A comparative study of the effect of 17β-estradiol and estriol on peripheral pain behavior in rats

Abstract

Although estradiol has been reported to influence pain sensitivity, the role of estriol (an estradiol metabolite and another widely used female sex hormone) remains unclear. In this study, pain behavior tests, whole-cell patch clamp recording and Western blotting were used to determine whether estriol plays a role in pain signal transduction and transmission. Either systemic or local administration of 17β-estradiol produced a significant rise of mechanical pain threshold, while estriol lacked this effect in normal and ovariectomized (OVX) rats following estriol replacement. Local administration of 17β-estradiol or estriol significantly decreased ATP-induced spontaneous hind-paw withdrawal duration (PWD), which was blocked by an estrogen receptor antagonist, ICI 182, 780. However, systemic application of estriol in normal or OVX rats lacked this similar effect. In cultured dorsal root ganglion neurons, estriol attenuated α,β-methylene ATP-induced transient currents which were blocked by ICI 182, 780. In complete Freund’s adjuvant treated (CFA) rats, systemic application of 17β-estradiol or estriol decreased the mechanical pain threshold significantly, but did not change the inflammatory process. Similar effects were observed after estriol replacement in OVX rats. The expression of c-fos in lumbosacral spinal cord dorsal horn (SCDH) was increased significantly by administration of 17β-estradiol but not estriol, and not by estriol replacement in OVX rats. These results suggest that 17β-estradiol but not estriol plays an anti-hyperalgesic role in physiological pain. However, both peripheral 17β-estradiol and estriol play anti-hyperalgesic roles in ATP-induced inflammatory pain. Systemic application of estriol as well as 17β-estradiol plays hyperalgesic roles in CFA-induced chronic pain.

Introduction

Sex differences in pain perception have been reported in numerous studies, from laboratory experiments to clinical analysis. In laboratory tests, pain thresholds and pain tolerance to heat, pressure and chemical irritants are generally lower in women than in men [1], [2]. In addition, a number of chronic pain conditions such as migraine, temporomandibular joint disorder, fibromyalgia, arthritis and interstitial cystitis are more prevalent in women than in men [3], [4]. These results indicate the sex differences in pain perception. Some studies have shown that estradiol induces hyperalgesia. In inflammatory episodes, the thermal and mechanical hypersensitivities that develop days to weeks after inflammation or injury were facilitated by estrogens [5], [6]. In the weeks after induction of arthritis using complete Freund’s adjuvant (CFA), females in proestrus (high ovarian hormones) showed the greatest thermal hyperalgesia [7]. However, studies also have shown that estradiol has anti-hyperalgesic effects. Longer latencies to acute nociceptive stimuli appeared in ovariectomized, estradiol-treated female rodents compared to those in hormone-depleted controls [8]. Systemically administered estradiol decreased the number or intensity of nociceptive behaviors during the tonic phase and thus played an anti-hyperalgesic role in the formalin test [9]. These results have reflected the important role of estrogen in pain perception. We cannot conclude that estrogens worsen or alleviate pain, because it depends on the type and chronicity of pain, as well as estrogen level and stability [10].

In previous studies, estradiol, including 17β-estradiol and 17α-ethinyl estradiol [11] were commonly used as candidates of estrogen. Estriol, another metabolite of estradiol, has not yet been studied. Clinically, estriol is often used to treat estrogen-deficiency symptoms, such as disorders of the sexual cycle [12]. Due to its weaker biological activity than estradiol, intravaginal use of estriol is safe, with a low risk of endometrial proliferation or hyperplasia [13]. Studies have shown that estriol-replacement therapy has less subjective side-effects than estradiol or progesterone replacement [14]. In addition, estriol is produced abundantly in the placenta during pregnancy. Therefore, it is desirable to study the relationship between estriol and pain and the possible differences between estradiol and estriol.

In our experiments, 17β-estradiol and estriol were either systemically or locally administered, to observe the changes in peripheral pain behavior of rats. The effects of 17β-estradiol or estriol on mechanical pain threshold, ATP-induced acute inflammatory pain and CFA-induced chronic inflammatory pain were investigated in normal, ovariectomized and estriol-treated rats. The effects of 17β-estradiol or estriol on α,β-methylene ATP (αβ-me ATP)-induced currents in dorsal root ganglion (DRG) neurons and on the expression of c-fos in lumbosacral spinal cord dorsal horn (SCDH) were investigated.