title: Implication of spinal protein kinase C in the suppression of morphine-induced rewarding effect under a neuropathic pain-like state in mice.
abstract: We previously demonstrated that spinal protein kinase C (PKC) is involved in the development of a neuropathic pain-like state induced by sciatic nerve ligation, and the morphine-induced rewarding effect is attenuated by sciatic nerve ligation in rodents. Here we first investigated whether sciatic nerve injury could change the activity of a conventional PKC (cPKC) and an atypical PKC isoform PKCzeta in the mouse spinal cord. The second experiment was to investigate whether direct inhibition of spinal PKC by intrathecal (i.t.) administration of a specific PKC inhibitor, 2-[8-[(dimethylamino)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl]-3-(1-methyl-1H-indole-3-yl)maleimide (RO-32-0432), could affect the rewarding effect induced by morphine following sciatic nerve ligation in mice. We found here that the activities of both cPKC and PKCzeta in the spinal cord were clearly increased following sciatic nerve ligation. Furthermore, i.t. administration of RO-32-0432 reversed a long-lasting pain-like syndrome as indicated by thermal hyperalgesia following sciatic nerve ligation in mice. These data provide direct evidence that activated cPKC and PKCzeta in the spinal cord may contribute to the development and maintenance of neuropathic pain. In the present study, we confirmed that the morphine-induced place preference was significantly suppressed by sciatic nerve ligation. It should be mentioned that i.t. pretreatment with RO-32-0432 significantly reversed the attenuation of morphine-induced rewarding effect following sciatic nerve ligation. These results suggest that activation of PKCs, including cPKC and PKCzeta, within the spinal cord is directly responsible for the attenuation of the morphine-induced rewarding effect under a neuropathic pain-like state following sciatic nerve ligation in mice.
authors.affiliation: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. narita@hoshi.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Narita
authors.forename: K
authors.initials: K
authors.lastname: Oe
authors.forename: H
authors.initials: H
authors.lastname: Kato
authors.forename: M
authors.initials: M
authors.lastname: Shibasaki
authors.forename: M
authors.initials: M
authors.lastname: Narita
authors.forename: Y
authors.initials: Y
authors.lastname: Yajima
authors.forename: M
authors.initials: M
authors.lastname: Yamazaki
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008026:Ligation; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000201:enzymology* / Q000503:physiopathology; D009437:Neuralgia / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D012201:Reward; D020426:Sciatic Neuropathy / Q000201:enzymology* / Q000503:physiopathology; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D000099221:Protein Kinase C zeta
chemical_list: D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D007211:Indoles; D009020:Morphine; D011493:Protein Kinase C; D011758:Pyrroles; D000099221:Protein Kinase C zeta; C085989:Ro 32-0432