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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Figure 5

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Human DRG neurons show selective sensitivity to RTX treatment. (A) H&amp...
Human DRG neurons show selective sensitivity to RTX treatment. (A) H&E section, adult human DRG (*large-sized neurons). (B_D) Green immunofluorescence human TRPV1-IR neurons (arrows), contrasted with satellite cell nuclei (blue). (C) TRPV1-IR (green) is adsorbed by the peptide antigen (D). Selective response of human embryonic DRG neurons to RTX assessed by increases in [Ca2+]i using Fluo-4 AM imaging (E and F). Arrows indicate responding neurons, and arrowheads indicate nonresponding neurons. E shows the baseline fluorescence depicted as near 0 for the first 30 seconds of the normalized data in the graph (G). In F, the transmembrane calcium flux leads to increases in intracellular calcium in specific neurons, which become brightly fluorescent. Magnification ∞200. (G) Traces of individual cells showing a substantial and abrupt response in vanilloid-sensitive sensory neurons (traces 1_4). Elevation of [Ca2+]i for a prolonged period of time is suggestive of imminent cell death in cells responding to vanilloid treatment. The RTX effect is clearly selective; nonresponding cells (traces 5_7) maintain normal calcium levels. Increase in normalized fluorescence intensity (numbered ØF/F0 traces refer to cells in E and F). Bars: 100 ∝m.