NITRIC-OXIDE AND OPIOID TOLERANCE

Under conditions in which N-G-nitro-L-arginine (NOArg) treatment preve nts morphine tolerance, NOArg induces a slow progressive inhibition of nitric oxide synthase (NOS), starting at approx. 20% after a single t reatment and increasing to approx. 65% after 10 days. Studies designed to examine potential changes in NOS levels with chronic morphine admi nistration reveal no change. Total NOS activity in both brainstem and cerebellum homogenates is unchanged, as are levels of NOS mRNA in a va riety of brain regions. L-Arginine, the precursor of nitric oxide (NO) , accelerates tolerance when coadministered with morphine and when giv en alone L-arginine decreases morphine's potency. Administration of L- arginine alone for 3-10 days shifts morphine's dose-response curve ove r 2-fold to the right while D-arginine is without effect, as is daily administration of L-arginine along with the NOS inhibitor NOArg. Thus, chronic L-arginine induces ''tolerance'' in opioid naive mice through NOS. Together, our data indicate an important role for NO in the modu lation of opioid analgesia.