Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli
Behavioral responses to painful stimuli require peripheral sensory neurons called nociceptors. Electrophysiological studies show that most C-fiber nociceptors are polymodal (i.e., respond to multiple noxious stimulus modalities, such as mechanical and thermal); nevertheless, these stimuli are perceived as distinct. Therefore, it is believed that discrimination among these modalities only occurs at spinal or supraspinal levels of processing. Here, we provide evidence to the contrary. Genetic ablation in adulthood of unmyelinated sensory neurons expressing the G protein-coupled receptor Mrgprd reduces behavioral sensitivity to noxious mechanical stimuli but not to heat or cold stimuli. Conversely, pharmacological ablation of the central branches of TRPV1+ nociceptors, which constitute a nonoverlapping population, selectively abolishes noxious heat pain sensitivity. Combined elimination of both populations yielded an additive phenotype with no additional behavioral deficits, ruling out a redundant contribution of these populations to heat and mechanical pain sensitivity. This double-dissociation suggests that the brain can distinguish different noxious stimulus modalities from the earliest stages of sensory processing.
© 2009 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by David J. Anderson, February 12, 2009 (sent for review December 22, 2008). Published online before print May 18, 2009, doi: 10.1073/pnas.0901507106 This work was supported, in part, by National Institutes of Health Grants PO1NS048499 (to D.J.A. and A.I.B.) and NS14627 (to A.I.B.); by awards from the National Alliance for Research on Schizophrenia and Depression, the Searle Scholars Program, and the Whitehall, Klingenstein, Sloan, and Rita Allen Foundations (to M.J.Z.); and by an award from the Christopher and Dana Reeve Foundation to (H.L.). We thank Kenji Kohno for the DTR (TRECK-1) cDNA clone, Joao Braz for help with retrograde tracing, Noritaka Imamachi for help with intrathecal injections, and Shirley Pease and staff for assistance with genetically modified mice. D.J.A. is an Investigator of the Howard Hughes Medical Institute. Author contributions: D.J.C., H.L., S.D.S., M.J.Z., A.I.B., and D.J.A. designed research; D.J.C., H.L., L.L., S.D.S., and M.J.Z. performed research; D.J.C., H.L., L.L., S.D.S., M.J.Z., A.I.B., and D.J.A. analyzed data; and D.J.C., A.I.B., and D.J.A. wrote the paper. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/cgi/content/full/0901507106/DCSupplemental.
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