 1995; 270: 1366-1369
        • Vanhagen P.M.
        • Markusse H.M.
        • Lamberts S.W.
        • et al.
        Somatostatin receptor imaging. The presence of somatostatin receptors in rheumatoid arthritis.
        Arthritis Rheum. 1994; 37: 1521-1527
        • Yin K.J.
        Distribution of somatostatin mRNA containing neurons in the primary pain relaying nuclei of the rat.
        Anat Rec. 1995; 241: 579-584
        • Mirza U.A.
        • Chait B.T.
        • Lander H.M.
        Monitoring reactions of nitric oxide with peptides and proteins by electrospray ionization-mass spectrometry.
        J Biol Chem. 1995; 270: 17185-17188
        • Bscheidl C.
        • Hanesch U.
        • Heppelmann B.
        NADPH-diaphorase reactivity in articular afferents of a normal and inflammed knee joint in the cat.
        Brain Res. 1994; 668: 266-270
        • Cramer K.S.
        • Sur M.
        Activity-dependent remodeling of connections in the mammalian visual system.
        Curr Opin Neurobiol. 1995; 5: 106-111
        • Doyle C.
        • Holscher C.
        • Rowan M.J.
        • Anwyl R.
        The selective neuronal NO synthase inhibitor 7-nitroindazole blocks both long term potentiation and depotentiation of field EPSPs in rat hippocampal CA1 in vivo.
        J Neurosci. 1996; 16: 418-424
        • Gapta S.
        • Moreland R.B.
        • Manarriz R.
        • et al.
        Possible role of Na+-K+-ATPase in the regulation of human corpus cavernosum smooth muscle contractility by nitric oxide.
        Br J Pharmacol. 1995; 116: 2201-2206
        • Kurenny D.E.
        • Moroz L.L.
        • Turner R.W.
        • et al.
        Modulation of ion channels in rod photoreceptors by nitric oxide.
        Neuron. 1994; 13: 315-324
        • Ahmad I.
        • Leinders-Zufall T.
        • Kocsis J.D.
        • et al.
        Retinal ganglion cells express a cGMP-gated cation-conductance activatable by nitric oxide donors.
        Neuron. 1994; 12: 155-165
        • Akira T.
        • Henry D.
        • Baldwin R.A.
        • Wasterlain C.G.
        Nitric oxide participates in excitotoxic mechanisms induced by chemical hypoxia.
        Brain Res. 1994; 645: 285-290
        • Kolhekar R.
        • Meller S.T.
        • Gebhart G.F.
        N-methyl-D-aspartate receptor-mediated changes in thermal nociception—allosteric modulation at glycine and polyamine recognition sites.
        Neuroscience. 1994; 63: 925-936
        • Ding J.M.
        • Chen D.
        • Weber E.T.
        • et al.
        Resetting the biological clock: mediation of nocturnal circadian shifts by glutamate and NO.
        Science. 1994; 266: 1713-1717
        • Nasutani H.
        • Nagai K.
        • Nakagawa H.
        Possible involvement of nitric oxide in generation of circadian rhythm.
        Biol Rhythm Res. 1994; 25: 433-441
        • Watanabe A.
        • Hamada T.
        • Shibata S.
        • Watanabe S.
        Effects of nitric oxide synthase inhibitors on N-methyl-D-aspartate-induced phase delay of circadian rhythm of neuronal activity in the rat suprachiasmatic nucleus in vitro.
        Brain Res. 1994; 646: 161-164
        • Linderoth B.
        • Fedorcsak I.
        • Meyerson B.A.
        Peripheral vasodilatation after spinal cord stimulation: animal studies of putative effector mechanisms.
        Neurosurgery. 1991; 28: 187-195
        • Olgart L.
        • Kerezoudis N.P.
        Nerve-pulp interactions.
        Arch Oral Biol. 1994; 39 (suppl): 47S-54S
        • Linderoth B.
        • Herregodts P.
        • Meyerson B.A.
        Sympathetic mediation of peripheral vasodilation induced by spinal cord stimulation: animal studies of the role of cholinergic and adrenergic receptor subtypes.
        Neurosurgery. 1994; 35: 711-719
        • Wiertelak E.P.
        • Furness L.E.
        • Watkins L.R.
        • Maier S.F.
        Illness-induced hyperalgesia is mediated by a spinal NMDA-nitric oxide cascade.
        Brain Res. 1994; 664: 9-16
        • Dickenson A.H.
        Central acute pain mechanisms.
        Ann Med. 1995; 27: 223-227
        • Meller S.T.
        • Gebhart G.F.
        The role of nitric oxide in spinal nociceptive processing.
        in: Takagi H. Toda N. Hawkins R.D. Nitric oxide: role in neuronal communication and neurotoxicity. Japan Scientific Societies Press and CRC Press, Tokyo1994: 103-114
        • Kawabata A.
        • Takagi H.
        The dual role of L-arginine in nociceptive processing in the brain: Involvement of nitric oxide and kyotorphin.
        in: Takagi H. Toda N. Hawkins R.D. Nitric oxide: role in neuronal communication and neurotoxicity. Japan Scientific Societies Press and CRC Press, Tokyo1994: 115-128
        • Jones A.K.
        • Cunningham V.J.
        • Ha-Kawa S.
        • et al.
        Changes in central opioid receptor binding in relation to inflammation and pain in patients with rheumatoid arthritis.
        Br J Rheumatol. 1994; 33: 909-916
        • Turnbull A.V.
        • Rivier C.
        Corticotropin-releasing factor, vasopressin, and prostaglandins mediate, and nitric oxide restrains, the hypothalamic-pituitary-adrenal response to acute local inflammation in the rat.
        Endocrinology. 1996; 137: 455-463
        • Denucci D.J.
        • Dionne R.A.
        • Dubner R.
        Identifying a neurobiologic basis for drug therapy in TMDs.
        J Am Dent Assoc. 1996; 127: 581-593
        • Crosby G.
        • Marota J.J.A.
        • Huang P.L.
        Intact nociception-induced neuroplasticity in transgenic mice deficient in neuronal nitric oxide synthase.
        Neuroscience. 1995; 69: 1013-1017
        • Wong M.L.
        • Rettori V.
        • al-Shekhlee A.
        • et al.
        Inducible nitric oxide synthase gene expression in the brain during systemic inflammation.
        Nature Med. 1996; 2: 581-584
        • Morris R.
        • Southam E.
        • Gittins S.R.
        • Garthwaite J.
        NADPH-diaphorase staining in autonomic and somatic cranial ganglia of the rat.
        Neuroreport. 1993; 4: 62-64
        • Shetty V.
        • Gratt B.M.
        • Flack V.
        Thermographic assessment of reversible inferior alveolar nerve deficit.
        J. Orofacial Pain. 1994; 8: 375-383
        • Babey A.M.
        • Kolesnikov Y.
        • Cheng J.
        • et al.
        Nitric oxide and opioid tolerance.
        Neuropharmacology. 1994; 33: 1463-1470
        • Brignola G.
        • Calignano A.
        • Di Rosa M.
        Modulation of morphine antinociception in the mouse by endogenous nitric oxide.
        Br J Pharmacol. 1994; 113: 1372-1376
        • Az-ma T.H.
        • Hardian A.
        • Yugo O.
        Inhibitory effect of lidocaine on cultured porcine aortic endothelial cell-dependent antiaggregation of platelets.
        Anesthesiology. 1995; 83: 374-381
        • Farhat M.Y.
        • Lavigne M.C.
        • Ramwell P.W.
        The vascular protective effects of estrogen.
        FASEB J. 1996; 10: 615-624
        • Hishikawa K.
        • Nakaki T.
        • Marumo T.
        • et al.
        Up-regulation of nitric oxide synthase by estradiol in human aortic endothelial cells.
        FEBS Lett. 1995; 360: 291-293
        • Hayashi T.
        • Yamada K.
        • Esaki T.
        • et al.
        Estrogen increases endothelial nitric oxide by a receptor-mediated systems.
        Biochem Biophy Res Commun. 1995; 214: 847-855
        • Mendelsohn M.E.
        • Karas R.H.
        Estrogen and the blood vessel wall.
        Curr Opin Cardiol. 1994; 9: 619-626
        • Veille J.C.
        • Li P.
        • Eisenach J.C.
        • et al.
        Effects of estrogen on nitric oxide biosynthesis and vasorelaxant activity in sheep uterine and renal arteries in vitro.
        Am J Obstet Gynecol. 1996; 174: 1043-1049
        • Gorodeski G.I.
        • Yang T.
        • Levy M.N.
        • et al.
        Effects of estrogen in vivo on coronary vascular resistance in perfused rabbit hearts.
        Am J Physiol. 1995; 269 (6 Pt 2): R1333-R1338
        • Figueroa J.P.
        • Massmann G.A.
        Estrogen increases nitric oxide synthase activity in the uterus of nonpregnant sheep.
        Am J Obstet Gynecol. 1995; 173: 1539-1545
        • Miller V.M.
        • Vanhoutte P.M.
        Progesterone and modulation of endothelium-dependent responses in canine coronary arteries.
        Am J Physiol. 1991; 261: R1022-R1027
        • Miller L.
        • Alley E.W.
        • Murphy W.J.
        • et al.
        Progesterone inhibits inducible nitric oxide synthase gene expression and nitric oxide production in murine macrophages.
        J Leukoc Biol. 1996; 59: 442-450
        • Rosselli M.
        • Imthurm B.
        • Macas E.
        • et al.
        Circulating nitric/nitrate levels increase with follicular development, indirect evidence for estradiol mediated NO release.
        Biochem Biophys Res Commun. 1994; 202: 1543-1552
        • Weiner C.P.
        • Knowles R.G.
        • Moncada S.
        Induction of nitric oxide synthases early in pregnancy.
        Am J Obstet Gynecol. 1994; 171: 838-843
        • Goetz R.M.
        • Morano I.
        • Calovini T.
        • et al.
        Increased expression of endothelial constitutive nitric oxide synthase in rat aorta during pregnancy.
        Biochem Biophys Res Commun. 1994; 205: 905-910
        • Collins P.
        • Shay J.
        • Jiang C.
        • Moss J.
        Nitric oxide accounts for dose-dependent estrogen-mediated coronary relaxation after acute estrogen withdrawal.
        Circulation. 1994; 90: 1964-1968
        • Weiner C.P.
        • Lizasoain I.
        • Baylis S.A.
        • et al.
        Induction of calcium-dependent nitric oxide synthases by sex hormones.
        in: Proc Natl Acad Sci USA. 91. 1994: 5212-5216
        • Hayashi T.
        • Ishikawa T.
        • Yamada K.
        • et al.
        Biphasic effect of estrogen on neuronal constitutive nitric oxide synthase via Ca(2+)-calmodulin dependent mechanism.
        Biochem Biophys Res Commun. 1994; 203: 1013-1019
        • Lizasoain I.
        • Weiner C.P.
        • Knowles R.G.
        • Moncada S.
        The ontogeny of cerebral and cerebliar nitric oxide synthase in the guinea pig and rat.
        Pediatr Res. 1996; 39: 779-783
        • Pu S.Y.
        • Xu B.
        • Kalra S.P.
        • Kalra P.S.
        Evidence that gonadal steroids modulate nitric oxide efflux in the medial preoptic area—effect of N-methyl-D-aspartate and correlation with leutinizing hormone secretion.
        Endocrinology. 1996; 137: 1949-1955
        • Mogil J.S.
        • Sternberg W.F.
        • Kes B.
        • et al.
        Sex differences in the antagonism of swim stress-induced analgesia: effects of gonadectomy and estrogen replacement.
        Pain. 1993; 53: 17-25
        • Szabo C.
        • Thiemermann C.
        • Wu C.C.
        • et al.
        Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo.
        in: Proc Natl Acad Sci USA. 91. 1994: 271-275
        • Bonello N.
        • McKie K.
        • Jasper M.
        • et al.
        Inhibition of nitric oxide: effects on interleukin-1 beta-enhanced ovulation rate, steroid hormones, and ovarian leukocyte distribution at ovulation in the rat.
        Biol Reprod. 1996; 54: 436-445
        • Imalawansa S.J.
        • De Marco G.
        • Gangula P.
        • Yallampalli C.
        Nitric oxide donor alleviates ovariectomy-induced bone loss.
        Bone. 1996; 18: 301-304
        • Miller-Blair D.J.
        • Robbins D.L.
        Rheumatoid arthritis: new science, new treatment.
        Geriatrics. 1993; 48: 28-31
        • Miller-Blair D.J.
        • Robbins D.L.
        Rheumatoid arthritis: new science, new treatment.
        Geriatrics. 1993; 48: 35-38
        • Jackel W.H.
        • Gerdes N.
        • Cziske R.
        • Jacobi E.
        Epidemiology of rheumatic complaints in Germany. Data on the prevalence and physical and psychosocial disability.
        Z Rheumatol. 1993; 52: 281-288
        • Da Silva J.A.
        • Hall G.M.
        The effects of gender and sex hormones on outcome in rheumatoid arthritis.
        Baillieres Clin Rheumatol. 1992; 6: 196-219
        • Abubaker A.O.
        • Raslan W.F.
        • Sotercanos G.C.
        Estrogen and progesterone receptors in temporomandibular joint discs of symptomatic and asymptomatic persons: a preliminary study.
        J Oral Maxilofac Surg. 1993; 51: 1096-1100
        • Campbell J.H.
        • Courey M.S.
        • Bourne P.
        • Odziemiec C.
        Estrogen receptor analysis of human temporomandibular disc.
        J Oral Maxillofac Surg. 1993; 51: 1101-1105
        • Anbar M.
        The role of nitric oxide in the evolution of living systems from premordial prokaryotes to eukaryotes—a hypothesis.
        in: Moncada S. Stamler J. Gross S. Higgs E.A. The biology of nitric oxide. Portland Press, London1996: 226a-226d (part 5)
        • Obi T.
        • Kabeyama A.
        • Nishio A.
        Equine coronary artery responds to 5-hydroxytryptamine with relaxaiion in vitro.
        J Vet Pharmacol Ther. 1994; 17: 218-225
        • Akiho H.
        • Chijiiwa Y.
        • Okabe H.
        • et al.
        Direct inhibitory effect of atrial natriuretic peptide on isolated caecal circular smooth muscle cells via soluble guanylate cyclase.
        Life Sci. 1994; 55: 1293-1299
        • Chiang L.W.
        • Schweizer F.E.
        • Tsien R.W.
        • Schulman H.
        Nitric oxide synthase expression in single hippocampal neurons.
        Mol Brain Res. 1994; 27: 183-188
        • Watanabe Y.
        • Saito H.
        • Abe K.
        Nitric oxide is involved in long-term potentiation in the medial but not lateral amygdala neuron synapses in vitro.
        Brain Res. 1995; 688: 233-236
        • Hawkins R.D.
        • Zhuo M.
        • Arancio O.
        Nitric oxide and carbon monoxide as possible retrograde messengers in hippocampal long-term potentiation.
        in: Takagi H. Toda N. Hawkins R.D. Nitric oxide: role in neuronal communication and neurotoxicity. Japan Scientific Societies Press and CRC Press, 1994: 12948 (xxx)
        • Abe K.
        • Mizutani A.
        • Saito H.
        Possible role of nitric oxide in long-term potentiation in the dentate gyrus.
        in: Takagi H. Toda N. Hawkins R.D. Nitric oxide: role in neuronal communication and neurotoxicity. Japan Scientific Societies Press and CRC Press, 1994: 149-160 (xxx)
        • Dawson T.M.
        • Dawson V.L.
        • Synder S.H.
        Molecular mechanisms of nitric oxide actions in the brain.
        Ann NY Acad Sci. 1994; 738: 76-85
        • Schulz J.B.
        • Matthews R.T.
        • Muqit M.M.
        • et al.
        Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice.
        J Neurochem. 1995; 64: 936-939
        • O'Dell T.J.
        • Huang P.L.
        • Dawson T.M.
        • et al.
        Endothelial NOS and the blockade of LTP by NOS inhibitors in mice lacking neuronal NOS.
        Science. 1994; 265: 542-546
        • Kosaka H.
        • Seiyama A.
        Physiological role of nitric oxide as an enhancer of oxygen transfer from erythrocytes to tissues.
        Biochem Biophys Res Commun. 1996; 218: 749-752
        • Goode H.F.
        • Howdle P.D.
        • Walker B.F.
        • Webster N.R.
        Nitric oxide synthase activity is increased in patients with sepsis syndrome.
        Clin Sci. 1995; 88: 131-133
        • Tsuneyoshi I.
        • Kanmura Y.
        • Yoshimura N.
        Nitric oxide as a mediator of reduced arterial responsiveness in septic patients.
        Crit Care Med. 1996; 24: 1083-1086
        • Doughty L.A.
        • Kaplan S.S.
        • Carcillo J.A.
        Inflammatory cytokine and nitric oxide responses in pediatric sepsis and organ failure.
        Crit Care Med. 1996; 24: 1137-1143
        • Herbertson M.J.
        • Werner H.A.
        • Walley K.R.
        Nitric oxide synthase inhibition partially prevents decreased LV contractility during endotoxemia.
        Am J Physiol. 1996; 270: H1979-H1984
        • Harbrecht B.G.
        • Wang S.C.
        • Simmons R.I.
        • Billiar T.R.
        Cyclic gmp and guanylate cyclase mediate lipopolysaccharide-induced kupffer cell tumor necrosis factor-alpha synthesis.
        J Leukoc Biol. 1995; 57: 297-302
        • Neilly I.J.
        • Copland M.
        • Haj M.
        • Adev G.
        • et al.
        Plasma nitrate concentrations in neutropenic and non-neutropenic patients with suspected septicaemia.
        Br J Haematol. 1995; 89: 199-202
        • Wong H.R.
        • Carcillo J.A.
        • Burchart G.
        • Kaplan S.S.
        Nitric oxide production in critically ill patients.
        Arch Dis Child. 1996; 74: 482-489
        • Fukatsu K.
        • Saito H.
        • Fukushima R.
        • et al.
        Effects of three inhibitors of nitric oxide synthase on host resistance to bacterial infection.
        Inflam Res. 1996; 45: 109-112
        • Villa P.
        • Sartor G.
        • Angelini M.
        • et al.
        Pattern of cytokines and pharmacomodulation in sepsis induced by cecal ligation and puncture compared with that induced by endotoxin.
        Clin Diagnos Lab Immunol. 1995; 2: 549-553
        • Moffat Jr., F.L.
        • Han T.
        • Li Z.M.
        • et al.
        Supplemental L-arginine HCl augments bacterial phagocytosis in human polymorphonuclear leukocytes.
        J Cell Physiol. 1996; 168: 26-33
        • Collins K.J.
        The autonomic nervous system and the regulation of body temperature.
        in: Bannister R. Mathias C.J. Autonomic failure. 3rd ed. Oxford University Press, New York1993: 212-230
        • Freeman G.
        • Dyer R.L.
        • Juhos L.
        • et al.
        Identification of nitric oxide (NO) in human blood.
        Arch Environ Health. 1978; 33: 19-23
        • Maeda N.
        • Imaizumi K.
        • Kon K.
        • Shiga T.
        A kinetic study on functional impairment of nitric oxide-exposed rat erythrocytes.
        Environ-Health Perspect. 1987; 73: 171-177
        • Sampath V.
        • Zhao X.J.
        • Caughey W.S.
        Characterization of interactions of nitric oxide with human hemoglobin A by infrared spectroscopy.
        Biochem Biophys Res Commun. 1994; 198: 281-287
        • Eriksson L.F.
        Binding of nitric oxide to intact human erythrocytes as monitored by electron paramagnetic resonance.
        Biochem Biophys Res Commun. 1994; 203: 176-181
        • Eich R.F.
        • Li T.
        • Lennon D.D.
        • et al.
        Mechanism of NO-induced oxidation of myoglobin and hemoglobin.
        Biochemistry. 1996; 35: 6976-6983
        • Feclisch M.
        • Kubitzek D.
        • Werringloer J.
        The oxyhemoglobin assay.
        in: Feelisch M. Stamler J.S. Methods in nitric oxide research. John Wiley and Sons, Chichester1996: 455-478
        • Radomski M.W.
