Contribution of alpha(2) receptor subtypes to nerve injury-induced pain and its regulation by dexmedetomidine.
There is evidence that noradrenaline contributes to the development and maintenance of neuropathic pain produced by trauma to a peripheral nerve. It is, however, unclear which subtype(s) of alpha adrenergic receptors (AR) may be involved. In addition to pro-nociceptive actions of AR stimulation, alpha(2) AR agonists produce antinociceptive effects. Here we studied the contribution of the alpha(2) AR subtypes, alpha(2A), alpha(2B) and alpha(2C) to the development of neuropathic pain. We also examined the antinociceptive effect produced by the alpha(2) AR agonist dexmedetomidine in nerve-injured mice. The studies were performed in mice that carry either a point (alpha(2A)) or a null (alpha(2B) and alpha(2C)) mutation in the gene encoding the alpha(2) AR. To induce a neuropathic pain condition, we partially ligated the sciatic nerve and measured changes in thermal and mechanical sensitivity. Baseline mechanical and thermal withdrawal thresholds were similar in all mutant and wild-type mice; and, after peripheral nerve injury, all mice developed comparable hypersensitivity (allodynia) to thermal and mechanical stimulation. Dexmedetomidine reversed the allodynia at a low dose (3 microg kg(-1), s.c.) and produced antinociceptive effects at higher doses (10 - 30 microg kg(-1)) in all groups except in alpha(2A) AR mutant mice. The effect of dexmedetomidine was reversed by intrathecal, but not systemic, injection of the alpha(2) AR antagonist RS 42206. These results suggest that neither alpha(2A), alpha(2B) nor alpha(2C) AR is required for the development of neuropathic pain after peripheral nerve injury, however, the spinal alpha(2A) AR is essential for the antinociceptive effects of dexmedetomidine.
Malmberg
A B
AB
Department of Anatomy, W.M. Keck Center for Integrative Neuroscience, University of California, San Francisco, California, CA 94143, USA. amalmberg@neurogesx.com
Hedley
L R
LR
Jasper
J R
JR
Hunter
J C
JC
Basbaum
A I
AI
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D020927:Dexmedetomidine / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006145:Guanethidine; D008297:Male; D051379:Mice; D010146:Pain / Q000503:physiopathology*; D059348:Peripheral Nerve Injuries; D017354:Point Mutation / Q000235:genetics; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000502:physiology*; D013563:Sympathectomy, Chemical; D013565:Sympatholytics
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D018341:Receptors, Adrenergic, alpha-2; D013565:Sympatholytics; D020927:Dexmedetomidine; D006145:Guanethidine