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 6

Immunohistochemical staining of DRG and spinal cord from human and canine subjects.

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Immunohistochemical staining of DRG and spinal cord from human and canin...
Dog and human sensory ganglia and spinal cord were harvested after intrathecal treatment with RTX, and immunohistochemical staining was performed. Trigeminal and DRG samples from dogs treated with RTX in an independently conducted GLP toxicology study were assessed by a pathologist. (A) At the maximum tolerated dose (3.6 μg/kg), 5 of 10 dogs treated with RTX showed mild pathology in the trigeminal, whereas 3 of 10 showed minimal pathology in the DRG after ICM injection (nonsignificant, Mantel-Haenszel χ2). (B) An example of an infrequent pathological manifestation is the formation of a neuronophagic nodule (arrows). (C) Dogs were injected in the cisterna magna. In the dog, a marked reduction in CGRP was observed in the cervical region of the dorsal spinal cord, with a near-total ablation of substance P (SP) staining at the same level (n = 5 dogs). **P ≤ 0.01. (D) One human patient was injected with RTX using an end-hole catheter positioned at the cauda equina. After RTX treatment, CGRP and SP staining was almost completely abolished in the lumbar spinal cord. Similar reductions were also observed in the thoracic spinal cord for CGRP and TRPV1. A single human was autopsied to procure tissue. To estimate the magnitude of the effect size, several sections of the single human sample (points shown in the graphs) were compared with untreated human sections.