Dexmedetomidine and ST-91 analgesia in the formalin model is mediated by alpha2A-adrenoceptors: a mechanism of action distinct from morphine

Background and purpose:

Intrathecal administration of α₂-adrenoceptor agonists produces potent analgesia. This study addressed the subtype of spinal α₂-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 (α₂ agonists) were tested on the formalin behavioural model. To determine the subtype of α₂-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 neurokinin₁ (NK₁) 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 NK₁ receptor internalization, while morphine significantly reduced the NK₁ 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.