        • Palmer R.M.
        • Moncada S.
        An L-arginine/nitric oxide pathway present in human platelets regulates aggregation.
        in: 9th ed. Proc Natl Acad Sci USA. 87. 1990: 5193-5197
        • Bode-Boger S.M.
        • Boger R.H.
        • Creutzig A.
        • et al.
        L-arginine infusion decreases peripheral arterial resistance and inhibits platelet aggregation in healthy subjects.
        Clin Sci. 1994; 87: 303-310
        • Anbar M.
        Quantitative dynamic telethermometry in medical diagnosis and management.
        CRC Press, Boca Raton1994
        • Anbar M.
        • Montoro J.C.
        • Lee K.-H.
        • D'Arcy S.
        Manifestation of neurological abnormalities through frequency analysis of skin temperature regulation.
        Thermology. 1991; 3: 234-241
        • Chinzei T.
        • Saito I.
        • Ikeda M.
        • et al.
        Thermal-rhythm imaging of skin temperature with a high-speed thermal camera.
        Biomed Thermol. 1995; 15: 150-152
        • Anbar M.
        • Grenn M.W.
        • Marino M.T.
        • et al.
        Fast dynamic area telethermometry (DAT) of the human forearm with a Ba/As quantum well infractured focal plane array camera.
        Thermologie Osterreich. 1997; 7: 105-118
        • Chen A.C.
        • Rappelsberger P.
        Brain and human pain: topographic EEG amplitude and coherence mapping.
        Brain Topogr. 1994; 7: 129-140
        • Ferracuti S.
        • Seri S.
        • Mattia D.
        • Cruccu G.
        Quantitative EEG modifications during the cold water pressor test: hemispheric and hand differences.
        Int J Psychophysiol. 1994; 17: 261-268
        • Sanders S.P.
        • Zweier J.L.
        • Kuppusamy P.
        • et al.
        Hyperoxic sheep pulmonary microvascular endothelial cells generate free radicals via mitochondrial electron transport.
        J Clin Invest. 1993; 91: 46-52
        • Lindau-Shepard B.
        • Shaffer J.B.
        • Del Vecchio P.J.
        Overexpression of manganous superoxide dismutase (MnSOD) in pulmonary endothelial cells confers resistance to hyperoxia.
        J Cell Physiol. 1994; 161: 237-242
        • Gardner P.R.
        • Nguyen D.D.
        • White C.W.
        Aconitase is a sensitive and critical target of oxygen poisoning in cultured mammalian cells and in rat lungs.
        in: 9th ed. Proc Natl Acad Sci USA. 91. 1994: 12248-12252
        • Gardner P.R.
        • Raineri I.
        • Epstein L.B.
        • White C.W.
        Superoxide radical and iron modulate aconitase activity in mammalian cells.
        J Biol Chem. 1995; 270: 13399-13405
        • Kong X.J.
        • Lee S.L.
        • Lanzillo J.J.
        • Fanburg B.I.
        Cu1Zn superoxide dismutase in vascular cells: changes during cell cycling and exposure to hyperoxia.
        Am J Physiol. 1993; 264: L365-L375
        • Quinlan T.
        • Spivack S.
        • Mossman B.T.
        Regulation of antioxidant enzymes in lung after oxidant injury.
        Environ Health Perspect. 1994; 102: 79-87
        • Lee C.Y.
        • Pastore J.N.
        • Tang G.
        • Tsan M.F.
        Cellular distribution of pulmonary Mn and CuZn superoxide dismutase: effect of hyperoxia and interleukin-1.
        J Histochem Cytochem. 1994; 42: 1201-1205
        • Mikawa K.
        • Nishina K.
        • Maekawa N.
        • Ohara H.
        Attenuation of hyperoxic lung injury in rabbits with superoxide dismutase—effects on inflammatory mediators.
        Acta Anaesthesiol Scand. 1995; 39: 317-322
        • Karadsheh N.S.
        • Khraisha S.
        Comparative study of the levels of antioxidants of students at Amman and Dead Sea level.
        Avit Space Environ Med. 1993; 64: 1125-1127
        • Beckmann J.S.
        • Ye Y.Z.
        • Anderson P.G.
        • et al.
        Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry.
        Biol Chem Hoppe Seyler. 1994; 375: 81-88
        • Squadrito G.L.
        • Pryor W.A.
        The formation of peroxynitrite in vivo from nitric oxide and superoxide.
        Chem Biol Interact. 1995; 96: 203-206
        • Anbar M.
        Mechanism of hyperthermia of the cancerous breast.
        Biomed Thermol. 1995; 15: 135-139
        • Burkart V.
        • Gross-Eick A.
        • Bellmann K.
        • et al.
        Suppression of nitric oxide toxicity in islet cells by alpha-tocopherol.
        FEBS Lett. 1995; 364: 259-263
        • Lee Y.S.
        • Wurster R.D.
        Potentiation of anti-proliferative effect of nitroprusside by ascorbate in human brain tumor cells.
        Cancer Lett. 1994; 78: 19-23
        • Mannick E.E.
        • Bravo L.E.
        • Zarama G.
        • et al.
        Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants.
        Cancer Res. 1996; 56: 3238-3243
        • Satarug S.
        • Haswellelkins M.R.
        • Tsuda M.
        • et al.
        Thiocyanate-independent nitrosation in humans with carcinogenic parasite infection.
        Carcinogenesis. 1996; 17: 1075-1081
        • DeFeudis F.V.
        Excess EDRF/NO, a potentially deleterions condition that may be involved in accelerated atherogenesis and other chronic disease states.
        Gen Pharmacol. 1995; 26: 667-680
        • Ghosh S.K.
        • Ekpo E.B.
        • Shah I.U.
        • et al.
        A double-blind, placebo-controlled parallel trial of vitamin C treatment in elderly patients with hypertension.
        Gerontology. 1994; 40: 268-272
        • Toohey L.
        • Harris M.A.
        • Allen K.G.
        • Melby C.L.
        Plasma ascorbic acid concentrations are related to cardiovascular risk factors in African-Americans.
        J Nutr. 1996; 126: 121-128
        • Bendich A.
        • Langseth L.
        The health effects of vitamin C supplementation: a review.
        J Am Coll Nutr. 1995; 14: 124-136
        • Ness A.R.
        • Khaw K.T.
        • Bingham S.
        • Day N.E.
        Vitamin C status and blood pressure.
        J Hypertens. 1996; 14: 503-508
        • Faucett J.
        • Gordon N.
        • Levine J.
        Differences in postoperative pain severity among four ethnic groups.
        J Pain Symptom Manage. 1994; 9: 383-389
        • Graff-Radford S.B.
        • Ketalaer M.-C.
        • Gratt B.M.
        • Solberg W.K.
        Thermographic assessment of neuropathic facial pain.
        J Orofacial Pain. 1995; 9: 138-146
        • Canavan D.
        • Graff-Radford S.B.
        • Gratt B.M.
        Traumatic dysesthesia of the trigeminal nerve.
        J Orofacial Pain. 1994; 8: 391-396
        • Bush F.M.
        • Harkins S.W.
        • Harrington W.G.
        • Price D.D.
        Analysis of gender effects on pain perception and symptom presentation in temporomandibular pain.
        Pain. 1993; 53: 73-80
        • Allerbring M.
        • Haegerstam G.
        Invasive dental treatment, pain reports, and disease conviction in chronic facial pain patients. A retrospective study.
        Acta Odontol Scand. 1995; 53: 41-43
        • Wallace J.L.
        • Reuter B.K.
        • Carino G.
        Nitric oxide-releasing non-steroidal anti-inflammatory drugs—a novel approach for reducing gastrointestinal toxicity.
        J Gastroenterol Hepatol. 1994; 9: S40-S44
        • Weisenberg M.
        • Tepper I.
        • Schwarzwald J.
        Humor as a cognitive technique for increasing pain tolerance.
        Pain. 1995; 63: 207-212
        • Syrjala K.L.
        • Donaldson G.W.
        • Davis M.W.
        • et al.
        Relaxation and imagery and cognitive-behavioral training reduce pain during cancer treatment—a controlled clinical trial.
        Pain. 1995; 63: 189-198