Bisphenol A Regulates Sodium Ramp Currents in Mouse Dorsal Root Ganglion Neurons and Increases Nociception

Sergi Soriano,Paloma Alonso-Magdalena,Angel Nadal,Minerva Gil-Rivera,Laura Marroqui,Juan Martinez-Pinna,Esther Fuentes,Jan-Ake Gustafsson

doi:10.1038/s41598-019-46769-6

Sergi Soriano, Paloma Alonso-Magdalena + Show 6 more

Open Access

https://doi.org/10.1038/s41598-019-46769-6

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Abstract

17β-Estradiol mediates the sensitivity to pain and is involved in sex differences in nociception. The widespread environmental disrupting chemical bisphenol A (BPA) has estrogenic activity, but its implications in pain are mostly unknown. Here we show that treatment of male mice with BPA (50 µg/kg/day) during 8 days, decreases the latency to pain behavior in response to heat, suggesting increased pain sensitivity. We demonstrate that incubation of dissociated dorsal root ganglia (DRG) nociceptors with 1 nM BPA increases the frequency of action potential firing. SCN9A encodes the voltage-gated sodium channel Nav1.7, which is present in DRG nociceptors and is essential in pain signaling. Nav1.7 and other voltage-gated sodium channels in mouse DRG are considered threshold channels because they produce ramp currents, amplifying small depolarizations and enhancing electrical activity. BPA increased Nav-mediated ramp currents elicited with slow depolarizations. Experiments using pharmacological tools as well as DRG from ERβ−/− mice indicate that this BPA effect involves ERα and phosphoinositide 3-kinase. The mRNA expression and biophysical properties other than ramp currents of Nav channels, were unchanged by BPA. Our data suggest that BPA at environmentally relevant doses affects the ability to detect noxious stimuli and therefore should be considered when studying the etiology of pain conditions.

Highlights

Alongside these symptoms of nociceptive hypersensitivity, trigeminal neurons showed an increased mRNA expression of estrogen receptors, extracellular signal–regulated kinases (ERK1/2) and Nav1.8 encoding Na+ channels[5]
We found that 1 nM bisphenol A (BPA) increased the frequency of action potential firing of dorsal root ganglia (DRG) neurons in response to current injection by increasing the magnitude of Nav ramp currents
To analyze if BPA had an action on pain sensitivity in vivo, we used adult mice treated with subcutaneous injection of either 50 μg/kg/day BPA or vehicle for 8 days

Summary

Introduction

Alongside these symptoms of nociceptive hypersensitivity, trigeminal neurons showed an increased mRNA expression of estrogen receptors, extracellular signal–regulated kinases (ERK1/2) and Nav1.8 encoding Na+ channels[5]. BPA seems to be involved in altered nociception, no study has yet investigated the BPA effects on nociceptors in vitro at doses that are relevant to human exposure. Numerous studies on both animals and humans have demonstrated that the natural hormone 17-β estradiol (E2) regulates pain sensitivity and plays a role in gender differences[7]. In pancreatic β-cells, BPA acts through extranuclear ERα and ERβ to modify the shape of action potentials as well as electrical activity which result from altered expression and biophysical properties of voltage-gated calcium-channels[15]. The effect of BPA on Nav ramp currents reported here was mediated by the activation of the estrogen receptor ERα in a pathway involving phosphoinositide 3-kinase (PI3K)

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