Estrogen and μ-opioid receptor antagonists counteract the 17β-estradiol-induced licking increase and interferon-γ reduction occurring during the formalin test in male rats

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Abstract
Women have a higher incidence of chronic pain syndromes than men and are generally more sensitive to experimental pain. Numerous studies have shown that the female gonadal hormones, estrogens, can profoundly affect the nervous and immune systems, including mechanisms involved in pain and nociception. In the present study, we used antagonists of estrogen receptors (ER) or μ-opioid receptors (μOR) to evaluate the effects of estrogens on formalin-induced behavioural and immune responses in male rats. After two days of priming with 17β-estradiol or saline (i.c.v.), animals were subjected to the formalin test; 15 min prior to formalin (50 μl, 5%) or sham injection in the hind paw, animals were treated with an ER antagonist (ICI 182,780, ICI) or a μOR antagonist (β-funaltrexamine, FNA) or saline. The spontaneous behaviours, pain-related behaviours and interferon-γ (IFN-γ) production by peripheral blood mononuclear cells were studied in all groups. We found that central administration of estradiol increased the amount of licking of the formalin-injected paw in the second phase of the formalin test. Whereas ICI and FNA had no effect on pain behaviour in saline-pre-treated animals, both antagonists reversed the estradiol-induced increase in licking. The immune system was differently affected by formalin and estradiol treatment. Indeed, formalin injection per se decreased IFN-γ production; estradiol had no effect on sham-injected animals but strongly reduce the decrease of IFN-γ production in formalin-injected animals. The results demonstrate that centrally acting estrogens affect ER- and μOR-mediated pain processing and influence immune function.