Ricerc@Sapienza

The current prescription opioid epidemic is characterized by high lifetime rates of relapse, often precipitated by the experience of pain. However, there is a dearth of preclinical studies examining the effect of pain on relapse into opioid use. Drug craving and relapse have been modeled in laboratory rats using the incubation of drug craving model, which refers to the time-dependent increase in drug seeking after withdrawal, a phenomenon that occurs in both rat models and humans. The objective of this proposal is to develop an animal model of prescription opioid craving and relapse and study the putative shared neurobiological mechanisms of prescription opioid relapse and pain. This proposal is focused on the central amygdala (CeA), a region involved in both the incubation of drug craving across drug classes and pain, and the neuropeptide Oxytocin (Oxt). This neuropeptide, classically associated with the hormonal regulation of reproductive functions and associated social bonding, also modulates neurotransmission in extrahypothalamic areas and decreases drug consumption, relapse and pain. Oxt receptors (OxtR) are expressed in the CeA and modulate local neurotransmission, but no studies have examined the role of CeA OxtR in drug craving and relapse with relation to pain. Our central hypothesis is that CeA OxtR signaling is a critical shared mechanism for incubation of oxycodone craving and pain. Here, we propose to develop a rat model of incubation of oxycodone craving and test the role of CeA OxtR in this model. Furthermore, given that the duration of pain in classical rodent models is not under experimenter control, we propose to develop a novel DREADD-based chemogenetic model of pain, in which repeated intermittent administration of clozapine n-oxide (CNO) will cause experimenter-controlled intermittent pain. We will test the role of CeA OxtR signaling in this novel model and determine the effect of intermittent pain on the incubation of oxycodone craving.