Estradiol and testosterone differently affect visceral pain‐related behavioural responses in male and female rats

Abstract

In the study of pain, the presence of sex differences is well known, with female subjects being more affected in a number of chronic painful conditions; however, the underlying mechanisms and the involvement of gonadal hormones, are still controversial. This study evaluated visceral pain in a validated rat model of artificial calculosis and the effects of estradiol and testosterone administration. Adult male and female rats were divided into groups and treated with one of the substances or Oil (vehicle) for 5 days, starting 2 days before surgery, with half receiving an artificial calculosis (Stone) and half only a sham (Sham) procedure. The animals' behaviour (ureteral crises, frequency and duration) were recorded for 72 h; estradiol and testosterone plasma levels were determined in all groups at the end of the observation period. After surgery, only Stone rats showed ureteral pain crises, with a significant sex difference in the Oil-treated groups in which the number and duration of crises were higher in females than in males. This difference was not present in the estradiol-treated groups in which ureteral crises were decreased only in females while testosterone treatment had no effect in either sex. Estradiol and testosterone plasma levels were affected by treatments in both sexes. These results confirm that, also in this model of visceral pain, females experience more pain than males; moreover, they show that supraphysiological levels of estradiol, but not of testosterone, are analgesic only in females. A dose and sex-dependent efficacy of gonadal hormones is suggested and discussed.

Importance of sex to pain and its amelioration; relevance of spinal estrogens and its membrane receptors

“…The effects of estrogens on nociception are bimodal being both pronociceptive as well as antinociceptive. Antinociceptive actions of estrogens include: (1) KOR antinociception and gene expression are enhanced by exogenous or endogenous estradiol in female [102], (2) long term (28 days) ovariectomy of adult rats induces thermal and mechanical hyperalgesia that can be reversed by estradiol replacement [169], (3) physiological concentrations of estradiol attenuate drug-induced temporomandibular joint (TMJ) pain [71,96], (4) in a rat model of calculosis, estradiol is an effective analgesic in females but not males [6], (5) in women, the follicular phase (elevated estradiol) has been associated with higher thresholds to pressure, thermal and ischemic muscle pain than later phases [162], which is consonant with studies in rats showing enhanced uretal pain sensitivity during metestrus / diestrus vs. proestrus / estrus [77]. These findings agree with reports of a greater incidence of colics in the perimenstrual period (equivalent to metestrus and diestrus in rats) in fertile women with urinary calculosis.…”

Estrogens synthesized and acting within a spinal oligomer suppress spinal endomorphin 2 antinociception: ebb and flow over the rat reproductive cycle

“…Notably, in female rats, 17-β-estradiol (estradiol), the predominant estrogen, can be pronociceptive [12; 43; 44; 60; 65; 88], as well as antinociceptive [4; 15; 32; 34; 50; 55; 66; 84; 89]. Modulation of nociception/opioid antinociception by estrogens occurs, in part, via classical nuclear estrogen receptors (ERs), which function as estrogen-activated transcription factors [21].…”

Repeated Water Avoidance Stress Alters Mucosal Mast Cell Counts, Interleukin-1β Levels with Sex Differences in the Distal Colon of Wistar Rats

“…27 In the field of visceral responses, most of the preclinical studies conducted were in male rodents, 37 but few studies in females indicated that sex hormones may have an effect on visceral sensitivity in rodents. 38,39 Some studies did not even mention the sex of experimental rodents. 33 The use of a balanced proportion of male and female rodents in preclinical studies and application of sex-based analysis are needed to elucidate sex-related differences in the pathophysiological mechanism of IBS.…”