Role of the phosphatidylinositol-specific phospholipase C pathway in δ-opioid receptor-mediated antinociception in the mouse spinal cord

Stimulation of δ-opioid receptors has been shown to activate phospholipase C via the activation of G-proteins in vitro. The present study was designed to determine, with the tail-flick method, whether the stimulatory effect of δ-opioid receptor agonists on phospholipase C and inositol lipid turnover participates in the mechanisms of the δ-opioid receptor-mediated antinociception in the mouse spinal cord. Intrathecal pretreatment with the phospholipase C inhibitors neomycin and U73122, which produced no changes in the basal tail-flick latencies when they were injected alone, significantly attenuated the antinociception induced by intrathecal administration of the selective δ-opioid receptor agonist [ d-Ala 2]deltorphin II in mice. The selective phosphatidylinositol-specific phospholipase C inhibitor ET-18-OCH 3 inhibited the antinociception induced by intrathecal administration of [ d-Ala 2]deltorphin II in a dose-dependent manner. In mice undergoing treatment with LiCl, which impairs phosphatidylinositol synthesis, the antinociception induced by intrathecal administration of [ d-Ala 2]deltorphin II was significantly reduced. Co-administration of d-myo-inositol-1,4,5-trisphosphate restored the [ d-Ala 2]deltorphin II-induced antinociception in LiCl-pretreated mice. On the other hand, intrathecal pretreatment with the selective protein kinase C inhibitor calphostin C, but not the protein kinase A inhibitor KT5720, resulted in a dose-dependent enhancement of the [ d-Ala 2]deltorphin II-induced antinociception. These results indicate a potential role for the phospholipase C–inositol-1,4,5-trisphosphate pathway in the expression of δ-opioid receptor-mediated antinociception in the mouse spinal cord. Furthermore, activation of protein kinase C by the stimulation of δ-opioid receptors may constitute a significant pathway involved in negative modulation of spinal δ-opioid receptor-mediated antinociception.