title: H4 receptor antagonism exhibits anti-nociceptive effects in inflammatory and neuropathic pain models in rats.
abstract: The histamine H(4) receptor (H(4)R) is expressed primarily on cells involved in inflammation and immune responses. To determine the potential role of H(4)R in pain transmission, the effects of JNJ7777120, a potent and selective H(4) antagonist, were characterized in preclinical pain models. Administration of JNJ7777120 fully blocked neutrophil influx observed in a mouse zymosan-induced peritonitis model (ED(50)=17 mg/kg s.c., 95% CI=8.5-26) in a mast cell-dependent manner. JNJ7777120 potently reversed thermal hyperalgesia observed following intraplantar carrageenan injection of acute inflammatory pain (ED(50)=22 mg/kg i.p., 95% CI=10-35) in rats and significantly decreased the myeloperoxide activity in the carrageenan-injected paw. In contrast, no effects were produced by either H(1)R antagonist diphenhydramine, H(2)R antagonists ranitidine, or H(3)R antagonist ABT-239. JNJ7777120 also exhibited robust anti-nociceptive activity in persistent inflammatory (CFA) pain with an ED(50) of 29 mg/kg i.p. (95% CI=19-40) and effectively reversed monoiodoacetate (MIA)-induced osteoarthritic joint pain. This compound also produced dose-dependent anti-allodynic effects in the spinal nerve ligation (ED(50)=60 mg/kg) and sciatic nerve constriction injury (ED(50)=88 mg/kg) models of chronic neuropathic pain, as well as in a skin-incision model of acute post-operative pain (ED(50)=68 mg/kg). In addition, the analgesic effects of JNJ7777120 were maintained following repeated administration and were evident at the doses that did not cause neurologic deficits in rotarod test. Our results demonstrate that selective blockade of H(4) receptors in vivo produces significant anti-nociception in animal models of inflammatory and neuropathic pain.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research & Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. gin.c.hsieh@abbott.com
authors.forename: Gin C
authors.initials: GC
authors.lastname: Hsieh
authors.forename: Prasant
authors.initials: P
authors.lastname: Chandran
authors.forename: Anita K
authors.initials: AK
authors.lastname: Salyers
authors.forename: Madhavi
authors.initials: M
authors.lastname: Pai
authors.forename: Chang Z
authors.initials: CZ
authors.lastname: Zhu
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Wensink
authors.forename: David G
authors.initials: DG
authors.lastname: Witte
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Miller
authors.forename: Joe P
authors.initials: JP
authors.lastname: Mikusa
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Baker
authors.forename: Jill M
authors.initials: JM
authors.lastname: Wetter
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hancock
authors.forename: Marlon D
authors.initials: MD
authors.lastname: Cowart
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Esbenshade
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy*; D011869:Radioligand Assay; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4
chemical_list: D000700:Analgesics; C498828:Hrh4 protein, rat; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4