Experimental mononeuropathy reduces the antinociceptive effects of morphine: implications for common intracellular mechanisms involved in morphine tolerance and neuropathic pain

Abstract

Recent evidence suggests that hyperalgesia and morphine tolerance, two seemingly unrelated phenomena, have in common certain neural substrates 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 and morphine tolerance, these cellular and intracellular commonalities might be expected to result in interactions between these two phenomena. Indeed, our previous studies have shown that thermal hyperalgesia develops when animals are made tolerant to the antinociceptive effects of morphine. In this study, we examined the hypothesis that reduction of morphine antinociception occurs following unilateral ligation of the rats's sciatic nerve, a procedure which produces symptoms of a neuropathic pain syndrome including thermal hyperalgesia. When tested using the paw-withdrawal test on day 8 (D8) after either nerve ligation or sham operation, a single intrathecal treatment with 10 micrograms morphine sulfate (30 min after administration) produced significant antinociception in sham-operated rats but not in nerve-injured ones. These results also were obtained when thermal hyperalgesia was reversed in nerve-injured rats by the non-competitive NMDA receptor antagonist MK-801. Consistently, 8 days after sciatic nerve ligation but not after a sham operation, an approximately 6-fold rightward shift occurred in the morphine antinociceptive dose-response curve. This rightward shift of the morphine antinociceptive dose-response curve did not occur at 24 h after either nerve ligation or sham operation. In addition, once daily treatment with 10 nmol MK-801 from D2 to D7 after nerve ligation prevented both the development of thermal hyperalgesia and the rightward shift of the morphine antinociceptive dose-response curve on D8. The results indicate that the antinociceptive effects of morphine are reduced in nerve-injured rats in the absence of daily exposure to morphine and that the NMDA receptor activation may have a critical role in mechanisms of this phenomenon. These data provide further evidence indicating that interactions do occur between neural mechanisms underlying thermal hyperalgesia and morphine tolerance.

Altered antinociceptive efficacy of tramadol over time in rats with painful peripheral neuropathy

“…First, the metabolite has higher affinity for the μ-opioid receptor and tramadol may not have been metabolized in sufficient quantities in the intrathecal space. Second, intrathecally injected opiates tend to show decreased efficacy in rats with neuropathic pain such that the doseresponse curve of intrathecal morphine is significantly shifted to the right in CCI rats (Granados-Soto and Arguelles, 2005;Mao et al, 1995). Alternatively, the lack of antinociception following intrathecal injection of tramadol in the current study suggests the possibility that the spinal dorsal horn has a negligible role in antinociceptive effects of tramadol.…”

Blockade and reversal of spinal morphine tolerance by peptide and non‐peptide calcitonin gene‐related peptide receptor antagonists

“…Recent studies have demonstrated that in models of in¯ammation, hyperalgesia and nerve injury, animals not previously exposed to opioids exhibit a reduced response to these agents (Dickenson & Sullivan, 1986;Xu & WiesenfeldHallin, 1991;Mao et al, 1995a), an eect that is also seen in patients suering from neuropathic pain. Moreover, the excitatory amino acid receptor-based neuronal adaptations that contribute to these pain states have also been implicated in tolerance (Mao et al, 1995b).…”

Peripheral cannabinoids attenuate carcinoma-induced nociception in mice

“…[25,26,33] Cannabinoids are analgesic in patients with neuropathic pain [12,13,20,24,34] and show promise in cancer pain. [32] Cannabinoids activate two receptors types: cannabinoid receptor 1 and 2 (CBr1 and CBr2, respectively).…”