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.
| Original language | American English |
|---|---|
| Article number | e153558 |
| Journal | Journal of Clinical Investigation |
| Volume | 133 |
| Issue number | 3 |
| DOIs | |
| State | Published - 1 Feb 2023 |
Bibliographical note
Funding Information: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.
Funding Information:
We thank Z. Granot and his group from the Hebrew University for help with isolation of PBMCs, N. Grover from the Hebrew University for expert advice on statistical analyses; A. Shaag, C. Rosenbluh, and H. Mor-Shaked from Hadassah University Hospital for help with the genomic sequencing and analysis; A. Nashef from the Hebrew University for help in communicating with A1 and his family members; R. Goldstein and R. Gutorov from the Hebrew University for help with the experiments; H. Vaknine from E. Walfson Medical Center for help with the pathology; A. Priel from the Hebrew University for providing DkTx; and M. Devor from the Hebrew University and A. Priel for useful comments and critical reading of the manuscript. We also thank the family of the affected individuals and healthy volunteers for participating in this study. This work is dedicated to the memory of Lily Safra, a great supporter of brain research. This work was supported by Israel Science Foundation grant 368/19 (to BM); Teva’s National Network of Excellence in Neuroscience grant 0394886 (to BM and AMB); and a Teva’s National Network of Excellence in Neuroscience postdoctoral fellowship (to BK).
Funding Information:
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. We thank Z. Granot and his group from the Hebrew University for help with isolation of PBMCs, N. Grover from the Hebrew University for expert advice on statistical analyses; A. Shaag, C. Rosenbluh, and H. Mor-Shaked from Hadassah University Hospital for help with the genomic sequencing and analysis; A. Nashef from the Hebrew University for help in communicating with A1 and his family members; R. Goldstein and R. Gutorov from the Hebrew University for help with the experiments; H. Vaknine from E. Walfson Medical Center for help with the pathology; A. Priel from the Hebrew University for providing DkTx; and M. Devor from the Hebrew University and A. Priel for useful comments and critical reading of the manuscript. We also thank the family of the affected individuals and healthy volunteers for participating in this study. This work is dedicated to the memory of Lily Safra, a great supporter of brain research. This work was supported by Israel Science Foundation grant 368/19 (to BM); Teva’s National Network of Excellence in Neuroscience grant 0394886 (to BM and AMB); and a Teva’s National Network of Excellence in Neuroscience postdoctoral fellowship (to BK).
Publisher Copyright:
© 2023, Katz et al.
