| 18846040 |
Nazarian A, Christianson CA, Hua XY, Yaksh TL: Dexmedetomidine and ST-91 analgesia in the formalin model is mediated by alpha2A-adrenoceptors: a mechanism of action distinct from morphine. Br J Pharmacol. 2008 Dec;155(7):1117-26. Epub 2008 Sep 1.
BACKGROUND AND PURPOSE: Intrathecal administration of alpha (2)-adrenoceptor agonists produces potent analgesia. This study addressed the subtype of spinal alpha (2)-adrenoceptor responsible for the analgesic effects of i.t. dexmedetomidine and ST-91 in the formalin behavioural model and their effects on primary afferent substance P (SP) release and spinal Fos activation. EXPERIMENTAL APPROACH: The analgesic effects of i.t. dexmedetomidine and ST-91 (alpha (2) agonists) were tested on the formalin behavioural model. To determine the subtype of alpha (2)-adrenoceptor involved in the analgesia, i.t. BRL44408 (alpha (2A) antagonist) or ARC239 (alpha (2B/C) antagonist) were given before dexmedetomidine or ST-91. Moreover, the ability of dexmedetomidine and ST-91 to inhibit formalin-induced release of SP from primary afferent terminals was measured by the internalization of neurokinin (1) (NK (1)) receptors. Finally, the effects of dexmedetomidine on formalin-induced Fos expression were assessed in the dorsal horn. KEY RESULTS: Intrathecal administration of dexmedetomidine or ST-91 dose-dependently reduced the formalin-induced paw-flinching behaviour in rats. BRL44408 dose-dependently blocked, whereas ARC239 had no effect on the analgesic actions of dexmedetomidine and ST-91. Dexmedetomidine and ST-91 had no effect on the formalin-induced NK (1) receptor internalization, while morphine significantly reduced the NK (1) receptor internalization. On the other hand, both dexmedetomidine and morphine diminished the formalin-induced Fos activation. The effect of dexmedetomidine on formalin-induced Fos activation was reversed by BRL44408, but not ARC239. CONCLUSION AND IMPLICATIONS: These findings suggest that alpha (2A)-adrenoceptors mediate dexmedetomidine and ST-91 analgesia. This effect could be through a mechanism postsynaptic to primary afferent terminals, distinct from that of morphine. |
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