Skip to main content

Advertisement

SpringerLink
Log in

The role of nitric oxide in nociception

  • Published:
Current Review of Pain Aims and scope Submit manuscript

Abstract

Pharmacologic, electrophysiologic, and immunohistochemical studies have suggested a role of nitric oxide (NO) in nociception processing. Recent studies have indicated that NO may modulate spinal and sensory neuron excitability through multiple mechanisms that may underlie its distinctive roles in different pain states. Differential regulation of a family of NO-producing enzymes, NO synthases, contributes mainly to the complexity underlying the role of NO in nociception. This review summarizes the latest advances in our understanding of the contribution of NO to pain transduction. Possible cellular mechanisms regarding the connection between NO production and the abnormal sensation derived from different stimuli and pathologic conditions are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Geller DA, Billiar TR: Molecular biology of nitric oxide synthases. Cancer Metastasis Rev 1998, 17:7–23. Provides a thorough review on the latest advances in our understanding of molecular regulation of the NOS genes.

    Article  CAS  PubMed  Google Scholar 

  2. Wang Y, Marsden PA: Nitric oxide synthases: gene structure and regulation. Adv Pharmacol 1995, 34:71–90.

    Article  CAS  PubMed  Google Scholar 

  3. Lewin MR, Walters ET: Cyclic GMP pathway is critical for inducing long-term sensitization of nociceptive sensory neurons. Nat Neurosci 1999, 2:18–23. Using electrophysiologic and pharmacologic approches, this study demonstrates that the NO-cGMP-protein kinase pathway is required for noxious stimulation-induced long-term hyperexcitability of nociceptive sensory neurons in the mollusc Aplysia.

    Article  CAS  PubMed  Google Scholar 

  4. Lin Q, Palecek J, Paleckova V, et al.: Nitric oxide mediates the central sensitization of primate spinothalamic tract neurons. J Neurophysiol 1999, 81:1075–85. Provides in vivo evidence to link spinal NO production to central sensitization and tissue injury-related pain states.

    CAS  PubMed  Google Scholar 

  5. Lin Q, Wu J, Peng YB, et al.: Nitric oxide-mediated spinal disinhibition contributes to the sensitization of primate spinothalamic tract neurons. J Neurophysiol 1999, 81:1086–1094. Suggests that a NO-mediated pathway may contribute to central sensitization through a mechanism of disinhibition.

    CAS  PubMed  Google Scholar 

  6. Ferreira J, Santos AR, Calixto JB: The role of systemic, spinal and supraspinal L-arginine-nitric oxide-cGMP pathway in thermal hyperalgesia caused by intrathecal injection of glutamate in mice. Neuropharmacology 1999, 38:835–842.

    Article  CAS  PubMed  Google Scholar 

  7. Inoue T, Mashimo T, Shibata M, et al.: Rapid development of nitric oxide-induced hyperalgesia depends on an alternate to the cGMP-mediated pathway in the rat neuropathic pain model. Brain Res 1998, 792:263–270.

    Article  CAS  PubMed  Google Scholar 

  8. Ichinose F, Mi WD, Miyazaki M, et al.: Lack of correlation between the reduction of sevoflurane MAC and the cerebellar cyclic GMP concentrations in mice treated with 7-nitroindazole. Anesthesiology 1998, 89:143–148.

    Article  CAS  PubMed  Google Scholar 

  9. Ashina M, Lassen LH, Bendtsen L, et al.: Effect of inhibition of nitric oxide synthase on chronic tension-type headache: a randomised crossover trial. Lancet 1999, 353:287–289.

    Article  CAS  PubMed  Google Scholar 

  10. Kimura S, Watanabe K, Yajiri Y, et al.: Cerebrospinal fluid nitric oxide metabolites in painful diseases. Neuroreport 1999, 10:275–279.

    Article  CAS  PubMed  Google Scholar 

  11. Korting GE, Smith SD, Wheeler MA, et al.: A randomized double-blind trial of oral L-arginine for treatment of interstitial cystitis. J Urol 1999, 161:558–565.

    Article  CAS  PubMed  Google Scholar 

  12. Christiansen I, Thomsen LL, Daugaard D, et al.: Glyceryl trinitrate induces attacks of migraine without aura in sufferers of migraine with aura. Cephalalgia 1999, 19:660–667.

    Article  CAS  PubMed  Google Scholar 

  13. Shimomura T, Murakami F, Kotani K, et al.: Platelet nitric oxide metabolites in migraine. Cephalalgia 1999, 19:218–222.

    Article  CAS  PubMed  Google Scholar 

  14. Lauretti GR, de Oliveira R, Reis MP, et al.: Transdermal nitroglycerine enhances spinal sufentanil postoperative analgesia following orthopedic surgery. Anesthesiology 1999, 90:734–739.

    Article  CAS  PubMed  Google Scholar 

  15. Takahashi T, Kondoh T, Ohtani M, et al.: Association between arthroscopic diagnosis of temporomandibular joint osteoarthritis and synovial fluid nitric oxide levels. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999, 88:129–136.

    Article  CAS  PubMed  Google Scholar 

  16. Luo ZD: Molecular dissection of pain mediators. Pain Rev 2000, 7:37–64.

    CAS  Google Scholar 

  17. Budziñski M, Misterek K, Gumulka W, Dorociak A: Inhibition of inducible nitric oxide synthase in persistent pain. Life Sci 2000, 66:301–305.

    Article  PubMed  Google Scholar 

  18. Osborne MG, Coderre TJ: Effects of intrathecal administration of nitric oxide synthase inhibitors on carrageenan-induced thermal hyperalgesia. Br J Pharmacol 1999, 126:1840–1846.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Beirith A, Creczynski-Pasa TB, Bonetti VR, et al.: Antinociceptive properties and nitric oxide synthase inhibitory action of new ruthenium complexes. Eur J Pharmacol 1999, 369:289–297.

    Article  CAS  PubMed  Google Scholar 

  20. Chen X, Levine JD: NOS inhibitor antagonism of PGE2-induced mechanical sensitization of cutaneous C-fiber nociceptors in the rat. J Neurophysiol 1999, 81:963–966.

    CAS  PubMed  Google Scholar 

  21. Urban MO, Coutinho SV, Gebhart GF: Involvement of excitatory amino acid receptors and nitric oxide in the rostral ventromedial medulla in modulating secondary hyperalgesia produced by mustard oil. Pain 1999, 81:45–55.

    Article  CAS  PubMed  Google Scholar 

  22. Kawamata T, Omote K: Activation of spinal N-methyl-D-aspartate receptors stimulates a nitric oxide/cyclic guanosine 3′,5′-monophosphate/glutamate release cascade in nociceptive signaling. Anesthesiology 1999, 91:1415–1424. Provides strong pharmacologic evidence to support a tight correlation between NMDA-induced pain states and activation of the NO-cGMP pathway in the spinal cord.

    Article  CAS  PubMed  Google Scholar 

  23. Dolan S, Field LC, Nolan AM: The role of nitric oxide and prostaglandin signaling pathways in spinal nociceptive processing in chronic inflammation. Pain 2000, 86:311–320.

    Article  CAS  PubMed  Google Scholar 

  24. Leong S, Liu H, Yeo J: Nitric oxide synthase and glutamate receptor immunoreactivity in the rat spinal trigeminal neurons expressing Fos protein after formalin injection. Brain Res 2000, 855:107–115.

    Article  CAS  PubMed  Google Scholar 

  25. Przewlocka B, Mika J, Capone F, et al.: Intrathecal oxotremorine affects formalin-induced behavior and spinal nitric oxide synthase immunoreactivity in rats. Pharmacol Biochem Behav 1999, 62:531–536.

    Article  CAS  PubMed  Google Scholar 

  26. Rodella L, Rezzani R, Agostini C, Bianchi R: Expression of NADPH-diaphorase and colocalization with Fos in the brain neurons of the rat following visceral noxious stimulation. Brain Res 1999, 834:173–177.

    Article  CAS  PubMed  Google Scholar 

  27. Lin Q, Wu J, Peng YB, et al.: Inhibition of primate spinothalamic tract neurons by spinal glycine and GABA is modulated by guanosine 3′,5′-cyclic monophosphate. J Neurophysiol 1999, 81:1095–1103. Demonstrates that a NO-cGMP pathway is involved in modulation of the spinal inhibitory tone and central sensitization.

    CAS  PubMed  Google Scholar 

  28. Callsen-Cencic P, Hoheisel U, Kaske A, et al.: The controversy about spinal neuronal nitric oxide synthase: under which conditions is it up- or downregulated? Cell Tissue Res 1999, 295:183–194. This review article has summarized regulation of nNOS expression in spinal dorsal horn neurons under different physiologic and pathologic circumstances. In addition, data from in vitro experiments were used to explain possible mechanisms underlying the discrepancies of in vivo data.

    Article  CAS  PubMed  Google Scholar 

  29. Bogdanov MB, Wurtman RJ: Possible involvement of nitric oxide in NMDA-induced glutamate release in the rat striatum: an in vivo microdialysis study. Neurosci Lett 1997, 221:197–201.

    Article  CAS  PubMed  Google Scholar 

  30. Valtschanoff JG, Weinberg RJ, Rustioni A, Schmidt HH: Nitric oxide synthase and GABA colocalize in lamina II of rat spinal cord. Neurosci Lett 1992, 148:6–10.

    Article  CAS  PubMed  Google Scholar 

  31. Haley JE, Dickenson AH, Schachter M: Electrophysiological evidence for a role of nitric oxide in prolonged chemical nociception in the rat. Neuropharmacology 1992, 31:251–258.

    Article  CAS  PubMed  Google Scholar 

  32. Zhuo M, Meller ST, Gebhart GF: Endogenous nitric oxide is required for tonic cholinergic inhibition of spinal mechanical transmission. Pain 1993, 54:71–78.

    Article  CAS  PubMed  Google Scholar 

  33. Choi Y, Raja SN, Moore LC, Tobin JR: Neuropathic pain in rats is associated with altered nitric oxide synthase activity in neural tissue. J Neurol Sci 1996, 138:14–20.

    Article  CAS  PubMed  Google Scholar 

  34. Luo ZD, Chaplan SR, Scott BP, et al.: Neuronal nitric oxide synthase mRNA upregulation in rat sensory neurons after spinal nerve ligation: lack of a role in allodynia development. J Neurosci 1999, 19:9201–9208. Provides evidence from molecular biology, genetics, immunohistochemistry, and behavioral pharmacology to indicate that increased nNOS expression in the DRG after peripheral nerve injury is not directly associated with neuropathic allodynia.

    CAS  PubMed  Google Scholar 

  35. Goff JR, Burkey AR, Goff DJ, Jasmin L: Reorganization of the spinal dorsal horn in models of chronic pain: correlation with behaviour. Neuroscience 1998, 82:559–574.

    Article  CAS  PubMed  Google Scholar 

  36. Yamamoto T, Shimoyama N: Role of nitric oxide in the development of thermal hyperesthesia induced by sciatic nerve constriction injury in the rat. Anesthesiology 1995, 82:1266–1273.

    Article  CAS  PubMed  Google Scholar 

  37. Yoon YW, Sung B, Chung JM: Nitric oxide mediates behavioral signs of neuropathic pain in an experimental rat model. Neuroreport 1998, 9:367–372.

    Article  CAS  PubMed  Google Scholar 

  38. Levy D, Zochodne DW: Local nitric oxide synthase activity in a model of neuropathic pain. Eur J Neurosci 1998, 10:1846–1855.

    Article  CAS  PubMed  Google Scholar 

  39. Levy D, Höke A, Zochodne DW: Local expression of inducible nitric oxide synthase in an animal model of neuropathic pain. Neurosci Lett 1999, 260:207–209.

    Article  CAS  PubMed  Google Scholar 

  40. Fox A, Eastwood C, Gentry C, et al.: Critical evaluation of the streptozotocin model of painful diabetic neuropathy in the rat. Pain 1999, 81:307–316.

    Article  CAS  PubMed  Google Scholar 

  41. Okuse K, Chaplan SR, McMahon SB, et al.: Regulation of expression of the sensory neuron-specific sodium channel SNS in inflammatory and neuropathic pain. Mol Cell Neurosci 1997, 10:196–207.

    Article  CAS  PubMed  Google Scholar 

  42. Marsala J, Marsala M, Vanicky I, Taira Y: Localization of NADPHd-exhibiting neurons in the spinal cord of the rabbit. J Comp Neurol 1999, 406:263–284.

    Article  CAS  PubMed  Google Scholar 

  43. Onaka M, Minami T, Nishihara I, Ito S: Involvement of glutamate receptors in strychnine- and bicucullineinduced allodynia in conscious mice. Anesthesiology 1996, 84:1215–1222.

    Article  CAS  PubMed  Google Scholar 

  44. Ibuki T, Hama AT, Wang XT, et al.: Loss of GABA-immunoreactivity in the spinal dorsal horn of rats with peripheral nerve injury and promotion of recovery by adrenal medullary grafts. Neuroscience 1997, 76:845–858.

    Article  CAS  PubMed  Google Scholar 

  45. Castro-Lopes JM, Tavares, Coimbra A: GABA decreases in the spinal cord dorsal horn after peripheral neurectomy. Brain Res 1993, 620:287–291.

    Article  CAS  PubMed  Google Scholar 

  46. Bhisitkul RB, Kocsis JD, Gordon TR, Waxman SG: Trophic influence of the distal nerve segment on GABAA receptor expression in axotomized adult sensory neurons. Exp Neurol 1990, 109:273–278.

    Article  CAS  PubMed  Google Scholar 

  47. Dawson VL, Dawson TM, London ED, et al.: Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci U S A 1991, 88:6368–6371.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Sugimoto T, Bennett GJ, Kajander KC: Transsynaptic degeneration in the superficial dorsal horn after sciatic nerve injury: effects of a chronic constriction injury, transection, and strychnine. Pain 1990, 42:205–213.

    Article  CAS  PubMed  Google Scholar 

  49. Fukami S, Uchida I, Mashimo T, et al.: Gamma subunit dependent modulation by nitric oxide (NO) in recombinant GABAA receptor. Neuroreport 1998, 9:1089–1092.

    Article  CAS  PubMed  Google Scholar 

  50. Moon C, Fraser SP, Djamgoz MB: Protein kinase and phosphatase modulation of quail brain GABA(A) and non-NMDA receptors co-expressed in Xenopus oocytes. Cell Signal 2000, 12:105–112.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, 92093-0818, La Jolla, CA, USA

    Z. David Luo MD, PhD

  2. Institute of Neurobiology, Slovak Academy of Sciences, 040 01, Soltesovej 6, Kosice, Slovakia

    Dasa Cizkova MVD, PhD

Authors
  1. Z. David Luo MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dasa Cizkova MVD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luo, Z.D., Cizkova, D. The role of nitric oxide in nociception. Current Review of Pain 4, 459–466 (2000). https://doi.org/10.1007/s11916-000-0070-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11916-000-0070-y

Keywords

Search

Navigation