Dexmedetomidine and ST‐91 analgesia in the formalin model is mediated by α 2A ‐adrenoceptors: a mechanism of action distinct from morphine

• Published in: British journal of pharmacology Vol. 155; no. 7; pp. 1117 - 1126
• Main Authors: Nazarian, A, Christianson, C A, Hua, X‐Y, Yaksh, T L
• Format: Journal Article
• Language: English
• Published: 29.01.2009
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.341

Background and purpose: Intrathecal administration of α 2 ‐adrenoceptor agonists produces potent analgesia. This study addressed the subtype of spinal α 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 (α 2 agonists) were tested on the formalin behavioural model. To determine the subtype of α 2 ‐adrenoceptor involved in the analgesia, i.t. BRL44408 (α 2A antagonist) or ARC239 (α 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 α 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. British Journal of Pharmacology (2008) 155 , 1117–1126; doi: 10.1038/bjp.2008.341 ; published online 1 September 2008