Sex differences in the analgesic effects of ICI 182,780 and Flutamide on ureteral calculosis in rats
Research Highlights
► There are sex differences between male and female rats also in visceral pain. ► Gonadal hormones modify pain behavior only in females. ► Estrogens and androgen receptor antagonists act as analgesic but only in females.
Introduction
The acknowledged presence of sex differences in pain has focused attention on steroid hormones (estrogens, androgens) which have been well investigated in several aspects of sexual dimorphism. Estrogens and androgens have been found to affect pain responses in humans as well as in experimental animals, although the results were sometimes contradictory due to sex, hormone concentration and the pain model used (Aloisi and Bonifazi, 2006, Clairborne et al., 2006, Craft et al., 2004, Kuba et al., 2006). The presence of higher pain in female subjects has focused attention on the role played by estrogens in pain mechanisms and several studies have confirmed their role in enhancing pain and hyperalgesia (Aloisi and Ceccarelli, 2000, Craft, 2007, Fehrenbacher et al., 2009); on the other hand estrogens have also been found to play an analgesic role, with particular reference to visceral pain, as demonstrated by several studies in which physiological changes, ovariectomy and estrogen receptor (ER) antagonists induced visceral hyperalgesia (Bradshaw and Berkley, 2002, Chaban and Micevych, 2005, Gaumond et al., 2002, Giamberardino et al., 2007). We recently showed, using a model of artificial calculosis in rats, that prolonged administration of estradiol in intact animals, to obtain supraphysiological concentrations of the hormone in both sexes, had a clear analgesic role but only in females (Aloisi et al., 2010).
Estrogens and androgens, although considered female and male sexual hormones respectively, are present in both sexes at detectable levels and have profound effects on the subject's physiology (differentiation, development, maintenance of homeostasis). These hormones act on their cell targets through specific receptors able to rapidly change the excitability of neurons or slowly change cell metabolism. Estrogens act on estrogen receptors (ERs) α and β, known to be affected by age, sex and 17β-estradiol administration (see Micevych and Mermelstein, 2008, Tetel et al., 2009 for review). More recently a G-protein-coupled estrogen receptor (GPR30) was considered as a mediator of estrogenic activity (i.e. Kuhn et al., 2008, Levin, 2009). All functions mediated by these receptors can be blocked by ICI 182,780 (ICI), a steroidal estrogen receptor antagonist (Howell et al., 2000, Maggiolini and Picard, 2010).
Testosterone is the best known androgen in males but is also present in females. It is considered a pro-hormone since most of its actions are not mediated by its direct binding with androgen receptors (ARs): depending on the enzyme present in the cell, it can be reduced to dihydrotestosterone (DHT), acting through AR, or aromatized to estradiol acting through ER. AR action can be blocked with Flutamide (FLU), an androgen receptor antagonist (Simard et al., 1986).
In the present study we used the rat model of ureteral calculosis to evaluate estrogen- and androgen-mediated effects by treating male and female rats with estrogen or androgen receptor antagonists (ICI and FLU, respectively) for a prolonged period of time, before and during visceral pain. Behavioral (visceral pain crises) parameters were collected in male and female rats during the 72 h following surgery. Hormones (estradiol and testosterone plasma levels) were determined in the blood collected at the end of the experiment.
Section snippets
Subjects
Ninety-six adult Wistar (Harlan Italy, Udine, Italy) age-matched male and female rats (males, N = 48, weight 260–320 g; females, N = 48, weight 200–250 g upon arrival) were used for the study. After their arrival the animals were left to acclimatize in the animal house for at least 8–10 days in Plexiglas cages (35 × 23 × 18 cm) in a temperature- and humidity-controlled environment with a 12:12 h dark–light cycle (19.00–7.00 h: artificial light), with free access to food and water. All animals were housed 4
Results
All animals recovered promptly from surgery and showed no changes in weight during the six experimental days (data not shown). Once treated, females belonging to the OIL and FLU groups continued to cycle, while females in the ICI group maintained the diestrus phase throughout the experimental period (6 days).
Discussion
The main result of the present experiment is the clear analgesic effect of ICI 182,780 (ICI) and Flutamide (FLU) in female rats suffering from visceral ureteral pain. The same treatments in males had no effect on pain behavior but significantly changed estradiol and testosterone plasma levels.
ICI and FLU are well-known substances used in experimental and clinical settings on account of their antagonistic actions on ERs and ARs, respectively. In the present experiment the prolonged
Acknowledgments
This study was supported by funds from PRIN-MIUR to the research program “Visceral pain: study of hormonal and behavioral effects in rats suffering artificial ureteral calculosis”.
References (33)
- et al.
Sex hormones, central nervous system and pain
Horm. Behav.
(2006) - et al.
Estradiol and testosterone differently affect visceral pain-related behavioural responses in male and female rats
Eur. J. Pain
(2010) - et al.
Estrogen replacement reverses ovariectomy-induced vaginal hyperalgesia in the rat
Maturitas
(2002) - et al.
Estradiol inhibits ATP-induced intracellular calcium concentration increase in dorsal root ganglia neurons
Neuroscience
(2003) Modulation of pain by estrogens
Pain
(2007)- et al.
Sex differences in pain and analgesia: the role of gonadal hormones
Eur. J. Pain
(2004) - et al.
Rapid pain modulation with nuclear receptor ligands
Brain Res. Rev.
(2009) - et al.
The role of sex hormones on formalin-induced nociceptive responses
Brain Res.
(2002) - et al.
Artificial ureteral calculosis in rats: behavioural characterization of visceral pain episodes and their relationship with referred lumbar muscle hyperalgesia
Pain
(1995) - et al.
Influence of endometriosis on pain behaviors and muscle hyperalgesia induced by a ureteral calculosis in female rats
Pain
(2002)
Contribution of myofascial trigger points to migraine symptoms
J. Pain
Comparison of anti-androgenic activity of flutamide, vinclozolin, procymidone, linuron, and p, p′-DDE in rodent 10-day Hershberger assay
Toxicology
Estradiol and progesterone differentially regulate formalin-induced nociception in ovariectomized female rats
Horm. Behav.
Sex differences in brain activity during aversive visceral stimulation and its expectation in patients with chronic abdominal pain: a network analysis
NeuroImage
Plasma membrane estrogen receptors
Trends Endocrinol. Metab.
Estrogen rapidly modulates 5-hydroxytrytophan-induced visceral hypersensitivity via GPR30 in rats
Gastroenterology
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