Nociception and pain in humans lacking a functional TRPV1 channel
Ben Katz, Rachel Zaguri, Simon Edvardson, Channa Maayan, Orly Elpeleg, Shaya Lev, Elyad Davidson, Maximilian Peters, Shlomit Kfir-Erenfeld, Esther Berger, Shifa Ghazalin, Alexander M. Binshtok, Baruch Minke
Ben Katz, Rachel Zaguri, Simon Edvardson, Channa Maayan, Orly Elpeleg, Shaya Lev, Elyad Davidson, Maximilian Peters, Shlomit Kfir-Erenfeld, Esther Berger, Shifa Ghazalin, Alexander M. Binshtok, Baruch Minke
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Clinical Research and Public Health Neuroscience

Nociception and pain in humans lacking a functional TRPV1 channel

Abstract

BACKGROUND Chronic pain is a debilitating illness with currently limited therapy, in part due to difficulties in translating treatments derived from animal models to patients. The transient receptor potential vanilloid 1 (TRPV1) channel is associated with noxious heat detection and inflammatory pain, and reports of adverse effects in human trials have hindered extensive efforts in the clinical development of TRPV1 antagonists as novel pain relievers.METHODS We examined 2 affected individuals (A1 and A2) carrying a homozygous missense mutation in TRPV1, rendering the channel nonfunctional. Biochemical and functional assays were used to analyze the mutant channel. To identify possible phenotypes of the affected individuals, we performed psychophysical and medical examinations.RESULTS We demonstrated that diverse TRPV1 activators, acting at different sites of the channel protein, were unable to open the cloned mutant channel. This finding was not a consequence of impairment in the expression, cellular trafficking, or assembly of protein subunits. The affected individuals were insensitive to application of capsaicin to the mouth and skin and did not demonstrate aversive behavior toward capsaicin. Furthermore, quantitative sensory testing of A1 revealed an elevated heat-pain threshold but also, surprisingly, an elevated cold-pain threshold and extensive neurogenic inflammatory, flare, and pain responses following application of the TRPA1 channel activator mustard oil.CONCLUSION Our study provides direct evidence in humans for pain-related functional changes linked to TRPV1, which is a prime target in the development of pain relievers.FUNDING Supported by the Israel Science Foundation (368/19); Teva’s National Network of Excellence in Neuroscience grant (no. 0394886) and Teva’s National Network of Excellence in Neuroscience postdoctoral fellowship.

Authors

Ben Katz, Rachel Zaguri, Simon Edvardson, Channa Maayan, Orly Elpeleg, Shaya Lev, Elyad Davidson, Maximilian Peters, Shlomit Kfir-Erenfeld, Esther Berger, Shifa Ghazalin, Alexander M. Binshtok, Baruch Minke

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Figure 5

AITC but not capsaicin induces neurogenic inflammation in A1.

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AITC but not capsaicin induces neurogenic inflammation in A1. (A–C) QST ...
(A–C) QST measurements of (A) HPT (n+/+ = 7, n+/N331K = 9, nN331K/N331K = 8 repeats), (B) CPT (n+/+ = 7, n+/N331K = 9, nN331K/N331K = 7 repeats), and (C) MPT (n+/+ = 7, n+/N331K = 9, nN331K/N331K = 7 repeats) before (black dots) and after (red dots) topical application of 5% (w/v) capsaicin to the forearm for 10 minutes (left, healthy volunteers; middle, heterozygous family members; right, A1). Note that the healthy volunteers and heterozygous family members showed thermal heat allodynia, cold hypoalgesia, and mechanical allodynia, whereas A1 did not show any of these phenomena. *P < 0.05 and **P < 0.01, by 1-tailed Wilcoxon signed-rank test. (E–G) QST measurements of (E) HPT (n+/+= 12, n+/N331K = 9, nN331K/N331K = 7 repeats), (F) CPT (n+/+ = 12, n+/N331K = 9, nN331K/N331K = 7 repeats), and (G) MPT (n+/+ = 12, n+/N331K = 9, nN331K/N331K = 7 repeats) before (black dots) and after (green dots) topical application of 25% (v/v) AITC to the forearm for 1 minute (left, healthy volunteers; middle, heterozygous family members; right, A1). Note that the control groups and A1 showed elevated HPT and minor mechanical allodynia but no change in their CPT. *P < 0.05 and **P < 0.01, by 2-tailed Wilcoxon signed-rank test. (D and H) Representative images of individual forearms (top) from a healthy volunteer (left), a heterozygous family member (middle), and A1 (right) after topical application of 5% (w/v) capsaicin for 10 minutes (D) or 25% (v/v) AITC for 1 minute (H) to the forearm using a Finn chamber (for extended data, see Supplemental Figure 6, B and C). Images were processed (bottom) for the extent of the flare using an imaging tool to detect areas of similar tone and color. Note that A1 did not develop a flare after topical application of capsaicin, but developed an extensive flare after topical application of AITC compared with individuals in the control groups. The QSTs were performed 1 minute after removal of the capsaicin or AITC. *P < 0.05 and **P < 0.01, by 1-tailed Wilcoxon signed-rank test (A–C and E–G).