The role of endogenous molecules in modulating pain through transient receptor potential vanilloid 1 (TRPV1)

Abstract

Key points• TRPV1 (transient receptor potential vanilloid 1) channels are found throughout the body in epithelial cells and in peripheral and central terminals in neurons. They exert a variety of functions ranging from inflammation, to nociception and pain.• TRPV1 is a molecular integrator in that it can be activated by different endogenous stimuli.These interact to alter the channels' properties, thereby changing the threshold to a given stimulus and resulting in sensitization.• TRPV1 has numerous agonists and antagonists, including lipids and their metabolites, as well as gases and ions. Here, we detail what is known about the mechanisms used by endogenous molecules to modulate the activity of this important transducer for environmental and painful stimuli.• Understanding how these compounds modify TRPV1 activity will allow us to comprehend how some pathologies are associated with its deregulation.Abstract Pain is a physiological response to a noxious stimulus that decreases the quality of life of those sufferring from it. Research aimed at finding new therapeutic targets for the treatment of several maladies, including pain, has led to the discovery of numerous molecular regulators of ion channels in primary afferent nociceptive neurons. Among these receptors is TRPV1 (transient receptor potential vanilloid 1), a member of the TRP family of ion channels. TRPV1 is a calcium-permeable channel, which is activated or modulated by diverse exogenous noxious stimuli such as high temperatures, changes in pH, and irritant and pungent compounds, and by selected molecules released during tissue damage and inflammatory processes. During the last decade the number of endogenous regulators of TRPV1's activity has increased to include lipids that can negatively regulate TRPV1, as is the case for cholesterol and PIP 2 (phosphatidylinositol 4,5-biphosphate) while, in contrast, other lipids produced in response to tissue injury and ischaemic processes are known to positively regulate TRPV1. Among the latter, lysophosphatidic acid activates TRPV1 while amines such as N -acyl-ethanolamines and N -acyl-dopamines can sensitize or directly activate TRPV1. It has also been found that nucleotides such as ATP act as mediators of chemically induced nociception and pain and gases, such as hydrogen sulphide and nitric oxide, lead to TRPV1 activation. Finally, the products of lipoxygenases and omega-3 fatty acids among other molecules, such as divalent cations, have also been shown to endogenously regulate TRPV1 activity. Here we provide a comprehensive review of endogenous small molecules that regulate the function of TRPV1. Acting through mechanisms that lead to sensitization and desensitization of TRPV1, these molecules regulate pathways involved in pain and nociception. Understanding how these compounds modify TRPV1 activity will allow us to comprehend how some pathologies are associated with its deregulation.

eIF2α phosphorylation controls thermal nociception

“…Because we found no evidence of alterations in TRPV1 protein levels or trafficking to the membrane, we postulate that the mechanism by which eIF2a phosphorylation affects thermal sensation involves modulation of TRPV1 activity. Under inflammatory conditions, TRPV1 can be sensitized by numerous inflammatory mediators (e.g., bradykinin, nerve growth factor, prostaglandins, serotonin, and histamine), via multiple agonists and modulators [protein kinase A (PKA), protein kinase C (PKC), metabolites of the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome-P450 (CYP)-pathways, phospholipids, protons, and heat, among others], leading to the reduction in the activation threshold and eventually to pain hypersensitivity (43,44). The modulators, which mediate the sensitization of TRPV1 activity by p-eIF2α, remain to be determined.…”

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

“…Endogenous activators include the cannabinoid receptor ligands anandamide and oleamide (structures shown in Fig. 5), the eicosanoids HPETE [12-(S)-5-hydroperoxyeicosatetraenoic acid], 15-(S)-HPETE, 5-(S)-hydroxyeicosatetraenoic acid, 20-hydroxyeicosatetraenoic acid, leukotriene B4 (LTB4), N-arachidonoyldopamine (NADA), N-oleoyldopamine, and polyamines (reviewed in Morales-Lázaro et al, 2013). Negatively charged intracellular lipids can also activate TRPV1 (Lukacs et al, 2013).…”

Structural Determinants of the Transient Receptor Potential 1 (TRPV1) Channel Activation by Phospholipid Analogs

“…This polymodal ion channel is activated by various stimuli that include low extracellular and high intracellular pH, pungent compounds found in some plants, high temperatures (8) and lipids such as lysophosphatidic acid 18:1 (LPA) (9).…”