3.2.2. Animal Studies
Preclinical studies yield ample evidence that testosterone and
androgenic activity are involved in nociceptive processes. Male rats
castrated as adults have lower nociceptive thresholds in response to
thermal and electrical stimuli than castrated rats given testosterone
replacement (Borzan & Fuchs, 2006; Pednekar & Mulgaonker, 1994).
Moreover, castrated male rats have lower nociceptive thresholds in
response to mechanical stimuli following carrageenan-induced
inflammation relative to castrated rats treated with testosterone
(Borzan & Fuchs, 2006). Testosterone also reduces formalin-induced
licking in females, suggesting that the effects of androgens on
nociceptive processes are not sex dependent (Aloisi et al., 2004). There
is also evidence that androgen-induced increases in nociceptive
thresholds are centrally mediated, given that intrahippocampal
administration of testosterone, DHT, or 3α-androstanediol (a DHT
metabolite) increases nociceptive thresholds in response to thermal
stimuli in castrated male rats (Edinger & Frye, 2004, 2005). Finally,
swimming increases nociceptive thresholds in castrated rats, and this
effect is enhanced by testosterone administration. Importantly, naloxone
blocks this effect, suggesting that the effects of testosterone on
nociceptive thresholds is mediated by endogenous opioids (Sharma et al.,
2019).
The effects of androgens on opioid-induced antinociception are somewhat
equivocal (see reviews by Craft et al., 2004; Dahan et al. 2008; and
Nasser & Afify; 2020), but an abundance of data suggest that androgens
increase opioid-mediated antinociception under many conditions. For
instance, neonatal castration decreases the antinociceptive effects of
morphine in adult male rats in both thermal and inflammation-related
nociceptive assays (Borzan & Fuchs, 2006; Krzanowska et al., 2002). In
addition, testosterone treatment in neonatal females increases the
antinociceptive effects of morphine in adulthood (Cicero et al., 2002b,
Krzanowska et al., 2002), thereby reducing the magnitude of sex
differences in opioid antinociception described previously (See Section
2.2.2). Similar effects have been reported in adult rats. For instance,
castration decreases sensitivity to a wide range of mu and kappa
agonists in adult rats, and these effects are observed across different
strains and behavioral assays (Bai et al., 2015; Terner et al., 2002;
Stoffel et al., 2005). Moreover, testosterone increases the
antinociceptive effects of both mu and kappa agonists in adult male rats
following castration (Stoffel et al., 2003, 2005; Sumner et al., 2006).
Finally, finasteride increases testosterone concentrations and enhances
the antinociceptive effects of morphine (Verdi & Ahmadiani, 2007).
Complicating a clear understanding of the role of androgens in
opioid-mediated antinociception are several studies reporting no effect
of androgen manipulation on opioid sensitivity. For instance, multiple
studies in male rats report that the antinociceptive effects of morphine
are not altered by castration (Cicero et al., 1996; Cicero et al.,
2002b; Islam et al., 1993; Kepler et al., 1989; Krzanowska & Bodnar,
1999) or by testosterone replacement (Peckham et al., 2011). Similarly,
neither acute nor chronic exposure to the androgen receptor agonist,
nandrolone, influences the antinociceptive effects of morphine in male
mice (Célérier et al., 2003), and chronic testosterone treatment does
not alter the antinociceptive effects of morphine in male monkeys (Negus
et al., 2001) or a kappa agonist in sheep (Cook et al., 1998).
Testosterone treatment also does not alter the antinociceptive effects
mu, kappa, or mixed-action opioids in female monkeys following
ovariectomy (Negus & Mello, 2002). The picture is also complicated by
isolated reports of androgen-induced decreases in opioid-mediated
antinociception. For example, nandrolone and DHT reduce the
antinociceptive effects of morphine in intact male rats (Philipova et
al., 2003; Tsutsui et al., 2016), and testosterone reduces the
antinociceptive effects of a delta agonist in gonadectomized male rats
(Stoffel et al., 2005). Findings such as these indicate that androgens
can interact with factors such as species, opioid receptor subtype, and
behavioral assay to influence opioid-mediated antinociceptive processes.
Despite these seemingly contradictory findings, there is a strong
correspondence within studies linking sex differences in opioid-induced
antinociception to androgenic modulation of opioid-induced
antinociception. For instance, sex differences between males and females
are partially or completely eliminated by neonatal (Cicero et al.,
2002b; Krzanoskwa et al., 2002) or adult (Bai et al., 2015; Stoffel et
al., 2003, 2005; Terner et al., 2002) castration of males, or by
masculinization of females via neonatal testosterone administration
(Cataldo et al., 2005; Cicero et al., 2002b; Krzanoskwa et al., 2002).
Indeed, studies failing to identify androgenic mechanisms of sex
differences in opioid sensitivity are much less common and often fail to
identify an alternative mechanism (e.g., Cicero et al., 1996; Kepler et
al., 1986; Peckham et al., 2011).