TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy

Abstract

Chemotherapy induced peripheral neuropathy (CIPN) is a frequent, disabling side effect of anticancer drugs. Oxaliplatin, a platinum compound used in the treatment of advanced colorectal cancer, often leads to a form of CIPN characterized by mechanical and cold hypersensitivity. Current therapies for CIPN are ineffective, often leading to the cessation of treatment. Transient receptor potential ankyrin 1 (TRPA1) is a polymodal, non-selective cation-permeable channel expressed in nociceptors, activated by physical stimuli and cellular stress products. TRPA1 has been linked to the establishment of CIPN and other painful neuropathic conditions. Sigma-1 receptor is an endoplasmic reticulum chaperone known to modulate the function of many ion channels and receptors. S1RA, a highly selective antagonist of Sigma-1 receptor has shown effectiveness in a phase II clinical trial for oxaliplatin CIPN. However, the mechanisms involved in the beneficial effects of S1RA are little understood. We combined biochemical and biophysical (i.e. intermolecular FRET) techniques to demonstrate the interaction between Sigma-1 receptor and human TRPA1. Pharmacological antagonism of Sigma-1R impaired the formation of this molecular complex and the trafficking of functional TRPA1 to the plasma membrane. Using patch-clamp electrophysiological recordings we found that antagonists of Sigma-1 receptor, including S1RA, exert a marked inhibition on plasma membrane expression and function of human TRPA1 channels. In TRPA1-expressing mouse sensory neurons, S1RA reduced inward currents and the firing of actions potentials in response to TRPA1 agonists. Finally, in a mouse experimental model of oxaliplatin neuropathy, systemic treatment with a S1RA prevented the development of painful symptoms by a mechanism involving TRPA1. In summary, the modulation of TRPA1 channels by Sigma-1 receptor antagonists suggests a new strategy for the prevention and treatment of CIPN and could inform the development of novel therapeutics for neuropathic pain.

Sigma Antagonists for Treatment of Neuropathic Pain Syndromes in Cancer Patients: A Narrative Review

“…However, antagonism of the S1R impaired the receptors' ability to traffic TRPA1 to the plasma membrane. In a mouse model of oxaliplatin chemotherapy, the administration of S1RA reduced inward current and lowered the firing of action potentials in response to TRPA1 agonists and prevented the development of painful neuropathy [37].…”

“…TRPA1, a nonselective cationpermeable channel present in nociceptors, has been associated with cold pain and cold-pain-associated neuropathy [36]. S1R antagonism by the drug S1RA has been shown to reduce CIPN in a phase 2 clinical trial, but the mechanisms behind this remain unclear [37]. However, antagonism of the S1R impaired the receptors' ability to traffic TRPA1 to the plasma membrane.…”

Ion Channel Genes in Painful Neuropathies

“…In a recent study, systematic therapy with Sigma-1 receptor (an endoplasmic reticulum chaperone) antagonists reduced painful symptoms in an oxaliplatin-induced neuropathy mice model through regulating TRPA1. Targeting TRPA1 with these antagonists has the potential to prevent and treat Chemotherapy-Induced Peripheral Neuropathy (CIPN) and other NP syndromes, opening the door to new pain management therapies [112]. A recent study discovered that TRPA1 in Schwann cells contributes to pain caused by CGRP and capsaicin in mice and rats.…”

Chemotherapy-induced peripheral neuropathy in children and adolescent cancer patients

“…The intense interest in the role of TRP channels in various pain states has also extended to CIPN, often with conflicting results that may arise due to species, dose, or other experimental differences. Particular interest in pathognomic cold hypersensitivity induced by oxaliplatin has seen the cold-thermosensors TRPA1 or TRPM8 implicated by several studies (Yamamoto et al, 2015b;Nakagawa and Kaneko, 2017;Chukyo et al, 2018;Rimola et al, 2021;Wu et al, 2021;Marcotti et al, 2022), although others have found no contribution (Deuis et al, 2013). TRPA1 and TRPM8, but also the heat-sensitive TRPV1 and more recently, TRPV4, have also been found to be involved in paclitaxel-, vincristine-and thalidomide-induced neuropathy, where both increased channel expression and analgesic effects from antagonists were reported (Alessandri-Haber et al, 2004;Chen et al, 2011;Materazzi et al, 2012;Hara et al, 2013;Chiba et al, 2017;Boehmerle et al, 2018).…”