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.
"To examine the role of TRPA1 in mechanical hypersensitivity under a myositis condition, we evaluated the effect of a selective TRPA1 antagonist, AP18, in the CFA model of inflammatory pain. When injected into craniofacial muscles, CFA induces a profound mechanical hypersensitivity that peaks within the first 3 days and gradually returns to baseline in 2–3 weeks (Ambalavanar et al., 2006; Shimizu et al., 2009; Niu et al., 2012). In the present study intramuscular administration of AP18 was found to reverse CFA-induced mechanical hypersensitivity at 24 h and 72 h post CFA treatment when mechanical hypersensitivity was most prominent. "
[Show abstract][Hide abstract] ABSTRACT: TRPA1 is expressed in muscle afferents and direct activation of these receptors induces acute mechanical hypersensitivity. However, the functional role of TRPA1 under pathological muscle pain conditions and mechanisms by which TRPA1 mediate muscle pain and hyperalgesia are not clearly understood. Two rodent behavioral models validated to assess craniofacial muscle pain conditions were used to study ATP- and NMDA-induced acute mechanical hypersensitivity and complete Freund's adjuvant (CFA)-induced persistent mechanical hypersensitivity. The rat grimace scale was utilized to assess inflammation-induced spontaneous muscle pain. Behavioral pharmacology experiments were performed to assess the effects of AP18, a selective TRPA1 antagonist under these conditions. TRPA1 expression levels in trigeminal ganglia were examined before and after CFA treatment in the rat masseter muscle. Pre-treatment of the muscle with AP18 dose-dependently blocked the development of acute mechanical hypersensitivity induced by NMDA and αβmeATP, a specific agonist for NMDA and P2X3 receptor, respectively. CFA-induced mechanical hypersensitivity and spontaneous muscle pain responses were significantly reversed by post-treatment of the muscle with AP18 when CFA effects were most prominent. CFA-induced myositis was accompanied by significant up-regulation of TRPA1 expression in TG. Our findings showed that TRPA1 in muscle afferents plays an important role in the development of acute mechanical hypersensitivity and in the maintenance of persistent muscle pain and hypersensitivity. Our data suggested that TRPA1 may serve as a downstream target of pro-nociceptive ion channels, such as P2X3 and NMDA receptors in masseter afferents, and that increased TRPA1 expression under inflammatory conditions may contribute to the maintenance of persistent muscle pain and mechanical hyperalgesisa. Mechanistic studies elucidating transcriptional or post-translational regulation of TRPA1 expression under pathological pain conditions should provide important basic information to further advance the treatment of craniofacial muscle pain conditions.
"Further studies are required to examine detailed mechanisms that underlie immune–hormone–MOR interactions in sensory ganglia. Cytokine-induced up-regulation of peripheral cannabinoid type 1 receptors (CB1R) is also dependent on the presence of testosterone (Niu et al., 2012). The up-regulation of CB1R is prevented in TG cultures from GDX male rats, only to be restored by testosterone replacement. "
[Show abstract][Hide abstract] 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) 02/2014; 18(2). DOI:10.1002/j.1532-2149.2013.00352.x · 2.93 Impact Factor
[Show abstract][Hide abstract] 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; 34(4). DOI:10.1016/j.yfrne.2013.07.002 · 7.04 Impact Factor
Toshiaki Utsumi, Naomi Kobayashi, Masahiro Hikichi, Kaori Ushimado, Yuki Ri
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