Pain control through selective chemo-axotomy of centrally projecting TRPV1+ sensory neurons
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
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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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 5

Intrathecal administration of a gadolinium-based contrast agent.

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Intrathecal administration of a gadolinium-based contrast agent. An MRI ...
An MRI scan was performed as part of a diagnostic evaluation using a dilute amount of gadolinium-based contrast agent injected intrathecally to trace the distribution of CSF in the lumbar region of a single patient. (A) A coronal maximum-intensity projection of T1-weighted fat-saturated MRI shows a high signal in the thecal sac, which extends along nerve root sheaths (arrowheads), without signal within the lumbar ganglia. (B) Axial sections through the lumbar nerve root sheaths (arrowheads) show contrast filling in the nerve root sheaths approaching the DRGs. (C) Axial sections through the DRG (arrows) show no contrast agent in or around the DRGs. Scale bars: 1 cm.