??2A Adrenoceptors Contribute to Feedback Inhibition of Capsaicin-induced Hyperalgesia:

Background: Studies on receptor knockout mice have so far shown that of the three alpha(2)-adrenoceptor subtypes, the alpha(2A) adrenoceptor has a major role in mediating the powerful central analgesia induced by synthetic alpha(2)-adrenoceptor agonists. However, because a knockout of the gene for the alpha(2A) adrenoceptor has produced only little if any change in the pain sensitivity of control, nerve-injured, or inflamed animals, it has not been clear whether activation of alpha(2A)-adrenoceptors by endogenous ligands has a significant pain regulatory role. Methods: The authors assessed spontaneous pain behavior and mechanical hypersensitivity induced by administration of capsaicin in the colon or paw of alpha(2A)-adrenoceptor knockout mice versus their wild-type controls. Results: Enhanced pain hypersensitivity was observed in alpha(2A)-adrenoceptor knockout mice 20 min or more after administration of capsaicin, but before, hypersensitivity and spontaneous pain were of equal magnitude in alpha(2A)-adrenoceptor knockout and wild-type mice. When wild-type mice were pretreated with an alpha(2)-adrenoceptor antagonist, capsaicin-induced pain hypersensitivity increased to a level equal to that in alpha(2A)-adrenoceptor knockout mice. Capsaicin-induced hypersensitivity was suppressed in wild-type but not alpha(2A)-adrenoceptor knockout mice by a centrally acting alpha(2)-adrenoceptor agonist, whereas a peripherally acting alpha(2)-adrenoceptor agonist was without effect on hypersensitivity, although it attenuated capsaicin-induced spontaneous pain behavior in wild-type mice. Conclusions: This study shows that central alpha(2A)-adrenoceptors contribute to feedback inhibition of pain hypersensitivity. Also, alpha(2A)-adrenoceptors are critical for not only somatic but also visceral antinociceptive effects induced by synthetic alpha(2)-adrenoceptor agonists.