Deletion of vanilloid receptor 1_expressing primary afferent neurons for pain control
Laszlo Karai, … , Zoltan Olah, Michael J. Iadarola
Laszlo Karai, … , Zoltan Olah, Michael J. Iadarola
Published May 1, 2004
Citation Information: J Clin Invest. 2004;113(9):1344-1352. https://doi.org/10.1172/JCI20449.
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Deletion of vanilloid receptor 1_expressing primary afferent neurons for pain control

Abstract

Control of cancer, neuropathic, and postoperative pain is frequently inadequate or compromised by debilitating side effects. Inhibition or removal of certain nociceptive neurons, while retaining all other sensory modalities and motor function, would represent a new therapeutic approach to control severe pain. The enriched expression of transient receptor potential cation channel, subfamily V, member 1 (TRPV1; also known as the vanilloid receptor, VR1) in nociceptive neurons of the dorsal root and trigeminal ganglia allowed us to test this concept. Administration of the potent TRPV1 agonist resiniferatoxin (RTX) to neuronal perikarya induces calcium cytotoxicity by opening the TRPV1 ion channel and selectively ablates nociceptive neurons. This treatment blocks experimental inflammatory hyperalgesia and neurogenic inflammation in rats and naturally occurring cancer and debilitating arthritic pain in dogs. Sensations of touch, proprioception, and high-threshold mechanosensitive nociception, as well as locomotor function, remained intact in both species. In separate experiments directed at postoperative pain control, subcutaneous administration of RTX transiently disrupted nociceptive nerve endings, yielding reversible analgesia. In human dorsal root ganglion cultures, RTX induced a prolonged increase in intracellular calcium in vanilloid-sensitive neurons, while leaving other, adjacent neurons unaffected. The results suggest that nociceptive neuronal or nerve terminal deletion will be effective and broadly applicable as strategies for pain management.

Authors

Laszlo Karai, Dorothy C. Brown, Andrew J. Mannes, Stephen T. Connelly, Jacob Brown, Michael Gandal, Ofer M. Wellisch, John K. Neubert, Zoltan Olah, Michael J. Iadarola

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RTX analgesia in naturally occurring neoplasms or osteoarthritis in the ...
RTX analgesia in naturally occurring neoplasms or osteoarthritis in the dog and morphological aspects of cell deletion in dog DRG and rat TG over time. (A) Intrathecal RTX reduced pain reports by the owners using a VAS in neoplastic (N), arthritic (A), and neoplastic plus arthritic (N + A) dogs (n = 8). Bars represent individual animals; inset represents summed data (*ANOVA with Scheffe’s post hoc test; P < 0.05). (B) High-power (∞40) image of an adult rat TG, 24 hours after 200 ng intraganglionic RTX administration, shows grossly normal appearance. (C) The enlargement reveals swollen eosinophilic cytoplasm and dislocated nuclei with partial wavy pattern of the nuclear membrane in many small- to medium-sized neurons (black arrows), characteristic of calcium cytotoxicity. Large neurons (red arrowheads) are normal. (D) DRG from an adult dog 21 days after intrathecal RTX injection shows patchy proliferation of satellite cells. (E) At higher magnification, neuronophagia is evident (black arrows). A necrotic neuron in which the nuclear membrane is faintly visible around a spot of condensed nuclear material is also visible (red arrowhead). By 30 days in dog ganglia, damaged and dead neurons are replaced by proliferating satellite cell colonies called nodules of Nageotte, which can be seen as a ball of proliferating cells (not shown). (F) One year after RTX treatment, the rat TG shows extended areas of acellular eosinophilic fields surrounded by rosetting satellite cells, indicated by red asterisks at higher magnification (G). There is no evidence of excessive, distorting glial proliferation. Bars: 100 ∝m (B, D, and F); 25 ∝m (C, E, and G).