Effects of mGlu1 and mGlu5 metabotropic glutamate antagonists to reverse morphine tolerance in mice.
Effects of mGlu1 and mGlu5 metabotropic glutamate antagonists to reverse morphine tolerance in mice.
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DOI：
10.1016/j.ejphar.2004.03.055
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发表时间：
2004-05
影响因子：
5
通讯作者：
F. Smith;P. Smith;W. Dewey;Ruby R Javed
中科院分区：
文献类型：
--
作者：
F. Smith;P. Smith;W. Dewey;Ruby R Javed
Intracerebroventricular (i.c.v.) injection of phospholipase C inhibitors and structurally dissimilar PKC inhibitors were shown to completely reverse morphine antinociceptive tolerance in mice. Since Group I metabotropic glutamate receptors (mGlu1and mGlu5) activate phospholipase C through GαqGα11proteins, we hypothesized that morphine tolerance could occur through an increase in mGlu1and mGlu5receptor stimulation. Seventy-two hours after implantation of placebo or 75 mg morphine pellets, mice were tested in the 56 °C warm-water tail-withdrawal test following i.c.v. injection of vehicle or test drug. The mGlu1receptor antagonist CPCCOEt (7-(Hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester) partly but significantly reversed morphine tolerance. The mGlu5receptor antagonist MPEP (2-Methyl-6-(phenylethynyl)pyridine hydrochloride) also partly reversed the antinociceptive tolerance. Co-administering CPCCOEt with MPEP completely reversed the tolerance. Furthermore, the mixed mGlu1/mGlu5antagonist AIDA ((RS)-1-Aminoindan-1,5-dicarboxylic acid) also completely reversed the tolerance. Thus, greater mGlu1and mGlu5receptor stimulation during morphine tolerance may lead to persistent activation of the phosphatidylinositol cascade.
