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 4

Effects of peripheral versus central targeting of TRPV1 on sensory ganglia.

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Effects of peripheral versus central targeting of TRPV1 on sensory gangl...
Trigeminal ganglia sections (10 μm, paraffin-embedded) were stained for TRPV1 following 250 ng RTX or vehicle treatment. (A) There was a significant decrease (1-way ANOVA, Scheffé post hoc test, n = 6 sections, n = 3 rats, *P < 0.05) in TRPV1+ cells in the trigeminal ganglia of rats treated with RTX perineurally around the ION as compared with rats treated with the PBS-vehicle. (B) ICM administration of either RTX or PBS-vehicle did not significantly affect the proportion of cells expressing TRPV1. Counts were completed in various regions of the trigeminal ganglia (V1, V2, V3), and the proportion of TRPV1+ cells did not vary significantly. (C) ICM injection of RTX reduced TRPV1 staining in the brainstem and upper cervical spinal cord regions by at least 90% (n = 1). Injection of RTX (250 ng, 10 μl) produced loss of TRPV1+ neurons within the upper cervical region, but there was return of staining at the lower cervical/upper thoracic level and regions more caudal. (D and E) There was a strong reduction in markers of DRG neuronal axons within the brainstem following ICM treatment with RTX (n = 1). Additional quantitation is provided in Supplemental Figure 8. (F–H) Peripheral DRG function was tested by examination of capsaicin-induced plasma extravasation in trigeminally innervated regions of the face after ICM and ION RTX. While ICM RTX completely blocked thermal responses on the ear (G, **P ≤ 0.01, n ≥ 4, ANOVA, Dunnett’s post hoc), it had no effect on capsaicin-induced extravasation (H, n ≥ 3, ANOVA, Dunnett’s post hoc). In contrast, ION injection of RTX significantly blocked extravasation (P ≤ 0.05, n = 5, Student’s t test).