Estrogen modulation of pain perception with a novel 17β-estradiol pretreatment regime in ovariectomized rats

Abstract

Estrogen plays substantial roles in pain modulation; however, studies concerning sex hormones and nociception often yield confusing results. The discrepancy could be a result of lack of consensus to regard estrogen as a variable when working with animal models; thus, the influence of hormones' fluctuations on nociception has continually been neglected. In the present study, we designed a novel hormone substitution model to aid us to evaluate the effects of estrogen's long-term alterations on ovariectomy (OVX)-induced mechanical hyperalgesia and the expression of estrogen receptors(ERs). OVX rats were implanted with slow-release estrogen pellets at differently arranged time points and doses, such that a gradual elevation or decrease of serum estrogen levels following a relatively stable period of estrogen replacement was achieved in rats. Our results demonstrated that gradual estrogen depletion rather than elevation following the stable period of estrogen substitution in OVX rats alleviated OVX-induced mechanical hyperalgesia in a dose-independent manner, and the opposite estrogen increase or decrease paradigms differently regulate the expression of spinal ERs. Specifically, in rats rendered to continuously increased serum estrogen, the early phase estrogen-induced anti-nociception effect in OVX rats was eliminated, which was accompanied by an over-activation of ERα and a strong depression of ERβ, while in the OVX rats subject to gradual decrease of estrogen replacement, both ERα and ERβ increased modestly compared with the OVX group. Thus, the present study demonstrated that estrogen increase or decrease modulate nociception differently through change of spinal ERs.

Estrogen receptors in pain modulation: cellular signaling

“…Obviously, the different types of ERs mediate different estrogenic effects. However, having been focused on the relationship between estrogen and pain over the past several years, our team highlights that the nociceptive effect of estrogen is dependent not only on its presence but also on its dynamic modulation at the system level [ 10 ], which may help explain the contradictory results regarding the mediation of nociception by estrogen.…”

“…Estrogen has long been found to affect the sensory and pain systems. Ovariectomized (OVX) rats or mice tend to manifest mechanical and thermal hyperalgesia [ 9 ], while supplementation with estrogen can reverse the symptoms [ 10 ]. 17-β estradiol (E2) can also alleviate neuropathic pain induced by spared nerve injury in male rats [ 11 ].…”

miR-1306-3p directly activates P2X3 receptors in primary sensory neurons to induce visceral pain in rats

“…To avoid the periodic effects of estrogen on pain, we did the studies only on male rats for ensuring the uniformity and repeatability of experiments. 23 , 32 , 61 The room temperature was controlled at 22 ± 2°C, and the light cycle was automatically controlled (light/dark 12-hour cycle). Chronic visceral pain was induced by neonatal colonic inflammation (NCI) as described previously.…”

Unveil the pain of endometriosis: from the perspective of the nervous system

“…A possible explanation is that oestrogen alters ERs in the spine, changing nociceptive sensation (Ref. 87). Experimental studies with endometriosis animals showed that inhibiting overactive protein kinase B (AKT) and ERK1/2 pathways reduced the pro-inflammatory microenvironment and aromatase P450 expression as well as E2 biosynthesis.…”