radolmidine and Neuralgia

Among brain structures receiving efferent projections from the histaminergic tuberomammillary nucleus is the pontine locus coeruleus (LC) involved in descending noradrenergic control of pain. Here we studied whether histamine in the LC is involved in descending regulation of neuropathic hypersensitivity. Peripheral neuropathy was induced by unilateral spinal nerve ligation in the rat with a chronic intracerebral and intrathecal catheter for drug administrations. Mechanical hypersensitivity in the injured limb was assessed by monofilaments. Heat nociception was assessed by determining radiant heat-induced paw flick. Histamine in the LC produced a dose-related (1-10μg) mechanical antihypersensitivity effect (maximum effect at 15min and duration of effect 30min), without influence on heat nociception. Pretreatment of LC with zolantidine (histamine H2 receptor antagonist), but not with pyrilamine (histamine H1 receptor antagonist), and spinal administration of atipamezole (an α2-adrenoceptor antagonist), prazosine (an α1-adrenoceptor antagonist) or bicuculline (a GABAA receptor antagonist) attenuated the antihypersensitivity effect of histamine. The histamine-induced antihypersensitivity effect was also reduced by pretreatment of LC with fadolmidine, an α2-adrenoceptor agonist inducing autoinhibition of noradrenergic cell bodies. Zolantidine or pyrilamine alone in the LC failed to influence pain behavior, while A-960656 (histamine H3 receptor antagonist) suppressed hypersensitivity. A plausible explanation for these findings is that histamine, due to excitatory action mediated by the histamine H2 receptor on noradrenergic cell bodies, promotes descending spinal α1/2-adrenoceptor-mediated inhibition of neuropathic hypersensitivity. Blocking the autoinhibitory histamine H3 receptor on histaminergic nerve terminals in the LC facilitates release of histamine and thereby, increases descending noradrenergic pain inhibition.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-2 Receptor Agonists; Adrenergic Neurons; Animals; Benzothiazoles; Bicuculline; GABA-A Receptor Antagonists; Histamine; Histamine H2 Antagonists; Hot Temperature; Hyperalgesia; Imidazoles; Indans; Locus Coeruleus; Male; Neuralgia; Phenoxypropanolamines; Physical Stimulation; Piperidines; Prazosin; Rats; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2; Receptors, Histamine; Spinal Nerves

Pontine A5, A6 (locus coeruleus) and A7 cell groups provide noradrenergic innervation of the spinal cord. Here, we assessed whether activation of α(2) -adrenoceptors in A7 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 A7 or for comparison into A6 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 A7, but not in A6, produced a tactile antihypersensitivity effect. Intrathecal atipamezole (5 μg) reversed the tactile antihypersensitivity effect by fadolmidine in A7. Atipamezole alone (5.0 μg) intrathecally or in A7 failed to influence tactile hypersensitivity. Fadolmidine in A7 failed to influence mechanical hyperalgesia or heat nociception at doses that produced a tactile antihypersensitivity effect. We propose that tonic noradrenergic drive of A6 by A7 promotes neuropathic hypersensitivity by suppressing descending noradrenergic inhibition originating in A6. Consequently, the activation of inhibitory α(2) -adrenoceptors within the pontine A7 cell group suppresses neuropathic hypersensitivity by disinhibiting A6 and its descending noradrenergic pathways acting on spinal α(2) -adrenoceptors.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperalgesia; Imidazoles; Indans; Male; Microinjections; Neuralgia; Pain Measurement; Pons; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-2; Spinal Cord