Contribution of α2 receptor subtypes to nerve injury-induced pain and its regulation by dexmedetomidine

Abstract

1. 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 α adrenergic receptors (AR) may be involved. In addition to pro-nociceptive actions of AR stimulation, α2 agonists produce antinociceptive effects. 2. Here we studied the contribution of the α2, AR subtypes, α2A, α2B and α2C to the development of neuropathic pain. We also examined the antinociceptive effect produced by the α2, AR agonist dexmedetomidine in nerve-injured mice. 3. The studies were performed in mice that carry either a point (α2A) or a null (α2B and α2C) mutation in the gene encoding the α2 AR. To induce a neuropathic pain condition, we partially ligated the sciatic nerve and measured changes in thermal and mechanical sensitivity. 4. 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. 5. Dexmedetomidine reversed the allodynia at a low dose (3 μg kg-1, s.c.) and produced antinociceptive effects at higher doses (10-30 μg kg-1) in all groups except in α2A AR mutant mice. The effect of dexmedetomidine was reversed by intrathecal, but not systemic, injection of the α2 AR antagonist RS 42206. 6. These results suggest that neither α2A, α2B nor α2C AR is required for the development of neuropathic pain after peripheral nerve injury, however, the spinal α2A AR is essential for the antinociceptive effects of dexmedetomidine.