Androgen receptor transcriptionally regulates μ-opioid receptor expression in rat trigeminal ganglia

Abstract

The involvement of testosterone in pain, inflammation, and analgesia has been reported, but the role of androgen receptor (AR), a steroid receptor for testosterone, is not well understood. We have previously shown that peripheral inflammation upregulates μ-opioid receptor (MOR) in rat trigeminal ganglia (TG) in a testosterone-dependent manner. In this study, we hypothesized that testosterone regulates MOR expression via transcriptional activities of AR in TG. We first examined whether AR is co-expressed with MOR in TG neurons. Our immunohistochemical experiment revealed that AR staining is detected in neurons of all sizes in TG and that a subset of AR is expressed in MOR as well as in TRPV1-positive neurons. We identified the promoter region of the rat MOR gene contains putative AR binding sites. Using chromatin immunoprecipitation assay, we demonstrated that AR directly binds to these sites in TG extracts. We confirmed with luciferase reporter assay that AR activated the MOR promoter in response to androgens in a human neuroblastoma cell line (5H-5YSY). These data demonstrated that AR functions as a transcriptional regulator of the MOR gene activity. Finally, we showed that flutamide, a specific AR antagonist, prevents complete Freund’s adjuvant (CFA)-induced upregulation of MOR mRNA in TG, and that flutamide dose-dependently blocks the efficacy of DAMGO, a specific MOR agonist, on CFA-induced mechanical hypersensitivity. Our results expand the knowledge regarding the role of androgens and their receptor in pain and analgesia and have important clinical implications, particularly for inflammatory pain patients with low or compromised plasma testosterone levels.

Testosterone deficiency in non-cancer opioid-treated patients

“…As well as opioids affecting testosterone levels, testosterone may also be involved in the regulation of endogenous opioid activity. In fact, androgen receptors are involved in the transcriptional regulation of the MOP receptor [ 94 ]. Therefore, in men treated with opioids, hypogonadism may manifest as poor control of pain and hyperalgesia, which can in turn cause sexual dysfunction and mood impairment.…”

Chronic 17β-estradiol pretreatment has pronociceptive effect on behavioral and morphological changes induced by orofacial formalin in ovariectomized rats

“…Hormonal receptors are present in both the trigeminal ganglion and the spinal trigeminal nucleus pars caudalis (TNC) providing the molecular basis for direct modulatory action on the peripheral and central sensitization in the trigeminal system. 18 – 21 At present, however, the exact mechanisms underlying sex-related differences in the prevalence of these craniofacial pain conditions remain obscure.…”

Testosterone modulation of ethanol effects on the �‑opioid receptor kinetics in castrated rats

“…In the cortex, ethanol induced an increase in B max ; when testosterone was administered with alcohol, the receptor numbers were reversed and returned to normal levels. Testosterone has been demonstrated to have analgesic effects in several pre-clinical and clinical (40) pain models (41-46). The analgesic effect of testosterone is promoted, at least in part, by µ-opioid receptor regulation (41,47).…”

“…Testosterone has been demonstrated to have analgesic effects in several pre-clinical and clinical (40) pain models (41-46). The analgesic effect of testosterone is promoted, at least in part, by µ-opioid receptor regulation (41,47). Testosterone modulated the expression of µ-opioid receptors in the midbrain periaqueductal gray (38).…”

“…These data provide evidence of involvement of the opioid system in testosterone-induced µ-opioid receptor effects, investigated previously (39). In addition, localization of AR expression and µ-opioid expression on the same neuron provides mechanisms by which testosterone may exert regulation of the µ-opioid receptors, through activation of the transcriptional machinery of the µ-opioid receptor gene in primary afferent nociceptors, where it binds directly to the region of the µ-opioid receptor gene promoter (41). In the present study, concurrent administration of testosterone and ethanol was accompanied by a significant decrease of B max and an increase of K d , which indicated a decreased affinity of the µ-opioid receptors in hypothalamus and midbrain regions.…”