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 development of tolerance to opioid drugs and for suppressing opioid withdrawal. Neurons in the locus coeruleus (LC) express opioid receptors and these neurons exhibit both tolerance to chronic administration of opioids 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 administered while recording single-cell extracellular activity in brain slices from rats who had been concurrently treated for 5 days with morphine (75 mg morphine sulfate base pellets) and L-NArg (10 mg/kg, i.p., bid). The average ED50 for morphine of cells from rats who received L-NArg injections and morphine pellets was similar to that in cells from rats who had been implanted with sham pellets (14.5-18 nM). In contrast, the average ED50 of cells from morphine pelleted animals who received saline injections was substantially higher (34.5 nM). These results demonstrate that L-NArg attenuates the development of tolerance to morphine in LC neurons.