Low-dose morphine induces hyperalgesia through activation of Gαs, protein kinase C, and L-type Ca2+ channels in rats

Opioids can induce analgesia and also hyperalgesia in humans and in animals. It has been shown that systemic administration of morphine induced a hyperalgesic response at an extremely low dose. However, the exact mechanism(s) underlying opioid-induced hyperalgesia has not yet been clarified. Here, we have investigated cellular events involved in low-dose morphine hyperalgesia in male Wistar rats. The data showed that morphine (0.01 mu g i.t.) could elicit hyperalgesia as assessed by the tail-flick test. G(alpha s) mRNA and protein levels increased significantly following exposure to the hyperalgesic dose of morphine. Furthermore, morphine at an analgesic dose (20 mu g i.t.) significantly decreased cAMP levels in the dorsal half of the lumbar spinal cord, whereas the tissue cAMP levels were not affected by morphine treatment at a hyperalgesic dose. Intrathecal administration of nifedipine, an L-type calcium channel blocker, antagonized the hyperalgesia induced by the low-dose of morphine. Furthermore, pretreatment with the selective protein kinase C (PKC) inhibitor chelerytrine resulted in prevention of the morphine-induced hyperalgesia. KT 5720, a specific inhibitor of protein kinase A (PKA), did not show any effect on low-dose morphine-induced hyperalgesia. These results indicate a role for G(alpha s), the PLC-PKC pathway, and L-type calcium channels in intrathecal morphine-induced hyperalgesia in rats. Activation of ordinary G(alpha s) signaling through cAMP levels did not appear to play a major role in the induction of hyperalgesia by low-dose of morphine. (c) 2007 Wiley-Liss, Inc.