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The Cellular Logic of Pain Modality Discrimination

  • Author(s): Cavanaugh, Daniel
  • Advisor(s): Basbaum, Allan I
  • et al.
Abstract

Noxious stimuli are detected by primary afferent neurons of the dorsal root ganglia (DRG). Such neurons, known as nociceptors, can be divided into several distinct populations based on the heterogeneous distribution of receptors, ion channels, and neurotransmitters, however, functional correlates of these anatomical differences are yet unidentified. The work in this thesis further examines the neurochemical and functional segregation of nociceptor subtypes through a genetic and pharmacological investigation of neurons that express the heat and capsaicin receptor, TRPV1.

TRPV1 is activated by noxious heat stimuli (>43 oC), and is robustly expressed by primary afferent nociceptors. In addition, some have argued that TRPV1 is widely distributed in cells outside of the DRG, although there is considerable disagreement as to the extent and localization of this expression. To address this question, we generated a line of mice in which TRPV1+ cells co-express two reporter genes: placental alkaline phosphatase and nuclear lacZ. These enzymes allow for the sensitive and accurate identification of TRPV1+ cells and processes. Using this approach, we observed that, in contrast to numerous previous reports, TRPV1 expression in the nervous system is largely limited to peptidergic, primary afferent neurons. We additionally found evidence for TRPV1 in arteriolar smooth muscle cells, highlighting an important substrate for the actions of heat, protons, and other TRPV1 agonists on vascular tone.

We then investigated the relative contribution of TRPV1+ and TRPV1- nociceptors to the behavioral responses to stimuli of different pain modalities. Surprisingly, despite the fact that most nociceptors show polymodal response properties in electrophysiological assays, we found that pharmacological ablation of the central branches of TRPV1+ nociceptors selectively abolished heat pain sensitivity without altering behavioral responses to mechanical or cold stimuli. Conversely, we found that genetic ablation of nociceptors expressing the G protein-coupled receptor, MrgprD, which marks a large subset of TRPV1- DRG neurons, selectively reduced behavioral sensitivity to noxious mechanical stimuli. This double-dissociation suggests that the brain can distinguish different noxious stimulus modalities from the earliest stages of sensory processing as a result of distinct contributions from molecularly-defined nociceptor subtypes.

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