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

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.