Pick your poison: not all opioids are created equal in the eyes of dopamine (commentary on Vander Weele et al.).

Abstract

In the current issue, Vander Weele et al. (2014) provide a previously unseen characterization of opioid-induced potentiation of dopamine release in the nucleus accumbens (NAc), an effect shared by all commonly abused drugs and thought to critically contribute to drug reinforcement. This work is extremely timely as prescription opioid abuse and addiction are currently at epidemic levels. Indeed, the rise in prescription opioid abuse may be driven by an elevated prevalence of more addictive opioids. The most common opioid analgesic has traditionally been morphine, a naturally occurring alkaloid from the opium poppy plant. However, newer synthetic opioids, such as oxycodone, are gaining popularity despite (or perhaps because of) their reportedly greater abuse potential. The work by Vander Weele et al. (2014) suggests that the greater abuse potential of oxycodone may arise from its increased ability to produce changes in NAc dopamine release. Fast-scan cyclic voltammetry was used to measure real-time dopamine fluctuations in the NAc of behaving rats. These measures add opioids to the growing list of abused drugs (including ethanol, nicotine, cocaine and cannabinoids) that elicit rapid surges in NAc dopamine concentrations. Because these dopamine ‘transients’ are causally linked to reward seeking, the ability of abused drugs to give rise to these signals is an important mechanism supporting drug reinforcement. Interestingly, Vander Weele et al. (2014) found that morphine exhibits a surprisingly brief effect on dopamine transients, augmenting these signals for <1 min. In stark contrast, oxycodone elicited a stable and significant increase in the frequency of transients for the entire 15 min recording period. Additionally, state-of-the-art microdialysis simultaneously sampled the extracellular levels of 15 different neurotransmitters at 60 s intervals. These elegant measures corroborated the fast-scan cyclic voltammetry dopamine recordings and also showed that morphine, but not oxycodone, elevated extracellular GABA levels in the NAc. If this increase in GABA acts to inhibit terminal dopamine release, it could explain morphine's weak effects on dopamine transmission. The source of this GABA signal, however, remains to be identified. Moreover, this increase in GABA is paradoxical, as it has been theorized that morphine exerts its dopamine-releasing effects through μ-opioid receptor-mediated disinhibition of dopamine neurons. Based on reported differences in the abuse potential of oxycodone and morphine, and their distinct effects on dopamine release, the current findings suggest that monitoring a drug's ability to pharmacologically elicit dopamine transients could serve as an objective assay for rational drug policy, as we have postulated for cannabinoids. Alternatively, the observed differences between morphine and oxycodone may have simply arisen from their different pharmacokinetic actions. Indeed, although both drugs were administered at the same dose, oxycodone can reach brain concentrations six times that of morphine. Nonetheless, the authors state that both drugs evoked a similar maximal increase in extracellular dopamine and inhibited movement for a similar duration. Clearly, future work will need to employ more rigorous behavioral assays (such as drug self-administration) to determine whether the differential effects of morphine and oxycodone on the dynamics of dopamine release cause their different reinforcing properties.