Translational Studies of Sex Differences in Sensitivity to Opioid Addiction

The rapid escalation of opioid addiction, fueled by the increased potency and availability of prescription opioid painkillers, has been declared an epidemic in the US. Although opioid addiction has historically exhibited a substantially higher prevalence in men, adolescent girls are now abusing opioids at a higher rate than boys, the prevalence of fatal opioid overdoses has increased at a higher rate among women relative to men, and women are more likely to use opioids to manage stress. This commentary highlights three examples of recent advancements and ongoing challenges in translational studies of sex differences in sensitivity to the addictive properties of mu opioid receptor (MOR) agonists such as morphine, oxycodone and heroin.

One recent advancement in mechanistic understanding of these sex differences is the finding in ex vivo hippocampal slice preparations that a form of MOR-dependent cellular learning is dramatically enhanced in proestrous female rats, when 17-β estradiol levels are at their peak (Harte-Hargrove et al, 2015). This female-specific, estradiol-dependent lowering of thresholds for synaptic plasticity may explain, in part, why female rats with high estradiol levels acquire opioid self-administration behavior more rapidly than males (Roth et al, 2002). Although these findings mirror the observed ‘telescoping' course of illness in women relative to men—characterized by a more rapid progression from initiation of opioid use to an opioid use disorder—there is not direct clinical evidence that estradiol contributes to the telescoping effect.

In a second example, a mouse model of the human MOR A118G SNP replicates many of the phenomena observed in human variants, including reduced morphine analgesia in G allele carriers. But detailed studies of the mouse model also demonstrate that G/G females are significantly less sensitive than A/A females to morphine reward and withdrawal-induced negative affective states, whereas males exhibit similar responses to morphine regardless of allele status (Mague et al, 2009). These types of sex by gene interactions, which can have profound effects on addiction risk, are an important future direction in human association studies.

As a final example, recent preclinical findings report that female rats are more sensitive than males to the stress peptide corticotropin releasing factor (CRF) in neural circuits that mediate opioid withdrawal-induced negative affective states (Valentino et al, 2013). Specifically, CRF-mediated internalization of CRF type 1 receptors is less efficient in females compared with males such that females have more CRF receptors available for activation in response to stress. Although this type of mechanism could explain why women are more likely than men to use opioids to self-medicate stress and anxiety (McHugh et al, 2013), there are no published clinical trials testing the efficacy of CRF antagonists in female opioid addicts.

Substantial sex differences exist across all substances of abuse and in almost every facet of substance use disorders (Greenfield et al, 2010). Recent mandates from funding and regulatory organizations (eg, NIH and FDA) requiring researchers to consider both sexes in their studies will certainly advance our understanding of these sex differences. However, translation from preclinical to clinical research often results in an apparent attenuation of effects, as highly controlled studies in simple systems can fail to match clinical findings from complex human samples. As such, it is essential to examine not only main effects of sex on behavioral endpoints, but also potential mechanistic differences that may vary between and within the sexes. Translational approaches designed with the power to identify these complex interactions are the most likely to lead to optimal therapeutic targets for opioid addiction in both males and females.

FUNDING AND DISCLOSURE

The authors declare no conflict of interest.