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).