ThermoTRPs and Pain

Abstract

The ability of the body to perceive noxious stimuli lies in a heterogeneous group of primary somatosensory neurons termed nociceptors. The molecular receptors of noxious mechanical, temperature, or chemical stimuli are expressed in these neurons and have drawn considerable attention as possible targets for analgesic development to improve treatment for the millions who suffer from chronic pain conditions. A number of thermoTRPs, a subset of the transient receptor potential family of ion channels, are activated by a wide range on noxious stimuli. In this review, we review the function of these channels and examine the evidence that thermoTRPs play a vital role in acute, inflammatory and neuropathic nociception.

Keywords: TRPA1; TRPM3; TRPM8; TRPV1; TRPV3; TRPV4; analgesia; nociception; pain; thermoTRPs.

Figure 1

Pain and inflammation. A. Inflammatory sensitization of nociceptors and the neurogenic response. Primary sensory nociceptors (blue) respond to tissue damage caused by noxious thermal, mechanical or chemical stimuli and contribute to the inflammatory response. In addition to sending painful signals to the spinal cord and then the brain, primary nociceptors release neuropeptides such as CGRP and Substance P which act on peripheral tissues to stimulate vasodialation, vascular leakage and promote the release of inflammatory mediators such as protons, NGF, bradykinin, lipids, prostaglandins, and ATP (also known as the inflammatory soup; colorful spheres) which in turn promote the sensitization of the nociceptor where the threshold of activation of these neurons by physical or chemical stimuli is lowered. B. Pain and coding by thermoTRP receptors. Noxious stimuli and temperatures activate thermoTRP receptors. TRPM8 is activated by cold (< 26°C) and cooling compounds such as menthol. TRPV1 is activated by noxious heat (43°C), vanilloids such as capsaicin, and acidic pH, while TRPA1 is activated by a wide variety of pungent compounds including AITC, cinnamaldehyde (the pungent compound of cinnamon) and allicin, the active ingredient of garlic. Co-expression of TRPV1 and TRPM8 has been reported (violet neurons) as well as co-expression of TRPV1 and TRPA1 (magenta neurons).

Figure 2

Schematic diagram of TRPV1 illustrating residues that are involved in activation and regulation of the channel.

Figure 3

TRPM8. A. Schematic diagram of TRPM8 illustrating residues that are involved in activation and regulation of the channel. B. Model for TRPM8 function showing possible connections involved in the perception of innocuous cool, noxious cold and analgesia. TRPM8 mediates both noxious cold (magenta neurons) and innocuous cool (blue neurons). Noxious cold perception may involve a pathway separate from innocuous cool sensation or could potentially involve a model in which a single type of TRPM8 expression primary afferent could synapse differentially with second order spinal neurons such that innocuous cool stimuli may be sufficient to activate innocuous cool second order spinal neurons whereas a more intense noxious cold stimulus is necessary to activate a second order nociceptive spinal neuron. Cool analgesia mediated by TRPM8 neurons could be accomplished by direct inhibition of nociceptors (red) or through inhibitory interneurons (yellow) in the spinal cord acting either pre- or post-synaptically in the dorsal horn. Black text indicates strong synapses and grey text indicates weaker synapses.

Figure 4

Schematic diagram of TRPA1 illustrating residues that are involved in activation and regulation of the channel.