Journal Article

Oxidative stress mediates thalidomide-induced pain by targeting peripheral TRPA1 and central TRPV4

Materazzi, Serena, Nassini, Romina, De Logu, Francesco, Padilha Dalenogare, Diéssica, Titiz, Mustafa, Marini, Matilde, Landini, Lorenzo, Li Puma, Simone, Geppetti, Pierangelo, Marone, Ilaria Maddalena, Souza Monteiro de Araujo, Daniel, Coppi, Elisabetta, De Siena, Gaetano, Trevisan, Gabriela

2020

Overview

Background The mechanism underlying the pain symptoms associated with chemotherapeutic-induced peripheral neuropathy (CIPN) is poorly understood. Transient receptor potential ankyrin 1 (TRPA1), TRP vanilloid 4 (TRPV4), TRPV1, and oxidative stress have been implicated in several rodent models of CIPN-evoked allodynia. Thalidomide causes a painful CIPN in patients via an unknown mechanism. Surprisingly, the pathway responsible for such proalgesic response has not yet been investigated in animal models. Results Here, we reveal that a single systemic administration of thalidomide and its derivatives, lenalidomide and pomalidomide, elicits prolonged (~ 35 days) mechanical and cold hypersensitivity in C57BL/6J mouse hind paw. Pharmacological antagonism or genetic deletion studies indicated that both TRPA1 and TRPV4, but not TRPV1, contribute to mechanical allodynia, whereas cold hypersensitivity was entirely due to TRPA1. Thalidomide per se did not stimulate recombinant and constitutive TRPA1 and TRPV4 channels in vitro, which, however, were activated by the oxidative stress byproduct, hydrogen peroxide. Systemic treatment with an antioxidant attenuated mechanical and cold hypersensitivity, and the increase in oxidative stress in hind paw, sciatic nerve, and lumbar spinal cord produced by thalidomide. Notably, central (intrathecal) or peripheral (intraplantar) treatments with channel antagonists or an antioxidant revealed that oxidative stress-dependent activation of peripheral TRPA1 mediates cold allodynia and part of mechanical allodynia. However, oxidative stress-induced activation of central TRPV4 mediated the residual TRPA1-resistant component of mechanical allodynia. Conclusions Targeting of peripheral TRPA1 and central TRPV4 may be required to attenuate pain associated with CIPN elicited by thalidomide and related drugs.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analgesics / Analysis / Animal models / Ankyrins / Antagonists / Antioxidants / Biomedical and Life Sciences / Cancer / Capsaicin receptors / Chemotherapeutic-induced peripheral neuropathy / Chemotherapy / Cold / Complications and side effects / Diabetic neuropathy / Diagnosis / Dosage and administration / Drug dosages / Drug targeting / Health aspects / Hematology / Hydrogen peroxide / Hypersensitivity / Immunotherapy / Life Sciences / Multiple myeloma / Oxidation resistance / Oxidative stress / Pain / Pain perception / Peripheral neuropathy / Physiological aspects / Polyneuropathies / Research Article / Risk factors / Sciatic nerve / Spinal cord / Thalidomide / Transient receptor potential proteins / TRPA1 / TRPV4 / Tumor necrosis factor-TNF