TRPA1 as a therapeutic target for nociceptive pain

Abstract

Introduction: Chronic pain affects approximatively 30-50% of the population globally. Pathologies such as migraine, diabetic neuropathy, nerve injury and treatment with chemotherapeutic agents, can induce chronic pain. Members of the transient receptor potential (TRP) channels, including the TRP ankyrin 1 (TRPA1), have a major role in pain.

Areas covered: We focus on TRPA1 as a therapeutic target for pain relief. The structure, localization, and activation of the channel and its implication in different pathways to signal pain are described. This paper underlines the role of pharmacological interventions on TRPA1 to reduce pain in numerous pain conditions. We conducted a literature search in PubMed up to and including July 2020.

Expert opinion: Our understanding of the molecular mechanisms underlying the sensitization of central and peripheral nociceptive pathways is limited. Preclinical evidence indicates that, in murine models of pain diseases, numerous mechanisms converge on the pathway that encompasses oxidative stress and Schwann cell TRPA1 to sustain chronic pain. Programs to identify and develop treatments to attenuate TRPA1-mediated chronic pain have emerged from this knowledge. Antagonists explored as a novel class of analgesics have a new and promising target in the TRPA1 expressed by peripheral glial cells.

Keywords: Inflammatory pain; TRP ankyrin 1 (TRPA1); Transient Receptor Potential (TRP) channels; neuropathic pain; nociception.

Figure 1. Phylogenetic tree of the eukaryote TRP ion channels superfamily.

Figure 2

Structure of the TRPA1 channel. The TRPA1 channel is a homotetramer with each subunit containing six transmembrane helices, a series of ankyrin repeats, and intracellular NH2- and COOH-termini. The transmembrane helices are labeled S1-S6. Orange box reports a list of the main TRPA1 agonists.

Figure 3

(a) Tissue injury generates a series of inflammatory agents, including reactive oxygen (ROS), nitrogen (nitric oxide) and carbonylic (4-hydroxy-2-nonenal, 4-HNE) species, bradykinin, prostaglandins, histamine, serotonin, kinins, cytokines, neuropeptides, and neurotrophins and chemokines. Some of these agents, such as ROS, cyclopentenone-prostaglandins (cyclo-PGs), nitric oxide, and 4-HNE, directly gate the channel, whereas other agents indirectly modulate TRPA1 activity, thus promoting intracellular signaling cascades. Activation of both pathways contributes to the generation of acute pain. (b) The injured nerve trunk releases proinflammatory chemokines, which recruit activated macrophages within the lesioned area. Phagocyte-dependent oxidative stress (ROS) activates TRPA1 in Schwann cells, which evokes a calcium (Ca²⁺)-dependent, NADPH oxidase 1 (NOX1)-mediated amplification of hydrogen peroxide (H₂O₂) release, which targets nociceptor TRPA1 to signal mechanical allodynia.