EXPERIMENTAL MONONEUROPATHY REDUCES THE ANTINOCICEPTIVE EFFECTS OF MORPHINE - IMPLICATIONS FOR COMMON INTRACELLULAR MECHANISMS INVOLVED IN MORPHINE-TOLERANCE AND NEUROPATHIC PAIN

Recent evidence suggests that hyperalgesia and morphine tolerance, two seemingly unrelated phenomena, have in common certain neural substrat es such as activation of the N-methyl-D-aspartate (NMDA) receptor and the subsequent intracellular activation of protein kinase C and nitric oxide. Should common cellular elements be involved in hyperalgesia an d morphine tolerance, these cellular and intracellular commonalities m ight be expected to result in interactions between these two phenomena . Indeed, our previous studies have shown that thermal hyperalgesia de velops when animals are made tolerant to the antinociceptive effects o f morphine. In this study, we examined the hypothesis that reduction o f morphine antinociception occurs following unilateral ligation of the rats's sciatic nerve, a procedure which produces symptoms of a neurop athic pain syndrome including thermal hyperalgesia. When tested using the paw-withdrawal test on day 8 (D-8) after either nerve ligation or sham operation, a single intrathecal treatment with 10 mu g morphine s ulfate (30 min after administration) produced significant antinocicept ion in sham-operated rats but not in nerve-injured ones. These results also were obtained when thermal hyperalgesia was reversed in nerve-in jured rats by the non-competitive NMDA receptor antagonist MK-801. Con sistently, 8 days after sciatic nerve ligation but not after a sham op eration, an approximately 6-fold rightward shift occurred in the morph ine antinociceptive dose-response curve. This rightward shift of the m orphine antinociceptive dose-response curve did not occur at 24 h afte r either nerve ligation or sham operation. In addition, once daily tre atment with 10 nmol MK-801 from D-2 to D-7 after nerve ligation preven ted both the development of thermal hyperalgesia and the rightward shi ft of the morphine antinociceptive dose-response curve on D-8. The res ults indicate that the antinociceptive effects of morphine are reduced in nerve-injured rats in the absence of daily exposure to morphine an d that the NMDA receptor activation may have a critical role in mechan isms of this phenomenon. These data provide further evidence indicatin g that interactions do occur between neural mechanisms underlying ther mal hyperalgesia and morphine tolerance.