Pain control through selective chemo-axotomy of centrally projecting TRPV1+ sensory neurons
Matthew R. Sapio, … , Andrew J. Mannes, Michael J. Iadarola
Matthew R. Sapio, … , Andrew J. Mannes, Michael J. Iadarola
Published February 6, 2018
Citation Information: J Clin Invest. 2018;128(4):1657-1670. https://doi.org/10.1172/JCI94331.
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Research Article Neuroscience

Pain control through selective chemo-axotomy of centrally projecting TRPV1+ sensory neurons

Abstract

Agonists of the vanilloid receptor transient vanilloid potential 1 (TRPV1) are emerging as highly efficacious nonopioid analgesics in preclinical studies. These drugs selectively lesion TRPV1+ primary sensory afferents, which are responsible for the transmission of many noxious stimulus modalities. Resiniferatoxin (RTX) is a very potent and selective TRPV1 agonist and is a promising candidate for treating many types of pain. Recent work establishing intrathecal application of RTX for the treatment of pain resulting from advanced cancer has demonstrated profound analgesia in client-owned dogs with osteosarcoma. The present study uses transcriptomics and histochemistry to examine the molecular mechanism of RTX action in rats, in clinical canine subjects, and in 1 human subject with advanced cancer treated for pain using intrathecal RTX. In all 3 species, we observe a strong analgesic action, yet this was accompanied by limited transcriptional alterations at the level of the dorsal root ganglion. Functional and neuroanatomical studies demonstrated that intrathecal RTX largely spares susceptible neuronal perikarya, which remain active peripherally but unable to transmit signals to the spinal cord. The results demonstrate that central chemo-axotomy of the TRPV1+ afferents underlies RTX analgesia and refine the neurobiology underlying effective clinical use of TRPV1 agonists for pain control.

Authors

Matthew R. Sapio, John K. Neubert, Danielle M. LaPaglia, Dragan Maric, Jason M. Keller, Stephen J. Raithel, Eric L. Rohrs, Ethan M. Anderson, John A. Butman, Robert M. Caudle, Dorothy C. Brown, John D. Heiss, Andrew J. Mannes, Michael J. Iadarola

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Figure 2

Gene expression map across data sets examining the effects of RTX on gene expression.

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Gene expression map across data sets examining the effects of RTX on gen...
Data from 7 experiments were mined and analyzed, including 3 experiments in which the TRPV1 agonist RTX was used to selectively damage TRPV1+ neurons. Genes decreasing by at least 40% are plotted for the 3 experiments in which RTX was used to damage TRPV1+ neurons, and compared with several data sets showing differentials between tissues or cell types to indicate where these genes are expressed. In general, these genes are contributed by neurons, as indicated by their enrichment in DRG versus sciatic nerve, and sorted eTRPV1 neurons versus eIB4+ cells, which includes non-neuronal cells such as microglia and vascular endothelia. Enrichment in TRPV1+ neurons in the single-cell data set was tabulated separately. Modest enrichment in these cells was observed in the rat and dog but not human data sets. Values were normalized such that the highest value in any data set is 1. Data from single cells are normalized differently, according to their original publication. Quantification of enrichment in TRPV1+ and nonpeptidergic 1 populations of cells versus other groups is presented. Genes from rat and dog samples showing a decrease after RTX treatment are enriched in the TRPV1+ cells.