TY - JOUR T1 - The Nitric Oxide/Cyclic GMP System at the Supraspinal Site Is Involved in the Development of Acute Morphine Antinociceptive Tolerance <sup>,</sup> JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 196 LP - 201 VL - 284 IS - 1 AU - Jimmy Y. Xu AU - Kevin P. Hill AU - Jean M. Bidlack Y1 - 1998/01/01 UR - http://jpet.aspetjournals.org/content/284/1/196.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -