Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Jun 1;90(11):5162–5166. doi: 10.1073/pnas.90.11.5162

Blockade of tolerance to morphine but not to kappa opioids by a nitric oxide synthase inhibitor.

Y A Kolesnikov 1, C G Pick 1, G Ciszewska 1, G W Pasternak 1
PMCID: PMC46675  PMID: 7685116

Abstract

The nitric oxide synthase inhibitor NG-nitro-L-arginine (NO2Arg) blocks morphine tolerance in mice. After implantation of morphine pellets the analgesic response decreases from 100% on the first day to 0% on the third. Coadministration of NO2Arg along with the pellets markedly retards the development of tolerance; 60% of mice are analgesic after 3 days, and 50% of mice are analgesic after 5 days. In a daily injection paradigm the analgesic response to morphine is reduced from 60% to 0% by 5 days. Concomitant administration of morphine along with NO2Arg at doses of 2 mg/kg per day prevents tolerance for 4 weeks. A single NO2Arg dose retards morphine tolerance for several days, and dosing every 4 days is almost as effective as daily NO2Arg. NO2Arg slowly reverses preexisting tolerance over 5 days despite the continued administration of morphine along with NO2Arg. NO2Arg also reduces dependence and reverses previously established dependence. NO2Arg does not prevent tolerance to analgesia mediated by the kappa 1 agonist trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolindinyl)cyclohexyl]- benzene-acetamide (U50,488H) or the kappa 3 agent naloxone benzoylhydrazone, indicating a selective action of NO in the mechanisms of mu tolerance and dependence.

Full text

PDF
5162

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baker T. B., Tiffany S. T. Morphine tolerance as habituation. Psychol Rev. 1985 Jan;92(1):78–108. [PubMed] [Google Scholar]
  2. Botney M., Fields H. L. Amitriptyline potentiates morphine analgesia by a direct action on the central nervous system. Ann Neurol. 1983 Feb;13(2):160–164. doi: 10.1002/ana.410130209. [DOI] [PubMed] [Google Scholar]
  3. Bredt D. S., Glatt C. E., Hwang P. M., Fotuhi M., Dawson T. M., Snyder S. H. Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase. Neuron. 1991 Oct;7(4):615–624. doi: 10.1016/0896-6273(91)90374-9. [DOI] [PubMed] [Google Scholar]
  4. Bredt D. S., Hwang P. M., Snyder S. H. Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature. 1990 Oct 25;347(6295):768–770. doi: 10.1038/347768a0. [DOI] [PubMed] [Google Scholar]
  5. Bredt D. S., Snyder S. H. Nitric oxide, a novel neuronal messenger. Neuron. 1992 Jan;8(1):3–11. doi: 10.1016/0896-6273(92)90104-l. [DOI] [PubMed] [Google Scholar]
  6. Chapman V., Dickenson A. H. The combination of NMDA antagonism and morphine produces profound antinociception in the rat dorsal horn. Brain Res. 1992 Feb 28;573(2):321–323. doi: 10.1016/0006-8993(92)90780-d. [DOI] [PubMed] [Google Scholar]
  7. Chen L., Huang L. Y. Sustained potentiation of NMDA receptor-mediated glutamate responses through activation of protein kinase C by a mu opioid. Neuron. 1991 Aug;7(2):319–326. doi: 10.1016/0896-6273(91)90270-a. [DOI] [PubMed] [Google Scholar]
  8. Danks J. A., Tortella F. C., Long J. B., Bykov V., Jacobson A. E., Rice K. C., Holaday J. W., Rothman R. B. Chronic administration of morphine and naltrexone up-regulate[3H][D-Ala2,D-leu5]enkephalin binding sites by different mechanisms. Neuropharmacology. 1988 Sep;27(9):965–974. doi: 10.1016/0028-3908(88)90125-6. [DOI] [PubMed] [Google Scholar]
  9. Dougherty P. M., Willis W. D. Modification of the responses of primate spinothalamic neurons to mechanical stimulation by excitatory amino acids and an N-methyl-D-aspartate antagonist. Brain Res. 1991 Feb 22;542(1):15–22. doi: 10.1016/0006-8993(91)90991-4. [DOI] [PubMed] [Google Scholar]
  10. Dourish C. T., Hawley D., Iversen S. D. Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L-364,718. Eur J Pharmacol. 1988 Mar 15;147(3):469–472. doi: 10.1016/0014-2999(88)90183-5. [DOI] [PubMed] [Google Scholar]
  11. Dwyer M. A., Bredt D. S., Snyder S. H. Nitric oxide synthase: irreversible inhibition by L-NG-nitroarginine in brain in vitro and in vivo. Biochem Biophys Res Commun. 1991 May 15;176(3):1136–1141. doi: 10.1016/0006-291x(91)90403-t. [DOI] [PubMed] [Google Scholar]
  12. Faris P. L., Komisaruk B. R., Watkins L. R., Mayer D. J. Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia. Science. 1983 Jan 21;219(4582):310–312. doi: 10.1126/science.6294831. [DOI] [PubMed] [Google Scholar]
  13. Garthwaite J., Charles S. L., Chess-Williams R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature. 1988 Nov 24;336(6197):385–388. doi: 10.1038/336385a0. [DOI] [PubMed] [Google Scholar]
  14. Gistrak M. A., Paul D., Hahn E. F., Pasternak G. W. Pharmacological actions of a novel mixed opiate agonist/antagonist: naloxone benzoylhydrazone. J Pharmacol Exp Ther. 1989 Nov;251(2):469–476. [PubMed] [Google Scholar]
  15. Higgins G. A., Nguyen P., Sellers E. M. The NMDA antagonist dizocilpine (MK801) attenuates motivational as well as somatic aspects of naloxone precipitated opioid withdrawal. Life Sci. 1992;50(21):PL167–PL172. doi: 10.1016/0024-3205(92)90452-u. [DOI] [PubMed] [Google Scholar]
  16. Kennedy C., Henderson G. Mu-opioid receptor inhibition of calcium current: development of homologous tolerance in single SH-SY5Y cells after chronic exposure to morphine in vitro. Mol Pharmacol. 1991 Dec;40(6):1000–1005. [PubMed] [Google Scholar]
  17. Kolesnikov Y. A., Pick C. G., Pasternak G. W. NG-nitro-L-arginine prevents morphine tolerance. Eur J Pharmacol. 1992 Oct 20;221(2-3):399–400. doi: 10.1016/0014-2999(92)90732-j. [DOI] [PubMed] [Google Scholar]
  18. Lahti R. A., Collins R. J. Chronic naloxone results in prolonged increases in opiate binding sites in brain. Eur J Pharmacol. 1978 Sep 15;51(2):185–186. doi: 10.1016/0014-2999(78)90343-6. [DOI] [PubMed] [Google Scholar]
  19. Law P. Y., Hom D. S., Loh H. H. Opiate receptor down-regulation and desensitization in neuroblastoma X glioma NG108-15 hybrid cells are two separate cellular adaptation processes. Mol Pharmacol. 1983 Nov;24(3):413–424. [PubMed] [Google Scholar]
  20. Moore P. K., Oluyomi A. O., Babbedge R. C., Wallace P., Hart S. L. L-NG-nitro arginine methyl ester exhibits antinociceptive activity in the mouse. Br J Pharmacol. 1991 Jan;102(1):198–202. doi: 10.1111/j.1476-5381.1991.tb12153.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pasternak G. W. Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol. 1993 Feb;16(1):1–18. doi: 10.1097/00002826-199302000-00001. [DOI] [PubMed] [Google Scholar]
  22. Paul D., Levison J. A., Howard D. H., Pick C. G., Hahn E. F., Pasternak G. W. Naloxone benzoylhydrazone (NalBzoH) analgesia. J Pharmacol Exp Ther. 1990 Nov;255(2):769–774. [PubMed] [Google Scholar]
  23. Pick C. G., Paul D., Eison M. S., Pasternak G. W. Potentiation of opioid analgesia by the antidepressant nefazodone. Eur J Pharmacol. 1992 Feb 18;211(3):375–381. doi: 10.1016/0014-2999(92)90395-k. [DOI] [PubMed] [Google Scholar]
  24. Puttfarcken P. S., Werling L. L., Cox B. M. Effects of chronic morphine exposure on opioid inhibition of adenylyl cyclase in 7315c cell membranes: a useful model for the study of tolerance at mu opioid receptors. Mol Pharmacol. 1988 May;33(5):520–527. [PubMed] [Google Scholar]
  25. Sharma S. K., Klee W. A., Nirenberg M. Dual regulation of adenylate cyclase accounts for narcotic dependence and tolerance. Proc Natl Acad Sci U S A. 1975 Aug;72(8):3092–3096. doi: 10.1073/pnas.72.8.3092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Siegel S. Morphine analgesic tolerance: its situation specificity supports a Pavlovian conditioning model. Science. 1976 Jul 23;193(4250):323–325. doi: 10.1126/science.935870. [DOI] [PubMed] [Google Scholar]
  27. Snyder S. H., Bredt D. S. Nitric oxide as a neuronal messenger. Trends Pharmacol Sci. 1991 Apr;12(4):125–128. doi: 10.1016/0165-6147(91)90526-x. [DOI] [PubMed] [Google Scholar]
  28. Spiegel K., Kalb R., Pasternak G. W. Analgesic activity of tricyclic antidepressants. Ann Neurol. 1983 Apr;13(4):462–465. doi: 10.1002/ana.410130418. [DOI] [PubMed] [Google Scholar]
  29. Trujillo K. A., Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science. 1991 Jan 4;251(4989):85–87. doi: 10.1126/science.1824728. [DOI] [PubMed] [Google Scholar]
  30. Umans J. G., Inturrisi C. E. Pharmacodynamics of subcutaneously administered diacetylmorphine, 6-acetylmorphine and morphine in mice. J Pharmacol Exp Ther. 1981 Aug;218(2):409–415. [PubMed] [Google Scholar]
  31. Watkins L. R., Kinscheck I. B., Mayer D. J. Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide. Science. 1984 Apr 27;224(4647):395–396. doi: 10.1126/science.6546809. [DOI] [PubMed] [Google Scholar]
  32. Xie Q. W., Cho H. J., Calaycay J., Mumford R. A., Swiderek K. M., Lee T. D., Ding A., Troso T., Nathan C. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science. 1992 Apr 10;256(5054):225–228. doi: 10.1126/science.1373522. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES