title: PKC and PKA inhibitors reverse tolerance to morphine-induced hypothermia and supraspinal analgesia in mice.
abstract: Morphine antinociceptive tolerance in the tail-flick test is completely reversed by inhibitors of protein kinase C (PKC) or cAMP-dependent protein kinase (PKA). The effects of these inhibitors on tolerance to supraspinally mediated antinociception, such as the hot-plate test was unknown, as well as their effects in tests of mechanical nociception. The PKC inhibitors bisinolylmaleimide I ((2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide) and Gö-7874 [2[1[(3-Dimethylaminopropyl)-5-methozyindol-3-yl]-3-(1H-indol-3-yl) hydrochloride] completely reversed the tolerance to morphine in both the hot-plate and tail-pinch tests. Similarly, the PKA inhibitor KT-5720 (8R, 9S, 11S)-(-)-9-hydroxy-9-hexoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[cde]trinden-1-one also reversed tolerance in both tests. The role of PKC and PKA in mediating tolerance to morphine-induced hypothermia was also investigated. Bisinolylmaleimide I, Gö-7874 and KT-5720 only partly reversed the 32-fold level of tolerance induced by the morphine pellets. However, co-administration of bisinolylmaleimide I with KT-5720 or Gö-7874 with KT-5720 completely reversed the tolerance. This demonstrates that tolerance in a non-behavioral system involves the actions of PKC and PKA.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, P.O. Box 980613, Richmond, VA 23298-0613, USA.
authors.forename: Ruby R
authors.initials: RR
authors.lastname: Javed
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
authors.forename: Paul A
authors.initials: PA
authors.lastname: Smith
authors.forename: Forrest L
authors.initials: FL
authors.lastname: Smith
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D007036:Hypothermia, Induced; D007211:Indoles / Q000494:pharmacology; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D010147:Pain Measurement; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology; D013623:Tail
chemical_list: C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D000701:Analgesics, Opioid; D002227:Carbazoles; D007211:Indoles; D008301:Maleimides; D011758:Pyrroles; C057416:KT 5720; D009020:Morphine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C070515:bisindolylmaleimide I