2.2.2. Animal Studies
Similar to that observed with humans, female animals exhibit greater baseline nociceptive sensitivity in preclinical models of pain (Mogil, 2020). In these models, opioid agonists produce greater antinociceptive effects in males than females, evidenced by greater potency and/or efficacy in males across a therapeutic dose range (See Craft, 2008; Bodnar & Kest, 2010). These differences are more apparent when opioids are administered via supraspinal than spinal or peripheral routes (see Craft, 2008; Dahan et al., 2008; Bodnar & Kest, 2010), suggesting that sex differences are mediated primarily by differences in the pharmacodynamics (rather than pharmacokinetics) of these drugs between males and females.
The magnitude of these sex differences differs across strain of subject, ranging from minimal to large differences in potency and/or efficacy between males and females (Barrett et al., 2002; Kasson & George,1984; Kest et al., 1999; Cook et al., 2000; Terner et al., 2003; 2006). The magnitude of these sex differences also vary across opioids based on their relative selectivity for – and their relative intrinsic efficacy at – the three primary opioid receptors (i.e., mu, kappa, delta; for review, see Bodnar & Kest, 2010; Dahan et al., 2008). Moreover, age differences in opioid-induced antinociception can interact with sex differences to amplify (or minimize) differences between males and females across age groups (White et al., 2008). Finally, differences between males and females can vary across nociceptive stimuli (e.g., mechanical vs. thermal), but these typically involve quantitative rather than qualitative differences across experimental endpoints, with males being more sensitive than females under the majority of experimental conditions (e.g., mechanical: Bai et al., 2015; Cicero et al., 1996; thermal: Cicero et al., 1996; Craft et al., 1999; Cook et al., 2000; Barrett et al., 2001; Craft & Bernal, 2001; Terner et al., 2002; Holtman et al., 2004; Holtman & Wala, 2004; Stoffel et al., 2005; Cataldo et al., 2005; Peckham et al., 2011). Although some examples of greater sensitivity in females have been reported (e.g., Stoffel et al., 2005; Tershner et al., 2000), there is no obvious commonality among these studies to predict conditions in which women would be more sensitive to opioid-induced analgesia than men in therapeutic settings.
Sex differences can be eliminated by a number of manipulations, but those manipulations generally involve rendering opioids less effective in both sexes. For instance, chronic morphine administration leads to antinociceptive tolerance in both sexes and abolishes the sex difference observed in naïve subjects (Holtman et al., 2004). Similarly, mutant mice that lack GIRK2 are less sensitive to opioid-induced antinociception than wildtype mice, and do not exhibit the sex differences that are apparent in wildtype mice (Mitrovic et al., 2002). Alternatively, sex differences in opioid-induced antinociception can be manipulated via hormonal manipulation, particularly via perturbation of endogenous androgens (e.g., Elliott et al., 2003; Terner et al., 2002, and see Section 3.2.2).