2.4.2. Opioid Receptors
Sex differences are also apparent for all three major opioid receptor subtypes. Male rats have significantly higher mu receptor protein levels in the spinal cord and midbrain (Kren et al., 2008; Bernal et al., 2007), and sex differences in sensitivity to the antinociceptive effects of mu opioids (M > F) can be traced to functional differences in the density of mu receptors in the periaqueductal grey area (M > F; Loyd et al., 2008). Data examining sex differences in other areas are less clear, with conflicting findings in the hypothalamus that vary across age (Rimanóczy & Vathy, 1995; Limonta et al., 1991; Maggi et al., 1991). Complicating matters further, sex differences in mu receptor concentrations can either be exaggerated or minimized by the sex and position of intrauterine siblings, with nearby male and female fetuses producing masculinizing and feminizing effects, respectively; however, this effect too varies across brain region (Morely-Fletcher et al., 2003).
Male rats have significantly greater concentrations of delta opioid receptors within the dentate gyrus than female rats (Williams et al., 2011). Male rats also have greater delta receptor concentrations within the CA1 region of the hippocampus, but this is dependent on the phase of the estrous cycle in females (Williams et al., 2011). Similarly, male rats have greater delta receptor concentrations in the amygdala, but this effect also depends on the estrous phase of females (Wilson, Mascagni, & McDonald, 2002). In both of these cases, sex differences are confined to the proestrus phase of the estrous cycle. Females exhibit greater concentrations of delta receptors in CA3 pyramidal cells of the hippocampus, but this effect is also dependent on the estrous cycle and only apparent during proestrus. Complicating matters further, acute and chronic stress alter delta receptors in a sexually dimorphic fashion, which has implications for sex differences in learning and memory in response to different types of stressors (Mazid et al., 2016).
Although limited, the available data suggest that female rats have significantly higher concentrations of kappa receptors in the spinal cord and hindbrain (but not necessarily midbrain) compared to males (Kren, Haller, & Welch, 2008; Drake et al., 2007). These differences are highly dependent on the estrous cycle, with kappa receptor density in females increasing within the spinal cord during proestrus and increasing in both the spinal cord and medulla during estrus (Drake et al., 2007; Harris et al., 2004). Less is known regarding sex differences in kappa receptors within the forebrain.
The studies described in this section reveal that differences in opioid peptides and opioid receptors vary across neuroanatomical region and vary across age and developmental stage. Importantly, concentrations of these various peptides and proteins are under dynamic regulation by gonadal hormones in both sexes. In females, concentrations of endogenous peptides and receptors fluctuate significantly over the course of the estrous cycle, creating and then eliminating sex differences in a cyclic fashion. Given evidence that these variations in peptide and receptor concentrations have functional consequences (e.g., Bradshaw et al., 2000; Flores et al., 2003; Loyd, Wang, & Murphy, 2008; Williams et al., 2011; Drake et al., 2007; Harris, Chang, & Drake, 2004), determinations of sex differences in opioid sensitivity should take into account the phase of the estrous cycle when those data are available.