Abstract
The role of the supraspinal nitric oxide (NO)/cyclic GMP system in the development of acute morphine antinociceptive tolerance was investigated by use of the mouse 55°C warm-water tail-flick test. A single intracerebroventricular (i.c.v.) pretreatment of mice with morphine (3 nmol, 140 min before testing) produced an acute antinociceptive tolerance to subsequent i.c.v. doses of morphine, as demonstrated by a 120-fold rightward shift of the morphine dose-response curve. When co-administered with morphine (140 min before testing), the NO synthase inhibitors: N-nitro-l-arginine methyl ester (l-NAME), 3-bromo-7-nitroindazole, 7-nitroindazole and NG-monomethyl-l-arginine, attenuated the development of morphine tolerance. All four NO synthase inhibitors completely blocked the rightward shift of the morphine dose-response curve caused by i.c.v. morphine pretreatment (3 nmol, 140 min before testing). This effect was partially antagonized byl-arginine, but not d-arginine, in a dose-dependent manner. Also, d-NAME did not block the development of tolerance. Like the NO synthase inhibitors, LY-83,583, a guanylyl cyclase inhibitor, blocked the development of tolerance, which suggests that NO acting through the cyclic GMP pathway is involved in the development of acute antinociceptive tolerance. The effects of increased NO production on acute morphine antinociceptive tolerance were also studied. When co-administered with morphine (140 min before testing), neither l-arginine (100 nmol) nor the NO donors, sodium nitroprusside (5 nmol) and isosorbide dinitrate (10 nmol), had any effect on the magnitude of morphine antinociceptive tolerance. These results suggest that NO, acting through the cyclic GMP pathway, mediates the development of acute antinociceptive tolerance, but that NO production does not alter the magnitude of antinociceptive tolerance.
Footnotes
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Send reprint requests to: Dr. Jean M. Bidlack, Department of Pharmacology and Physiology, P.O. Box 711, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642-8711.
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↵1 This work was supported by U.S. Public Health Service grants DA03742 and DA07232 from the National Institute on Drug Abuse.
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↵2 Animals used in these studies were maintained in accordance with the University Committee on Animal Resources, University of Rochester, and guidelines of the Committee on the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council (Department of Health, Education and Welfare, Publication No. (NIH)-23, revised 1983).
- Abbreviations:
- NO
- nitric oxide
- NOS
- nitric oxide synthase
- l-NAME
- N-nitro-l-arginine methyl ester
- l-NOARG
- N-nitro-l-arginine
- d-NAME
- N-nitro-d-arginine methyl ester
- l-NMMA
- NG-monomethyl-l-arginine
- LY-83
- 583, 6-(phenylamine)-5,6-quinolinedione, 6-anillno-5,8-quinolinedione
- NMDA
- N-methyl-d-aspartate
- SNP
- sodium nitroprusside
- ISDN
- isosorbide dinitrate
- DAMGO
- [d-Ala2,(Me)Phe4,Gly(ol)5]enkephalin
- i.c.v.
- intracerebroventricular(ly)
- i.t.
- intrathecal(ly)
- i.p.
- intraperitoneal(ly)
- s.c.
- subcutaneous
- Received January 21, 1997.
- Accepted September 8, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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