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


METHODS
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.


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.


CONCLUSIONS
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.
Department of Anesthesiology, University of California-San Diego, La Jolla, CA 91766-1854, USA. anazarian@westernu.edu
A
A
Nazarian
C A
CA
Christianson
X-Y
XY
Hua
T L
TL
Yaksh
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D003000:Clonidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D020927:Dexmedetomidine / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde; D005786:Gene Expression Regulation / Q000187:drug effects; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D020671:Posterior Horn Cells / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000187:drug effects / Q000378:metabolism
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D016760:Proto-Oncogene Proteins c-fos; D018341:Receptors, Adrenergic, alpha-2; D018040:Receptors, Neurokinin-1; D005557:Formaldehyde; D013373:Substance P; C011266:ST 91; D020927:Dexmedetomidine; D009020:Morphine; D003000:Clonidine