title: Icilin reduces voltage-gated calcium channel currents in naïve and injured DRG neurons in the rat spinal nerve ligation model.
abstract: Recently, the transient receptor potential (TRP) channels TRPM8 and TRPA1 have been identified as molecular sensors for cold, and it has been suggested that they play a crucial role in allodynia by modulating voltage-gated calcium channel currents (ICa(V)). The aim of this study was to analyze the modulation of ICa(V) by the TRPM8-agonist icilin in vitro and to investigate the analgesic effect of icilin in a neuropathic pain model in vivo. Whole cell patch-clamp recordings were performed on isolated naïve and injured rat dorsal root ganglia (DRG) neurons, and the analgesic efficacy of icilin applied topically to the paws or intrathecally was tested in rats after spinal nerve ligation (SNL). ICa(V) (depolarization from -80 to 0mV) in naïve DRG neurons was reduced dose dependently (0.002-200µM) by icilin (18-80%). Subtype isolation of calcium channels show a marked reduction of L-type channel currents compared to N-type channel currents. The effects of icilin on ICa(V) were not significantly different in non-injured and SNL-injured DRG neurons. In vivo, neither topical (10-200µM) nor intrathecal application of icilin (0.1nM to 1µM) affected tactile allodynia or thermal hyperalgesia after SNL, but it increases cold allodynia 6h after application. We conclude that the icilin-induced modulation of ICa(V) in DRG neurons is unlikely to mediate analgesic effects or contribute directly to the pathogenesis of cold allodynia in the rat SNL model, but it is a potential mechanism for the analgesic effects of icilin in other pain models.
authors.affiliation: Department of Neurology, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany. Electronic address: tim.hagenacker@uk-essen.de.
authors.forename: T
authors.initials: T
authors.lastname: Hagenacker
authors.affiliation: Department of Neurology, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Lampe
authors.affiliation: Department of Neurology, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schäfers
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism; D002478:Cells, Cultured; D003080:Cold Temperature; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000503:physiopathology; D006930:Hyperalgesia / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology; D008026:Ligation; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013127:Spinal Nerves / Q000293:injuries*; D050053:TRPM Cation Channels / Q000819:agonists / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D011744:Pyrimidinones; D050053:TRPM Cation Channels; C498947:Trpm8 protein, rat; C490483:icilin
keywords: Cold allodynia; Electrophysiology; Neuropathic pain; Patch clamp; Voltage gated calcium channel current