Opioids induce dissociable forms of long-term depression of excitatory inputs to the dorsal striatum

In this study, the authors show that there are multiple forms of opioid-induced long-term depression (OP-LTD) in the dorsal striatum, each mediated by the mu, delta or kappa opioid receptor. The mu and delta OP-LTD are presynaptic and can summate, but only mu OP-LTD occludes endocannabinoid-induced LTD. Furthermore, mu OP-LTP, but not kappa or delta OP-LTP, is blocked by the analgesic oxycodone. As prescription opioid analgesic abuse rates rise, so does the need to understand the long-term effects of opioid exposure on brain function. The dorsal striatum is an important site for drug-induced neuronal plasticity. We found that exogenously applied and endogenously released opioids induced long-term depression (OP-LTD) of excitatory inputs to the dorsal striatum in mice and rats. Mu and delta OP-LTD, although both being presynaptically expressed, were dissociable in that they summated, differentially occluded endocannabinoid-LTD and inhibited different striatal inputs. Kappa OP-LTD showed a unique subregional expression in striatum. A single in vivo exposure to the opioid analgesic oxycodone disrupted mu OP-LTD and endocannabinoid-LTD, but not delta or kappa OP-LTD. These data reveal previously unknown opioid-mediated forms of long-term striatal plasticity that are differentially affected by opioid analgesic exposure and are likely important mediators of striatum-dependent learning and behavior.