17β-estradiol Potentiates Acid-sensing Ion Channel Activity In Primary Sensory Neurons: A Novel Mechanism Underlying Sex Difference In Acidosis-induced Nociception

Sex differences have been reported in a number of pain conditions. Women are ingeneral more sensitive to pain than men，and estrogen plays a key role in the sexdifferences in pain. However, it is unclear whether the sex difference inacidosis-evoked pain also occurs. We report here a sex difference in aceticacid-induced nociception in both male and female rats, with females being moresensitive than males to acetic acid. Local application of exogenous17β-estradiol (E2)exacerbated acidosis-evoked nociceptive response in male rats. E2and ERα agonistMPP, but not ERβ agonist DPN, replacement also reversed attenuation of the aceticacid-induced nociceptive response in OVX females. Moreover, E2can exert a rapidpotentiating effect on the functional activity of acid-sensing ion channels (ASICs),which mediated the acidosis-induced events. E2dose-dependently increased theamplitude of ASIC currents with a42.8±1.6nM of EC50. E2shifted theconcentration–response curve for proton upwards with a50.1±6.2%increase of themaximal current response to proton. E2potentiated ASIC currents via an ERα andERK1/2signaling pathway. E2also altered acidosis-evoked membrane excitability ofDRG neurons and caused a significant increase in the amplitude of the depolarizationand the number of spikes induced by acid stimuli. E2potentiation of the functionalactivity of ASICs revealed a peripheral mechanism underlying this sex difference inacetic acid-induced nociception.