TRPA1 and TRPM8 Receptors May Promote Local Vasodilation that Aggravates Oxaliplatin-Induced Peripheral Neuropathy Amenable to 17β-Estradiol Treatment.

Abstract

Oxaliplatin is a widely used chemotherapeutic agent that induces both acute and chronic peripheral neuropathy. Based on previous research indicating that estrogen replacement may attenuate some forms of pain in ovariectomized animals, we examined the effects of 17β-estradiol in OXAIPN. We discovered that local cold exposure induces an abnormal vascular response in both acute and chronic models of OXAIPN (oxaliplatin-induced peripheral neuropathy) that may be used as an easy and non-invasive method to predict which patients may be susceptible to the development of severe, chronic OXAIPN. Neuropathy was induced by injection of oxaliplatin on the first two days for the short-term OXAIPN group and twice a week for 3 weeks for the long-term OXAIPN group. Local cold-induced vascular responses were recorded in the presence or absence of subcutaneously injected transient receptor potential ankyrin 1 (TRPA1) antagonist HC033031 or transient receptor potential melastatin 8 (TRPM8) antagonist AMTB using laser Doppler flowmetry. Both short-term and long-term OXAIPN groups exhibited abnormal local cold-induced vascular responses, characterized by initial vasodilation followed by vasoconstriction. Local blockade of TRPA1 or TRPM8 receptors attenuated the initial vasodilation. Changes in release of calcitonin gene related peptide (CGRP) and nitric oxide (NO) metabolites due to local cold exposure at the hind paw were also involved. Administration of 17β-estradiol resulted in an anti-nociceptive effect and attenuating abnormal vasodilation.