Electroacupuncture alleviates chemotherapy-induced peripheral neuropathy and anxiety by reducing TRPC6/PKC-dependent activation of glutamatergic neurons in the paraventricular thalamic nucleus.

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting side effect of neurotoxic cancer treatments, generally alongside anxiety disorders. The paraventricular thalamic nucleus (PVT), as an integrative node of sensory perceptions and emotional reactions, remains unclear in CIPN modulation. This study aimed to investigate the role of PVT in CIPN and reveal the mechanisms through which electroacupuncture (EA) alleviates CIPN. In this study, a CIPN mouse model with emotional disorders was established through the intervention of cisplatin for 21 d, which was validated by the von Frey test, adhesive removal test, open-field test and elevated plus-maze test. Data showed that the cisplatin-related CIPN was characterized by the increase of calcium channel proteins TRPC6 and PKC, as well as the activation of glutamatergic neurons in PVT. Inhibition of TRPC6 and PKC using SAR7334 significantly hindered sensory neuron damage and the loss of intra-epidermal nerve fibers (IENFs) and Merkel cells, while improving anxiety-like behaviors. EA treatment ameliorated the symptoms of CIPN, including neuropathic pain, impairment of cutaneous sensation, and loss of IENFs and Merkel cells in the acral skin, which exhibited similar effects of SAR7334. Mechanically, EA treatment significantly inhibited TRPC6 activation, reducing the Cainflux and attenuating p-PKC level, thereby decreasing the release of excitatory neurotransmitter glutamate in the PVT. Our findings revealed a novel mechanism through which calcium influx-mediated glutamatergic neuron activation in PVT participated in the CIPN and provided evidence that TRPC6/PKC may be potent targets for the EA effect.