Alpha(2A) adrenoceptors contribute to feedback inhibition of capsaicin-induced hyperalgesia.
BACKGROUND
Studies on receptor knockout mice have so far shown that of the three alpha2-adrenoceptor subtypes, the alpha(2A) adrenoceptor has a major role in mediating the powerful central analgesia induced by synthetic alpha2-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 alpha2-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 alpha2-adrenoceptor agonist, whereas a peripherally acting alpha2-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 alpha2-adrenoceptor agonists.
Mansikka
Heikki
H
Department of Anesthesia and Intensive Care, Turku University Central Hospital, Turku, Finland.
Lähdesmäki
Janne
J
Scheinin
Mika
M
Pertovaara
Antti
A
D000285:Administration, Rectal; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002211:Capsaicin / Q000008:administration & dosage; D003106:Colon; D005246:Feedback / Q000187:drug effects*; D005528:Foot; D018698:Glutamic Acid / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced* / Q000503:physiopathology*; D007267:Injections; D051379:Mice; D018345:Mice, Knockout; D010147:Pain Measurement / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
C547769:Adra2a protein, mouse; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018341:Receptors, Adrenergic, alpha-2; D018698:Glutamic Acid; D002211:Capsaicin