Regulation of Neuropathic Hypersensitivity by α 2 ‐Adrenoceptors in the Pontine A 7 Cell Group

Abstract Pontine A 5, A 6 (locus coeruleus) and A 7 cell groups provide noradrenergic innervation of the spinal cord. Here, we assessed whether activation of α 2 ‐adrenoceptors in A 7 influences peripheral nerve injury‐induced hypersensitivity in the rat, and whether spinal α 2 ‐adrenoceptors mediate the descending effect. Fadolmidine, an α 2 ‐adrenoceptor agonist that because of its pharmacokinetic properties has a limited spread from the injection site, was microinjected through a chronic guide cannula into A 7 or for comparison into A 6 ipsilateral to the nerve injury. Moreover, atipamezole, an α 2 ‐adrenoceptor antagonist, was injected intrathecally in an attempt to reverse the possible antihypersensitivity effect. Tactile hypersensitivity was assessed in the injured limb by determining limb withdrawal evoked by calibrated monofilaments, mechanical hyperalgesia by determining withdrawal evoked by noxious mechanical stimulation of the paw, and thermal nociception by assessing heat‐induced withdrawal of the intact tail. Fadolmidine (1.0 or 3.0 μg) in A 7, but not in A 6, produced a tactile antihypersensitivity effect. Intrathecal atipamezole (5 μg) reversed the tactile antihypersensitivity effect by fadolmidine in A 7. Atipamezole alone (5.0 μg) intrathecally or in A 7 failed to influence tactile hypersensitivity. Fadolmidine in A 7 failed to influence mechanical hyperalgesia or heat nociception at doses that produced a tactile antihypersensitivity effect. We propose that tonic noradrenergic drive of A 6 by A 7 promotes neuropathic hypersensitivity by suppressing descending noradrenergic inhibition originating in A 6. Consequently, the activation of inhibitory α 2 ‐adrenoceptors within the pontine A 7 cell group suppresses neuropathic hypersensitivity by disinhibiting A 6 and its descending noradrenergic pathways acting on spinal α 2 ‐adrenoceptors.