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.

Striving toward hyperthermia-free analgesia: lessons from loss-of-function mutations of human TRPV1

“…The results from Katz, Zaguri, and colleagues ( 9 ) suggest species differences in the roles of TRPV1 and help us to anticipate the potential effects of TRPV1 antagonism in humans. The homozygous carrier of TRPV1 N331K/N331K showed a reduction in cold pain ( 9 ), which is consistent with the necessity of TRPV1 for cold nociception and cold hyperalgesia in rodents ( 11 ). Therefore, TRPV1 antagonism possibly influences the protection from both noxious heat and cold.…”

“…In studies of individuals carrying another rare TRPV1 mutation ( TRPV1 N331K ), Katz, Zaguri, and co-authors ( 9 ) report on phenotypes resulting from the complete loss of function of TRPV1 ( Figure 1 ). Individuals with the functional knockout commonly carried the rare homozygous missense mutation of TRPV1 N331K .…”

“…The affected individuals showed a modest reduction in heat pain. Heterozygous TRPV1 N331K/+ carriers did not show such phenotypes ( 9 ). These findings are consistent with the phenotypes of mice lacking the expression of TRPV1 or humans treated with a TRPV1 antagonist ( 2 ).…”

“…Further genetic analysis of the affected individuals and their family strongly suggested that the phenotypes are primarily derived from the missense mutation of TRPV1 . Although another homozygous missense mutation in PROKR1 , which is also implicated in pain, was identified in the family, two individuals carrying the homozygous mutation of PROKR1 with heterozygous TRPV1 N331K/+ did not show phenotypes comparable to those of the TRPV1 N331K/N331K carriers ( 9 ). Therefore, the findings convincingly support the contribution of TRPV1 to chemical and thermal pain in humans.…”

“…Therefore, TRPV1 antagonism possibly influences the protection from both noxious heat and cold. In the carrier homozygous for TRPV1 N331K/N331K , pain and flare induced by allyl isothiocyanate (mustard oil), an agonist of transient receptor potential ankyrin subtype 1 (TRPA1), was increased ( 9 ). This finding is reminiscent of a report of an individual carrying mutations in the introns of TRPV1 who is completely insensitive to capsaicin and exhibits increased sensitivity to a garlic extract, another TRPA1 activator ( 5 ).…”