Development of new analgesic agents targeted the neural Ca channels.

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To investigate the neural types of the voltage-dependent Ca channels as a target molecule for analgesia, effects of various Ca channel blockers were observed on the mechanical, thermal and chemical (bradykinin & ATP) stimuli by means of conventional behavior pharmacological methods. Both N-and P/Q-type blockers significantly suppressed the nociceptive responses induced by above stimuli. Ca channel blockers produced different responses against the algesic responses by two chemical stimuli (bradykinin & ATP), suggesting stimulus-specific utilization of the Ca channels. Furthermore, Ca channel blockers enhanced the morphine-induced analgesic responses, with subthreshold concentrations. Streptozotocin and vincristine induced hyperalgesia for mechanical nociception, but both chemicals did not induce hyperalgesia on thermal stimulation. Hyperalgesia (lowering the nociceptive threshold) induced by streptozotocin and vinceistine was suppressed by P/Q-and N-type Ca channel blocker, respectively, but not by morphine. On the other hand, antinociceptive effects of L-type Ca channel blocker was weaker than either N-or P/Q-type blockers, indicating minor contribution of the L-type Ca channel on the spinal nociceptive transmission. These results suggest that (1) stimulus-specific nerve pathway is present in the dorsal horn, which recruit specific Ca channels for transmission, (2) inhibition of this pathway cooperatively suppressed the nociceptive responses with the morphine-mediated pathway, and (3) N-and P/Q-type Ca channel blockers are effective to the morphine-resistant hyperalgesia. Our results indicate that neural type of the voltage-dependent Ca channels is a new target for analgesia against the neuropathic pain.