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.

Effects of β-estradiol on cold-sensitive receptor channel TRPM8 in ovariectomized rats

“…Past research involving cold stress-induced detrusor overactivity revealed that the loss of estrogen due to ovariectomy increased expression of TRPM8 channel mRNA and cognate protein in lumbar skin [ 23 ]. Other recent studies also showed that OVX rats or mice with a long-term deficiency of estrogen exhibited greater sensitivity to thermal and mechanical stimuli, while estrogen replacement relieved such hyperalgesia [ 19 , 25 , 27 ]. This suggests that the TRPM8 channel may be overexpressed in dermal layers of postmenopausal women with low estrogen levels, who have symptoms of hypersensitivity to cold, and that estrogen replacement may improve the overexpression of TRPM8 channel mRNA.…”

“…Ding et al [ 8 ] reported that Icilin, a TRPM8/TRPA1 agonist, produces a dose-related hyperthermic response mediated by NO production in rats. Furthermore, Pan et al [ 25 ] reported that, in rats, TRPM8/TRPA1 promotes oxaliplatin-induced-vasodilation, which is associated with NO metabolites, and this vasodilation is attenuated by 17β-estradiol. Together with these reports, TRPM8 and estradiol seem to be related with mechanisms of thermosensation, involving vascular regulation mediated by NO production.…”

Estrogen modulation of visceral pain

“…Estrogen alters signal transduction and cellular activity by regulating the response of neurons to nociceptive receptors and ion channels (Chaban, 2012;Pan et al, 2016). The transient receptor potential ion channel (TRPV) and purinergic receptors (P2X2R and P2X3R) are known to participate in visceral nociceptive integration (Basbaum, 2009).…”

Effect of Danggui Sini Decoction on the Behaviour and Dorsal Root Ganglion TRP Channel of Neuropathic Pain in CCI Rats

“…The TRP family is broadly reflected in the nervous system. TRP vanilloid 1 (TRPV1), TRP vanilloid 2 (TRPV2), TRP vanilloid 3 (TRPV3), TRP vanilloid 4 (TRPV4), TRP ankyrin 1 (TRPA1) and TRP melastatin 8 (TRPM8), which belong to the large TRP ion channel superfamily, are critical contributors to normal and pathological pain [14,15] . Smith et al concluded that there was increased expression of TRPA1, TRPV1 and TRPM8 in DRG neurons [16] .…”

“…Smith et al concluded that there was increased expression of TRPA1, TRPV1 and TRPM8 in DRG neurons [16] . Pan et al reported that the TRPM8 and TRPA1 expression were up-regulated in both acute and chronic pain [14] . Ceppa et al considered that TRPV4 could contribute to pain and TRPA1 might contribute to inflammation [15] .…”