title: Neurotrophin-3 suppresses thermal hyperalgesia associated with neuropathic pain and attenuates transient receptor potential vanilloid receptor-1 expression in adult sensory neurons.
abstract: Neurotrophin-3 (NT-3) negatively modulates nerve growth factor (NGF) receptor expression and associated nociceptive phenotype in intact neurons, suggesting a beneficial role in treating aspects of neuropathic pain mediated by NGF. We report that NT-3 is effective at suppressing thermal hyperalgesia associated with chronic constriction injury (CCI); however, NT-3 does not alter the mechanical hypersensitivity that also develops with CCI. Thermal hyperalgesia is critically linked to expression and activation of the capsaicin receptor, transient receptor potential vanilloid receptor-1 (TRPV1). Thus, its modulation by NT-3 after CCI was examined. CCI results in elevated TRPV1 expression at both the mRNA and protein levels in predominantly small-to-medium neurons, with the percentage of neurons expressing TRPV1 remaining unchanged at approximately 56%. Attenuation of thermal hyperalgesia mediated by NT-3 correlates with decreased TRPV1 expression such that only approximately 26% of neurons ipsilateral to CCI expressed detectable TRPV1 mRNA. NT-3 effected a decrease in expression of the activated component of the signaling pathway linked to regulation of TRPV1 expression, phospho-p38 MAPK (Ji et al., 2002), in neurons ipsilateral to CCI. Exogenous NT-3 could both prevent the onset of thermal hyperalgesia and reverse established thermal hyperalgesia and elevated TRPV1 expression 1 week after CCI. Continuous infusion is required for suppression of both thermal hyperalgesia and TRPV1 expression, because removal of NT-3 resulted in a prompt reestablishment of the hyperalgesic state and corresponding CCI-associated TRPV1 phenotype. In conclusion, although NGF drives inflammation-associated thermal hyperalgesia via its regulation of TRPV1 expression, NT-3 is now identified as a potent negative modulator of this state.
authors.affiliation: Department of Anatomy and Cell Biology, Cameco Multiple Sclerosis Neuroscience Research Center, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5.
authors.forename: Tracy D
authors.initials: TD
authors.lastname: Wilson-Gerwing
authors.forename: Myles V
authors.initials: MV
authors.lastname: Dmyterko
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Zochodne
authors.forename: Jayne M
authors.initials: JM
authors.lastname: Johnston
authors.forename: Valerie M K
authors.initials: VM
authors.lastname: Verge
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003250:Constriction; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006358:Hot Temperature; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology*; D007263:Infusions, Parenteral; D007473:Ion Channels / Q000096:biosynthesis*; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D020933:Neurotrophin 3 / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D050916:TRPV Cation Channels; D014110:Touch; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D007473:Ion Channels; D020933:Neurotrophin 3; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases