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).