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The Journal of Neuroscience, January 19, 2005, 25(3):758-767; doi:10.1523/JNEUROSCI.3909-04.2005

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Development/Plasticity/Repair
Neurotrophin-3 Suppresses Thermal Hyperalgesia Associated with Neuropathic Pain and Attenuates Transient Receptor Potential Vanilloid Receptor-1 Expression in Adult Sensory Neurons

Tracy D. Wilson-Gerwing,¹ Myles V. Dmyterko,¹ Douglas W. Zochodne,² Jayne M. Johnston,¹ and Valerie M. K. Verge¹

¹Department of Anatomy and Cell Biology, Cameco Multiple Sclerosis Neuroscience Research Center, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5, and ²Department of Clinical Neurosciences and the Neuroscience Research Group, University of Calgary, Calgary, Alberta, Canada T2N 4N1

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 56%. Attenuation of thermal hyperalgesia mediated by NT-3 correlates with decreased TRPV1 expression such that only 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.

Key words: dorsal root ganglion; NT-3; NGF; trkA; pain; thermal hyperalgesia

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Received March 2, 2004; revised December 1, 2004; accepted December 2, 2004.

This article has been cited by other articles:

				Y. H. Zhang, X. X. Chi, and G. D. Nicol Brain-derived neurotrophic factor enhances the excitability of rat sensory neurons through activation of the p75 neurotrophin receptor and the sphingomyelin pathway J. Physiol., July 1, 2008; 586(13): 3113 - 3127. [Abstract] [Full Text] [PDF]

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