3.3. Effects of Androgens on Unconditioned Effects of Opioids
Opioid use decreases androgenic activity in males, leading to clinically relevant hypogonadism in long-term users of medicinal and recreational mu agonists (see reviews by AminiLari et al., 2019; Bawor et al., 2015b; O’Rourke & Wosnitzer, 2016; Yilmaz et al., 1999; Ho, 2019). In contrast, comparatively less research has been conducted on both endogenous and exogenous androgens influence unconditioned opioid-mediated effects. The few available studies report little consistency across the disparate endpoints examined.
Chronic self-administration of intracerebroventricular testosterone produces significant mortality resulting from severe autonomic depression in as little as two weeks (Peters & Woods, 2004), and lethality from AAS overdoses resembles that of morphine and heroin (Peters & Woods, 2004; Wood, 2006). Repeated exposure to testosterone decreases respiration, body temperature, and locomotor activity in male hamsters, and these effects can be blocked by the opioid receptor antagonist, naltrexone (Peters & Woods, 2004). Moreover, both acute and chronic administration of nandrolone increases morphine-induced hypothermia in intact male mice (Célérier et al., 2003). In contrast, exogenous androgens do not alter morphine-induced locomotor activity in intact male rats and mice (Célérier et al., 2003; Cooper & Wood, 2014), and castration (with or without testosterone replacement) does not alter morphine-induced locomotor activity (Craft et al., 2006).
G protein-coupled inwardly rectifying potassium channels (GIRKs) are the primary post-synaptic effector of mu opioids and are at least partly responsible for sex differences in opioid-induced antinociception. Endogenous androgens increase GIRK2 gene expression in the brain and spinal cord in male rats as evidenced by decreases in GIRK2 expression following castration; however, these effects cannot be reversed by exogenous testosterone treatment (Ahanagar et al., 2008). In intact male rats, mu opioid agonists acutely increasec-fos and JunB gene expression in multiple brain regions (e.g., D’Souza et al, 2001; Harlan et al., 2000). Chronic treatment with exogenous androgens significantly decreases morphine-inducedc-fos and JunB gene expression in the caudate putamen (Harlan et al., 2000), suggesting that androgens can functionally antagonize the effects of mu opioids under some conditions. Some of the effects of androgens on opioid-mediated responses can be attributed to activational rather than developmental effects, given that a single bolus dose of testosterone on postnatal day 1 does not alter the expression of mu opioid receptors, morphine-induced dopamine release, morphine-induced locomotor effects, or morphine-induced conditioned place preference in adulthood in either male or female rats (Velásquez et al., 2019).