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Introduction: Uncoupling protein 2 (UCP2) in the inner mitochondrial membrane changes the activity of KATP channels and the cell excitability, probably by decreasing the ATP production. Given the expression of UCP2 in primary afferent neurons, and the importance of these channels in morphine-induced analgesia, genipin, an UCP2 inhibitor, may affect these processes, when administrated intrathecally. Methods: Tail flick assay and formalin test were used to study thermal and chemical pain, respectively, in adult male Wistar rats. Catheterization of the spinal subarachnoid space was used to localize the effects of genipin. Results: Genipin increased pain sensation in tail flick assay and in the first phase of the formalin test, but decreased pain in the second phase of the formalin test (P<0.001 in all groups). Genipin also antagonized analgesic effect of morphine (P<0.01 in tail flick and P<0.001 in the first phase of the formalin test) and did potentiate it in the second phase of the formalin test (P<0.001) but had no effect on hyperalgesic effects of ultra-low dose of morphine. Conclusion: Probably, genipin increases ATP/ADP ratio, thereby inhibits KATP channels in primary pain afferents and lowers pain threshold and decreases analgesic effects of morphine, at least in part, by inhibition of UCP2. Apparently, the anti-inflammatory effect of genipin causes analgesia in the formalin test. Genipin had no effect on hyperalgesic effects of ultra-low dose of morphine, maybe due to the common signaling mechanisms such as KATP channels.

Keywords: UCP2, Genipin, KATP channel, Morphine.

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