title: Comparison of icilin- and cold-evoked responses of spinal neurones, and their modulation of mechanical activity, in a model of neuropathic pain.
abstract: Cold allodynia is a poorly understood symptom of neuropathic pain. Two members of the transient receptor potential (TRP) family of proteins, TRPM8 and TRPA1, may contribute to cold somatosensation. The aim of the present study was to investigate the usefulness of icilin as a pharmacological tool to study primary afferent fibre responses to cold stimuli and to determine whether there are differences in the responses of spinal neurones to cooling of peripheral receptive fields in control versus neuropathic rats. The effects of icilin, a TRPM8 and TRPA1 agonist, on intracellular Ca(2+) ([Ca(2+)](i)) responses of small diameter adult dorsal root ganglia (DRG) neurones were determined. Icilin (10 nM-10 microM) produced a concentration-related increase in [Ca(2+)](i) in DRG neurones, which was attenuated by the non-selective TRP channel antagonist ruthenium red (10 microM). In vivo electrophysiology in naïve, sham-operated and SNL rats demonstrated that application of ice to receptive fields evoked firing of wide dynamic range (WDR) neurones, which was significantly greater in SNL rats than naïve and sham-operated rats. Intraplantar injection of icilin did not evoke firing of WDR neurones in naïve, sham-operated or SNL rats but inhibited mechanically-evoked responses of WDR neurones in naïve and sham-operated rats, whilst facilitating mechanically-evoked responses in SNL rats. Icilin increased both innocuous (sham-operated and SNL rats) and noxious (SNL rats) receptive field sizes of WDR neurones. Our data suggests that icilin modulates the mechanosensitivity of dorsal horn neurones. The differing effects of ice and icilin on dorsal horn neurones indicate different mechanisms of action.
authors.affiliation: Institute of Neuroscience, School of Biomedical Sciences, E-floor, Medical School, Queens Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK. jlm33@le.ac.uk
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Brignell
authors.forename: Victoria
authors.initials: V
authors.lastname: Chapman
authors.forename: David A
authors.initials: DA
authors.lastname: Kendall
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017487:Ankyrins; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D003080:Cold Temperature; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005071:Evoked Potentials; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006941:Hyperesthesia / Q000209:etiology / Q000378:metabolism*; D008026:Ligation; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000378:metabolism; D009437:Neuralgia / Q000150:complications / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013127:Spinal Nerves / Q000378:metabolism / Q000601:surgery; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050053:TRPM Cation Channels / Q000819:agonists* / Q000378:metabolism
chemical_list: D017487:Ankyrins; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D011744:Pyrimidinones; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050053:TRPM Cation Channels; C480976:Trpa1 protein, rat; C498947:Trpm8 protein, rat; C490483:icilin; D002118:Calcium