Neuronal and non-neuronal TRPA1 as therapeutic targets for pain and headache relief

Abstract

The transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily of channels, has a major role in different types of pain. TRPA1 is primarily localized to a subpopulation of primary sensory neurons of the trigeminal, vagal, and dorsal root ganglia. This subset of nociceptors produces and releases the neuropeptide substance P (SP) and calcitonin gene-related peptide (CGRP), which mediate neurogenic inflammation. TRPA1 is characterized by unique sensitivity for an unprecedented number of reactive byproducts of oxidative, nitrative, and carbonylic stress and to be activated by several chemically heterogenous, exogenous, and endogenous compounds. Recent preclinical evidence has revealed that expression of TRPA1 is not limited to neurons, but its functional role has been reported in central and peripheral glial cells. In particular, Schwann cell TRPA1 was recently implicated in sustaining mechanical and thermal (cold) hypersensitivity in mouse models of macrophage-dependent and macrophage-independent inflammatory, neuropathic, cancer, and migraine pain. Some analgesics and herbal medicines/natural products widely used for the acute treatment of pain and headache have shown some inhibitory action at TRPA1. A series of high affinity and selective TRPA1 antagonists have been developed and are currently being tested in phase I and phase II clinical trials for different diseases with a prominent pain component. Abbreviations: 4-HNE, 4-hydroxynonenal; ADH-2, alcohol dehydrogenase-2; AITC, allyl isothiocyanate; ANKTD, ankyrin-like protein with transmembrane domains protein 1; B2 receptor, bradykinin 2 receptor; CIPN, chemotherapeutic-induced peripheral neuropathy; CGRP, calcitonin gene related peptide; CRISPR, clustered regularly interspaced short palindromic repeats; CNS, central nervous system; COOH, carboxylic terminal; CpG, C-phosphate-G; DRG, dorsal root ganglia; EP, prostaglandins; GPCR, G-protein-coupled receptors; GTN, glyceryl trinitrate; MAPK, mitogen-activated protein kinase; M-CSF, macrophage-colony stimulating factor; NAPQI, N-Acetyl parabenzoquinone-imine; NGF, nerve growth factor; NH2, amino terminal; NKA, neurokinin A; NO, nitric oxide; NRS, numerical rating scale; PAR2, protease-activated receptor 2; PMA, periorbital mechanical allodynia; PLC, phospholipase C; PKC, protein kinase C; pSNL, partial sciatic nerve ligation; RCS, reactive carbonyl species; ROS, reactive oxygen species; RNS, nitrogen oxygen species; SP, substance P; TG, trigeminal ganglion; THC, Δ9-tetrahydrocannabinol; TrkA, neurotrophic receptor tyrosine kinase A; TRP, transient receptor potential; TRPC, TRP canonical; TRPM, TRP melastatin; TRPP, TRP polycystin; TRPM, TRP mucolipin; TRPA, TRP ankyrin; TRPV, TRP vanilloid; VG, vagal ganglion.

Keywords: CGRP; TRP channels; TRPA1; nociception; pain.

Figure 1.

(a) Targeting of the TRPA1 ion channel by a series of endogenous and exogenous agonists with relevance in pain. The TRPA1 activation signals acute nociception and allodynia to the brain and elicits CGRP and SP release from peripheral fibers to produce neurogenic inflammation. Partial agonists and desensitizing agents of the channel are reported in italics. Commonly used stimulants of TRPA1 are in bold. (b) Schematic representation of TRPA1 ion channel structure and as determined by single particle electron cryo-microscopy. Structure is based on atomic coordinates in the Protein Data Bank (https://www.rcsb.org). Image created with Biorender.com. AITC, allyl isothiocyanate; ANK, ankyrin; CGRP; calcitonin gene related peptide; Cys, cysteine; Lys, lysine; NO, nitric oxide; RCS, reactive carbonyl species; ROS, reactive oxygen species; SP, substance P; TRPA1, Transient receptor potential ankyrin.

Figure 2.

Intracellular modulation of TRPA1. G protein-coupled receptors (GPCRs) including bradykinin receptor 2 (B2), prostaglandins receptors (EP), MAS-related GPCRs (MrgprC11 and MrgprA3), protease-activated receptor 2 (PAR2), and bile acid receptor 5 (TGR5), through their second messenger signaling cascades regulate TRPA1 function. TRPA1 can also be activated or sensitized by mechanisms that increase cytoplasmic calcium levels (e.g. TRPV1 or other calcium permeable channels activation). Image created with Biorender.com. AC, adenyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; GPCR, G protein–coupled receptor; PIP2, phosphatidyl inositol-4,5-bisphosphate; PLC, phospholipase C; PKA, protein kinase A; PKC, Protein kinase C; TRPA1, Transient receptor potential ankyrin; TRPV1, transient receptor potential vanilloid.

Figure 3.

The mechanism of CGRP released from peptidergic trigeminal fibers to elicit mechanical allodynia. CGRP targets the CGRP receptor complex in adjacent Schwann cells (possibly of the Remak subtype) that, following internalization in endosomes, promotes a series of intracellular events that eventually targets Schwann cell TRPA1 to initiate a feed-forward pathway that amplifies the oxidative stress signal. On one hand, ROS by continuous Schwann cell TRPA1 targeting amplify and prolong neuroinflammation and on the other hand by targeting the neuronal TRPA1 sustain mechanical allodynia. Image created with Biorender.com. AC, adenyl cyclase; cAMP, cyclic adenosine monophosphate; CLR, calcitonin receptor-like receptor; CGRP; calcitonin gene related peptide; eNOS, endothelial nitric-oxide synthase; NO, nitric oxide; NOX1, NAD(p)H oxidase 1; PKA, protein kinase A; RCP, receptor component protein; ROS, reactive oxygen species;RAMP1, receptor activity modifying protein 1; TRPA1, transient receptor potential ankyrin 1.