title: Histamine in the locus coeruleus promotes descending noradrenergic inhibition of neuropathic hypersensitivity.
abstract: 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.
authors.affiliation: Institute of Biomedicine/Physiology, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Hong
authors.initials: H
authors.lastname: Wei
authors.affiliation: Institute of Biomedicine/Physiology, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Cong-Yu
authors.initials: CY
authors.lastname: Jin
authors.affiliation: Institute of Biomedicine/Physiology, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Viisanen
authors.affiliation: Center for Biomedical Research on Pain (CBRP), College of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Hao-Jun
authors.initials: HJ
authors.lastname: You
authors.affiliation: Institute of Biomedicine/Physiology, University of Helsinki, 00014 Helsinki, Finland. Electronic address: antti.pertovaara@helsinki.fi.
authors.forename: Antti
authors.initials: A
authors.lastname: Pertovaara
mesh_terms: D059331:Adrenergic Neurons / Q000502:physiology; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D006632:Histamine / Q000502:physiology*; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology; D008125:Locus Coeruleus / Q000502:physiology*; D008297:Male; D009437:Neuralgia / Q000503:physiopathology*; D050198:Phenoxypropanolamines / Q000494:pharmacology; D010812:Physical Stimulation; D010880:Piperidines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D011968:Receptors, Histamine / Q000502:physiology; D013127:Spinal Nerves / Q000293:injuries
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D058647:Adrenergic alpha-2 Receptor Agonists; D052160:Benzothiazoles; D058787:GABA-A Receptor Antagonists; D006635:Histamine H2 Antagonists; D007093:Imidazoles; D007189:Indans; D050198:Phenoxypropanolamines; D010880:Piperidines; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D011968:Receptors, Histamine; D006632:Histamine; C055302:zolantidine; C400294:radolmidine; D011224:Prazosin; D001640:Bicuculline
keywords: Atipamezole HCl (PubChem CID: 13649426); Bicuculline methiodide (PubChem CID: 104871); Cimetidine (PubChem CID: 2756); Descending pathways; Fadolmidine HCl (PubChem CID: 6433097); Histamine dihydrochloride (PubChem CID: 5818); Histaminergic receptor; Locus coeruleus; Neuropathic pain; Prazosin HCl (PubChem CID: 68546); Pyrilamine maleate (PubChem CID: 5284451); Zolantidine (PubChem CID: 11957725); α-Adrenoceptor