3.4.2.1. Mu Receptors
Androgens decrease mu opioid receptors in neuronal cells across multiple brain regions. In human neuroblastoma cells, mu receptor mRNA decreases following nandrolone treatment, and this effect is fully blocked by simultaneous treatment with an androgenic receptor antagonist (Guarino & Spampinato, 2008). Androgens also decrease mu opioid receptor protein concentrations in the thalamus and midbrain. Castration increases mu receptor density in these areas, and this effect is blocked by chronic treatment with testosterone (Takayama et al., 1990, but see Šlamberová et al., 2002 for opposing effects in superior colliculus). Further supporting androgenic decreases in mu opioid receptor density, testosterone-treated castrated rats have lower concentrations of mu receptors in the CA1 and CA3 regions of the hippocampus relative to vehicle-treated castrated rats, and similar effects are observed in the dentate gyrus of castrated rats prenatally exposed to morphine (Šlamberová et al., 2003). Finally, intact male rats exhibit lower mu receptor density in the hypothalamus than intact female rats, and these sex differences are eliminated by either proandrogenic manipulations in females or by antiandrogenic manipulations in males (Limonta et al., 1991). Castration increases mu receptor density in the hypothalamus of male rats, and neonatal testosterone administration slows developmental increases in mu receptor density in the hypothalamus of female rats (Limonta et al., 1991; but see Piva et al., 1987 and Takayma et al., 1990 for examples of null effects of androgens on hypothalamic mu receptors).
Androgen-induced decreases in mu receptor density in some of these areas may be explained, in part, by androgen-induced increases in endogenous beta-endorphin concentrations. Increases in the concentrations of endogenous opioid peptides produce compensatory decreases in opioid receptor density similar to those observed following chronic agonist administration (Bergasa et al., 1992; Hnatowich et al., 1986; Smith & Yancey, 2003). Consequently, androgenic-induced decreases in mu receptor density in areas such as the midbrain and hypothalamus can be explained, in part, by increased concentrations of beta-endorphin in these regions; however, this does not rule out possible direct effects of androgens on mu receptor mRNA expression or protein synthesis.
It must be noted that androgens increase mu opioid receptor density under some (albeit limited) conditions. For instance, castration prevents inflammation-induced upregulation of mu receptors in the sensory ganglion of the trigeminal nerve, and upregulation is restored following chronic treatment with testosterone (Zhang et al., 2014). Similarly, subchronic treatment with the androgen receptor antagonist, flutamide, prevents inflammation-induced upregulation of mu receptor mRNA in the trigeminal ganglia and dose-dependently blocks the antihyperalgesic effects of a mu opioid agonist in intact male rats (Lee et al., 2017).