TRPA1 and TRPV1 are differentially involved in heat nociception of mice

Abstract

Background: Two transient receptor potential (TRP) channels, TRPV1 and TRPA1, have been physiologically studied with regard to noxious heat transduction. Evidence argues against these channels as sole transducers of noxious heat or cold, respectively. Moreover, in submammalian species the TRPA1 orthologue shows heat sensitivity. Methods:In vitro, single-fibre and compound action potential recordings from C-fibres as well as measurements of stimulated cutaneous CGRP release are combined with behavioural experiments to assess heat responsiveness in wild type mice, TRPA1 and TRPV1 as well as double-null mutants.Results: Heat thresholds of cutaneous C-mechano-heat sensitive fibres were significantly higher in TRPA1−/− (43°C) than +/+ (40°C) mice, and averaged heat responses were clearly weaker, whereas TRPV1−/− showed normal heat thresholds and responses (up to 46°C). Compound action potential recordings revealed much less activity-dependent slowing of conduction velocity upon noxious heat stimulation in TRPA1−/− and a delayed deficit in TRPV1−/− in comparison to controls. Heat-induced calcitonin gene-related peptide release was reduced in TRPV1−/− but not TRPA1−/− animals. Paw withdrawal latencies to radiant heat were significantly elevated in TRPA1−/−, more so in TRPV1−/− animals. In general, double-null mutants were similar to TRPV1−/− except for the single-fibre heat responses which appeared as weak as in TRPA1−/−. Conclusions: Our results indicate that in addition to TRPV1, TRPA1 plays a role in heat nociception, in particular in definition of the heat threshold, and might therefore serve as a therapeutic target in acute inflammatory pain.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…It is more difficult to explain why these heat-responsive receptors are coexpressed with the "cold receptor" TRPA1. Of note, TRPA1 was reported to be heat activated in some studies (Hoffmann et al, 2013). Adding to the complexity, TRPA1 seems to be present on both peptidergic and nonpeptidergic neurons (Hjerling-Leffler et al, 2007).…”

“…If this controversial observation holds true, such neurons may respond to temperature changes in either direction (warm or cold) with nerve impulses. Indeed, TRPA1 was reported to respond to both heat and cold (Hoffmann et al, 2013).…”

Thermal Sensitivity and Dimethyl Sulfoxide (DMSO)

“…Both TRPA1 and TRPVI colocalize in neurons of the dorsal root ganglia at the lumbar level which innervate the hindpaw in the mouse (Hoffmann et al 2013), and both are expressed in unmyelinated peripheral nerve fibers (Weller et al 2011). Coordinated and apparently not cross-dependent action of both channel types underlies the response to suprathreshold heat stimulation, which in the mouse corresponds to >42 C. Recent evidence gathered from TRPA1 knock-out mouse studies indicates that TRPA1 has a critical role in suprathreshold pain responsiveness specifically concerning the stimuli applied to the plantar surface of a hindpaw in the mouse (Minett et al 2014), which is exactly what the current hotplate investigation was about.…”

“…Coordinated and apparently not cross-dependent action of both channel types underlies the response to suprathreshold heat stimulation, which in the mouse corresponds to >42 C. Recent evidence gathered from TRPA1 knock-out mouse studies indicates that TRPA1 has a critical role in suprathreshold pain responsiveness specifically concerning the stimuli applied to the plantar surface of a hindpaw in the mouse (Minett et al 2014), which is exactly what the current hotplate investigation was about. However, even in TRPA1/V1 double-knockout mice there still remains a substantial component of pain-reflex behavior (Hoffmann et al 2013), which underscores the complexity of as yet unresolved mechanisms of noxious heat stimulation. How exactly the plantar nerve endings determine the summation of temperature intensity and duration into the above pain threshold level is by far unclear.…”

Smart polymers in drug delivery systems on crossroads: Which way deserves following?

“…A natural case of combination of ligand responsivity and thermoresponsivity is the biological effect of capsaicine (burning-taste compound from hot peppers), a potent vanilloid TRPV1 1 receptor agonist (a temperaturegated ion channel) that after binding to this receptor lowers its switching temperature causing high temperature (>43.25°C) alert signal to occur at body temperature (37°C), resulting in burning taste [190,191]. Ligand-responsive polymers are attractive for e.g., D-glucose-triggered insulin releasing depots based on D-glucose moieties containing polymer crosslinked with concanavalin A, a lectin binding multiple D-glucose molecules [192].…”