Role of the phosphatidylinositol-specific phospholipase C pathway in delta-opioid receptor-mediated antinociception in the mouse spinal cord.
Stimulation of delta-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 delta-opioid receptor agonists on phospholipase C and inositol lipid turnover participates in the mechanisms of the delta-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 delta-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 delta-opioid receptor-mediated antinociception in the mouse spinal cord. Furthermore, activation of protein kinase C by the stimulation of delta-opioid receptors may constitute a significant pathway involved in negative modulation of spinal delta-opioid receptor-mediated antinociception.
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee 53226, USA.
M
M
Narita
M
M
Ohsawa
H
H
Mizoguchi
T
T
Aoki
T
T
Suzuki
L F
LF
Tseng
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002227:Carbazoles; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004963:Estrenes / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009281:Naphthalenes / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D010716:Phosphatidylinositols / Q000037:antagonists & inhibitors / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000502:physiology*
D000700:Analgesics; D002227:Carbazoles; D004963:Estrenes; D007211:Indoles; D009281:Naphthalenes; D009842:Oligopeptides; D010716:Phosphatidylinositols; D011758:Pyrroles; D011760:Pyrrolidinones; D017465:Receptors, Opioid, delta; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C060209:deltorphin II, Ala(2)-; C057416:KT 5720; D015544:Inositol 1,4,5-Trisphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010738:Type C Phospholipases; C058819:calphostin C