Effects of gonadal hormones on the peripheral cannabinoid receptor 1 (CB1R) system under a myositis condition in rats.
ABSTRACT In this study, we assessed the effects of peripherally administered cannabinoids in an orofacial myositis model, and the role of sex hormones in cannabinoid receptor (CBR) expression in trigeminal ganglia (TG). Peripherally administered arachidonylcyclopropylamide (ACPA), a specific CB1R agonist, significantly attenuated complete Freund's adjuvant (CFA)-induced mechanical hypersensitivity in the masseter muscle in male rats. The ACPA effect was blocked by a local administration of AM251, a specific CB1R antagonist, but not by AM630, a specific CB2R antagonist. In female rats, a 30-fold higher dose of ACPA was required to produce a moderate reduction in mechanical hypersensitivity. CFA injected in masseter muscle significantly upregulated CB1R mRNA expression in TG in male, but not in female, rats. There was a close correlation between the CB1R mRNA levels in TG and the antihyperalgesic effect of ACPA. Interleukin (IL)-1β and IL-6, which are elevated in the muscle tissue following CFA treatment, induced a significant upregulation of CB1R mRNA expression in TG from male rats. The upregulation of CB1R was prevented in TG cultures from orchidectomized male rats, which was restored by the application of testosterone. The cytokines did not alter the CB1R mRNA level in TG from intact as well as ovariectomized female rats. Neither estradiol supplement nor estrogen receptor blockade had any effects on CB1R expression. These data indicate that testosterone, but not estradiol, is required for the regulation of CB1Rs in TG under inflammatory conditions, which provide explanations for the sex differences in the antihyperalgesic effects of peripherally administered cannabinoids.
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ABSTRACT: Women disproportionately suffer from many deep tissue pain conditions. Experimental studies show that women have lower pain thresholds, higher pain ratings and less tolerance to a range of painful stimuli. Most clinical and epidemiological reports suggest female gonadal hormones modulate pain for some, but not all, conditions. Similarly, animal studies support greater nociceptive sensitivity in females in many deep tissue pain models. Gonadal hormones modulate responses in primary afferents, dorsal horn neurons and supraspinal sites, but the direction of modulation is variable. This review will examine sex differences in deep tissue pain in humans and animals focusing on the role of gonadal hormones (mainly estradiol) as an underlying component of the modulation of pain sensitivity.Frontiers in Neuroendocrinology 07/2013; · 7.99 Impact Factor
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ABSTRACT: Peripheral opioid receptor expression is up-regulated under inflammatory conditions, which leads to the increased efficacy of peripherally administered opioids. Sex differences in the effects of inflammation, cytokines and gonadal hormones on μ-opioid receptor (MOR) expression in trigeminal ganglia (TG) are not well understood. MOR mRNA and protein levels in TG from male and female Sprague Dawley rats following complete Freund's adjuvant (CFA)-induced muscle inflammation were assessed. Cytokine-induced changes in MOR mRNA expression from TG cultures prepared from intact and gonadectomized male and female, and gonadectomized male rats with testosterone replacement were examined. Behavioural experiments were then performed to examine the efficacy of a peripherally administered MOR agonist in male, female and gonadectomized male rats under a myositis condition. CFA and cytokine treatments induced significant up-regulation of MOR expression in TG from male, but not from female, rats. The cytokine-induced up-regulation of MOR mRNA expression was prevented in TG from orchidectomized (GDX) male rats, which was restored with testosterone replacement. Peripherally administered DAMGO, a specific MOR agonist, significantly attenuated CFA-induced masseter mechanical hypersensitivity only in intact male rats. Collectively, these data indicate that testosterone plays a key role in the regulation of MOR in TG under inflammatory conditions, and that sex differences in the anti-hyperalgesic effects of peripherally administered opioids are, in part, mediated by peripheral opioid receptor expression levels.European journal of pain (London, England) 06/2013; 18(2). · 3.37 Impact Factor
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ABSTRACT: We have previously shown that anti-hyperalgesic effects of cannabinoid agonists under inflammatory condition are much greater in male than female, and that inflammatory cytokines upregulate cannabinoid receptor type 1 (CB1) expression in male, but not female, trigeminal ganglia (TG) in a testosterone-dependent manner. In this study, we investigated the mechanisms underlying the testosterone-mediated regulation of peripheral CB1 expression. We hypothesized that testosterone upregulates CB1 through transcriptional modulation by androgen receptor (AR). IL-1β, a pro-inflammatory cytokine, upregulated CB1 mRNA expression in TG of male rats. The cytokine-induced upregulation was prevented by the pretreatment with flutamide, a specific antagonist for AR, but not by ICI 182,780, a specific antagonist for estrogen receptor, suggesting that the effects of testosterone are not mediated by estradiol, a testosterone metabolite. The expression levels of AR and IL-1β receptors were comparable between male and female TG, suggesting that the male specific IL-1β effects on CB1 upregulation occurs downstream to these receptors. The chromatin immunoprecipitation assay showed AR binding to the CB1 promoter in the rat TG. Furthermore, luciferase reporter assay revealed that AR activated the CB1 gene in response to testosterone or dihydrotestosterone treatment. These experiments provided compelling evidence that testosterone regulates CB1 gene transcription in TG through AR following cytokine stimulation. These results should provide mechanistic bases for understanding cytokine-hormone-neuron interactions in peripheral cannabinoid systems, and have important clinical implications for pain patients in whom testosterone level is naturally low, gradually declining or pharmacologically compromised.Neuroscience 09/2013; · 3.33 Impact Factor