NG-NITRO-L-ARGININE, AN NOS INHIBITOR, REDUCES TOLERANCE TO MORPHINE IN THE RAT LOCUS-COERULEUS

Ng-nitro-L-arginine (L-NArg), a potent nitric oxide synthase inhibitor , has been implicated as a potential mechanism for attenuating the dev elopment of tolerance to opioid drugs and for suppressing opioid withd rawal. Neurons in the locus coeruleus (LC) express opioid receptors an d these neurons exhibit both tolerance to chronic administration of op ioids and antagonist-precipitated withdrawal hyperactivity. This study tested the hypothesis that L-NArg would attenuate the development of opioid tolerance in LC neurons. Challenge doses of morphine were admin istered while recording single-cell extracellular activity in brain sl ices from rats who had been concurrently treated for 5 days with morph ine (75 mg morphine sulfate base pellets) and L-NArg (10 mg/kg, ip, bi d). The average ED50 for morphine of cells from rats who received L-NA rg injections and morphine pellets was similar to that in cells from r ats who had been implanted with sham pellets (14.5-18 nM). In contrast , the average ED50 Of cells from morphine pelleted animals who receive d saline injections was substantially higher (34.5 nM). These results demonstrate that L-NArg attenuates the development of tolerance to mor phine in LC neurons. (C) 1998 Wiley-Liss, Inc.