THE NITRIC-OXIDE CYCLIC-GMP SYSTEM AT THE SUPRASPINAL SITE IS INVOLVED IN THE DEVELOPMENT OF ACUTE MORPHINE ANTINOCICEPTIVE TOLERANCE

The role of the supraspinal nitric oxide (NO)/cyclic GMP system in the development of acute morphine antinociceptive tolerance was investiga ted by use of the mouse 55 degrees C warm-water tail-flick test. A sin gle intracerebroventricular (i.c.v.) pretreatment of mice with morphin e (3 nmol, 140 min before testing) produced an acute antinociceptive t olerance to subsequent i.c.v. doses of morphine, as demonstrated by a 120-fold rightward shift of the morphine close-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-nitroi ndazole, 7-nitroindazole and N-G-monomethyl-L-arginine, attenuated the development of morphine tolerance. All four NO synthase inhibitors co mpletely blocked the rightward shift of the morphine dose-response cur ve caused by i.c.v. morphine pretreatment (3 nmol, 140 min before test ing). This effect was partially antagonized by L-arginine, but not D-a rginine, in a dose-dependent manner. Also, D-NAME did not block the de velopment of tolerance. Like the NO synthase inhibitors, LY-83,583, a guanylyl cyclase inhibitor, blocked the development of tolerance, whic h suggests that NO acting through the cyclic GMP pathway is involved i n the development of acute antinociceptive tolerance. The effects of i ncreased NO production on acute morphine antinociceptive tolerance wer e also studied. When co-administered with morphine (140 min before tes ting), neither L-arginine (100 nmol) nor the NO donors, sodium nitropr usside (5 nmol) and isosorbide dinitrate (10 nmol), had any effect on the magnitude of morphine antinociceptive tolerance. These results sug gest that NO, acting through the cyclic GMP pathway, mediates the deve lopment of acute antinociceptive tolerance, but that NO production doe s not alter the magnitude of antinociceptive tolerance.