1993 Fiscal Year Final Research Report Summary
Inhibition of the development of morphine tolerance
| Project/Area Number |
04671223
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
外科・放射線系歯学
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| Research Institution | Osaka University |
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Principal Investigator |
MATSUMOTO Ken Dentistry, OMFS II, Lecturer, 歯学部付属病院, 講師 (20127301)
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| Co-Investigator(Kenkyū-buntansha) |
JOHTOKU Yoshiyuki Dentistry, OMFS II, Resident, 歯学部付属病院, 医員
OHNISHI Tetsuo Dentistry, OMFS II, Resident, 歯学部付属病院, 医員
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| Project Period (FY) |
1992 – 1993
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| Keywords | Morphine / Tolerance / Cross-tolerance / Calcium / Calcium channel |
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| Research Abstract |
1. In acetic acid-induced writhing test, intraperitoneal administration of clonidine exhibited the analgesic effect in a does dependent manner. The decrease in morphine-induced analgesia was also observed following prolonged administration of clonidine. Furthermore, intracerebroventricular administrations of omega-conotoxin, a selective N-type calcium channel antagonist, have exhibited the analgesic effect and these action were mimicked in morphine chronic administered mice.
2. Significant decrease in ^3H-PN-200-110 binding to cortical membrane fraction was observed in clonidine-tolerant mice whereas increase in morphine-tolerant mice. In contrast, significant increase of ^<125>I-omega-conotoxin bindings were observed in clonidine- or morphine-tolerant group. These results suggested that cross-tolerance may develop between clonidine and morphine through the change in L or N-type calcium channels.
3. In the measurement of intracellular concentration of Ca^<2+> ([Ca_<2+>]i) in human neuroblastoma SH-SY5Y cells, morphine or clonidine inhibited carbachol-induced calcium influx dose-dependent manner and these actions were inhibited by naloxone or yohimbine, respectively.
4. In photoaffinity labelling and SDS-PAGE experiments, specific accumulation (220-300 KDa) of ^<125>I-omega-conotoxin were observed in mice cortical membrane fractions. Significant increase of these accumulation were also observed in membrane fractions obtained from mice following chronic administration with morphine or clonidine.
Above results suggest N-type calcium channels may have a possible role in the formation of morphine tolerance and cross-tolerance between morphine and clonidine.
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