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.