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).