title: Inhibition of morphine tolerance by processed Aconiti tuber is mediated by kappa-opioid receptors.
abstract: Previously, we found that processed Aconiti tuber (PAT) could inhibit morphine tolerance in mice. In the present study, we investigated mechanisms underlying this effect. Mice received subcutaneous (s.c.) morphine (10 mg/kg) and oral PAT at a subanalgesic dose (0.3 g/kg), once a day for 12 days. Additional PAT-treated groups received morphine and PAT, at 120 min after pretreatment with s.c. clocinnamox mesylate (C-CAM) (0.5 mg/kg), or nor-binaltorphimine (nor-BNI) (5 mg/kg). The antinociceptive effect was assessed with the tail pressure test, at 60 min after the daily s.c. morphine injections were given. In the placebo-treated group, repeated morphine injections caused morphine tolerance, and morphine antinociception was abolished by day 6, whereas in PAT-treated groups, significant antinociception was maintained until day 12, suggesting that PAT inhibited morphine tolerance, thereby sustaining morphine antinociception. C-CAM, a selective mu-opioid receptor (MOR) antagonist, blocked morphine antinociception whereas nor-BNI, a selective kappa-opioid receptor (KOR) antagonist, did not. However, both C-CAM and nor-BNI could block the antinociception maintained by the morphine-PAT combination. Results of the study suggested that chronic treatment with PAT at a subanalgesic dose maintained MOR-mediated morphine antinociception by attenuating development of morphine tolerance, and that this tolerance-attenuating effect of PAT was mediated by KOR.
authors.affiliation: Department of Anesthesiology, Graduate School of Medicine, Surgical Center Research Hospital, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Haihua
authors.initials: H
authors.lastname: Shu
authors.forename: Hideko
authors.initials: H
authors.lastname: Arita
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hayashida
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Chiba
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sekiyama
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hanaoka
mesh_terms: D031841:Aconitum; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002934:Cinnamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D035281:Plant Tubers; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D002934:Cinnamates; D004365:Drugs, Chinese Herbal; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; C076806:clocinnamox; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; D009020:Morphine