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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Categories: Article Neuroscience

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 1

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Single intraganglionic treatment. RTX was microinjected unilaterally int...
Single intraganglionic treatment. RTX was microinjected unilaterally into the TG using a transcranial stereotaxic approach. (A) Coomassie blue dye depicts trigeminal injection site at the base of the skull and (B) excised, stained TG. (C) RTX-induced blockade of neurogenic inflammation was evaluated by extravasation of Evans blue_stained plasma proteins. Blue areas of skin identify regions with intact C-fiber innervation. Extravasation was blocked on the RTX-injected side, which remains white. (D) Dose-related blockade of nociceptive afferent transmission from the cornea after unilateral intraganglionic RTX administration. CAP eye-wipe response was assessed 1_3 days after injection. *Pairwise t test; P < 0.01; n = 30, 6, and 18 for administration of 200 ng, 20 ng, and vehicle, respectively. (E) Block of CAP-induced eye-wipe response is evident as up to about 1 year in unilaterally intraganglionically treated rats, consistent with the permanent deletion of TRPV1-IR neurons, as shown in F and G (*repeated pairwise t test; P < 0.01; n = 7). On the RTX-treated side (F), there is a reduction (∼80%, similar to animals examined within 1 to 3 days after RTX treatment; see Figure 2) of TRPV1-IR neurons compared with the contralateral nontreated side (G). Bars: 100 μm.