The present study was undertaken to investigate pharmacological actions induced by morphine and oxycodone under a neuropathic pain-like state. In the m-opioid receptor (MOR) binding study and G-protein activation, we confirmed that both morphine and oxycodone showed MOR agonistic activities. Mice with sciatic nerve ligation exhibited the marked neuropathic pain-like behavior. Under these conditions, antinociception induced by subcutaneously (s.c.) injected morphine was significantly decreased by sciatic nerve ligation, whereas s.c. injection of oxycodone produced a profound antinociception in sciatic nerve-ligated mice. There were no significant differences in spinal or supraspinal antinociception of morphine and oxycodone between sham operation and nerve ligation. Moreover, either morphine-or oxycodone-induced increase in guanosine-5 0 -o-(3-thio) triphosphate ([ 35 S]GTPgS) binding in the spinal cord, periaqueductal gray matter and thalamus in sciatic nerve-ligated mice was similar to that in sham-operated mice. Antinociception induced by s.c., intrathecal, or intracerebroventricular injection of the morphine metabolite morphine-6-glucuronide (M-6-G) was significantly decreased by sciatic nerve ligation. Furthermore, the increase in the G-protein activation induced by M-6-G was eliminated in sciatic nerve ligation. In addition, either morphine-or oxycodone-induced rewarding effect was dramatically suppressed under a neuropathic pain-like state. The increased [ 35 S]GTPgS binding by morphine or oxycodone was significantly lower in the lower midbrain of mice with sciatic nerve ligation compared with that in control mice. These findings provide further evidence that oxycodone shows a profound antinociceptive effect under a neuropathic pain-like state with less of a rewarding effect. Furthermore, the reduction in G-protein activation induced by M-6-G may, at least in part, contribute to the suppression of the antinociceptive effect produced by morphine under a neuropathic pain-like state.

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