Histamine in the locus coeruleus attenuates neuropathic hypersensitivity

Abstract

Abstract Aims Among brain structures receiving efferent projections from the histaminergic tuberomammillary nucleus is the pontine locus coeruleus (LC), a structure involved in descending noradrenergic control of pain. Here we studied whether histamine in the LC is involved in descending regulation of neuropathic hypersensitivity. Methods Peripheral neuropathy was induced by unilateral spinal nerve ligation (SNL) 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. Results Histamine in the LC (ipsilateral to nerve injury) produced a dose-related (1–10 μg) mechanical antihypersensitivity effect (maximum effect at 15 min and duration of effect 30 min), without influence on heat nociception. Pretreatment of LC with zolantidine (H2 receptor antagonist), but not with pyrilamine (H1 receptor antagonist), reversed the antihypersensitivity effect of histamine. Zolantidine or pyrilamine alone in LC failed to influence pain behavior. The antihypersensitivity effect induced by histamine in LC was reduced also by spinal administration of atipamezole (an α2-adrenoceptor antagonist). Conclusions The results indicate that histamine acting on H2 receptors in the LC attenuates mechanical hypersensitivity in peripheral neuropathy. The histamine-induced descending antihypersensitivity effect is at least partly mediated by noradrenergic pathways acting on the spinal α2-adrenoceptor.