title: Potent analgesic effects of a store-operated calcium channel inhibitor.
abstract: Chronic pain often accompanies immune responses and immune cells are known to be involved in chronic pain. Store-operated calcium (SOC) channels are calcium-selective cation channels and play an important role in the immune system. YM-58483, a potent SOC channel inhibitor, has been shown to inhibit cytokine production from immune cells and attenuate antigen-induced hypersensitivity reactions. Here, we report that YM-58483 has analgesic actions in chronic pain and produces antinociceptive effects in acute pain and prevents the development of chronic pain in mice. Oral administration of 10mg/kg or 30 mg/kg YM-58483 dramatically attenuated complete Freund adjuvant (CFA)-induced thermal hyperalgesia and prevented the development of thermal and mechanical hypersensitivity in a dose-dependent manner. Analgesic effects were observed when YM-58483 was administered systemically, intrathecally and intraplantarly. YM-58483 decreased spared nerve injury (SNI)-induced thermal and mechanical hypersensitivity and prevented the development of SNI-induced pain hypersensitivity. Pretreatment with YM-58483 strongly reduced both the first and second phases of formalin-induced spontaneous nocifensive behavior in a dose-dependent manner. YM-58483 produced antinociception in acute pain induced by heat or chemical or mechanical stimuli at a dose of 30 mg/kg. YM-58483 diminished CFA-induced paw edema, and reduced production of TNF-α, IL-1β and PGE2 in the CFA-injected paw. In vitro, SOC entry in nociceptors was more robust than in nonnociceptors, and the inhibition of SOC entry by YM-58483 in nociceptors was much greater than in nonnociceptors. Our findings indicate that YM-58483 is a potent analgesic and suggest that SOC channel inhibitors may represent a novel class of therapeutics for pain.
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Ruby
authors.initials: R
authors.lastname: Gao
authors.forename: Xinghua
authors.initials: X
authors.lastname: Gao
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Xia
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Tian
authors.forename: James E
authors.initials: JE
authors.lastname: Barrett
authors.forename: Yue
authors.initials: Y
authors.lastname: Dai
authors.forename: Huijuan
authors.initials: H
authors.lastname: Hu
mesh_terms: D000700:Analgesics / Q000008:administration & dosage*; D000813:Anilides / Q000008:administration & dosage*; D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013830:Thiadiazoles / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000700:Analgesics; D000813:Anilides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D013830:Thiadiazoles
keywords: Dorsal root ganglia; Inflammation; Pain; Store-operated calcium channels; Tumor necrosis factor alpha; YM-58483