The Cloned Capsaicin Receptor Integrates Multiple Pain-Producing Stimuli

Abstract

Capsaicin, the main pungent ingredient in "hot" chili peppers, elicits buming pain by activating specific (vanilloid) receptors on sensory nerve endings. The cloned vanilloid receptor (VR1) is a cation channel that is also activated by noxious heat. Here, analysis of heat-evoked single channel currents in excised membrane patches suggests that heat gates VR1 directly. We also show that protons decrease the temperature threshold for VR1 activation such that even moderately acidic conditions (pH < or = 5.9) activate VR1 at room temperature. VR1 can therefore be viewed as a molecular integrator of chemical and physical stimuli that elicit pain. Immunocytochemical analysis indicates that the receptor is located in a neurochemically heterogeneous population of small diameter primary afferent fibers. A role for VR1 in injury-induced hypersensitivity at the level of the sensory neuron is presented.

Increased hyperpolarized [1‐13C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized 13C‐labelled bicarbonate

“…The results presented here would suggest, therefore, that tissue acidosis is not itself a primary contributor to the pain observed in the CFA‐induced arthritis model, which might perhaps explain the lack of relief from either mechanical or thermal hyperalgesia in mice lacking ASIC1, ASIC2 or ASIC3 34. Although TRPV1 knockout mice display diminished thermal hyperalgesia in the CFA model,33 this is likely due to a shift in the thermal sensitivity of TRPV1 activation resulting from inflammatory mediators such as nerve growth factor dependent removal of phosphatidylinositol 4,5‐bisphosphate inhibition of TRPV1,57 rather than due to acid‐mediated modulation of the TRPV1 thermal activation threshold, which can also occur 58…”

CGRP and migraine: neurogenic inflammation revisited

“…Evidence indicates a range of G protein-coupled receptors that include those for bradykinin, prostanoids, opioids, 5-hydroxytryptamine (5-HT1 receptor), histamine (H3 receptor), neuropeptide Y, somatostatin, vasoactive intestinal polypeptide, purines and galanin. Among the channels the TRPV1 is the best known and it can be activated by noxious temperatures, low extracellular pH and a series of lipid derivatives [2,[38][39][40][41]. TRPV1 activity can be regulated by the stimulation of certain G protein coupled receptors (bradykinin and prostaglandins) or tyrosine kinase receptor (NGF) [42,43].…”

Is TRPV1 a useful target in respiratory diseases?

“…TRPV1 is also activated by acid [43][44][45], heat [24], arachidoynlethanolamide (AFA and anandamide) [46,47] In addition to exogenous stimuli, TRPV1 is sensitized by a number of endogenous inflammatory mediators. TRPV1 has several consensus phosphorylation sites where phosphorylation by protein kinases A, C and G (PKA,C and G) or tyrosine kinase might take place [49][50][51].…”

“…The airway C-fiber response to acid has both transient and sustained components. Electrophysiological and pharmacological studies show that the TRPV1-mediated response to acid is sustained, while most of the ASIC-type receptors mediate brief transient responses [45,67].…”