Abstract
Despite their indisputable efficacy for pain management, opiate prescriptions remain highly controversial partially due to their elevated addictive potential. Relapse in drug use is one of the principal problems for addiction treatment, with drug-associated memories being among its main triggers. Consequently, the extinction of these memories has been proposed as a useful therapeutic tool. Hence, by using the conditioned place aversion (CPA) paradigm in rats, we investigated some of the molecular mechanisms that occurr during the retrieval and extinction of morphine withdrawal memories in the basolateral amygdala (BLA) and the hippocampal dentate gyrus (DG), which control emotional and episodic memories, respectively. The retrieval of aversive memories associated with the abstinence syndrome paralleled with decreased mTOR activity and increased Arc and GluN1 expressions in the DG. Additionally, Arc mRNA levels in this nucleus very strongly correlated with the CPA score exhibited by the opiate-treated rats. On the other hand, despite the unaltered mTOR phosphorylation, Arc levels augmented in the BLA. After the extinction test, Arc and GluN1 expressions were raised in both the DG and BLA of the control and morphine-treated animals. Remarkably, Homer1 expression in both areas correlated almost perfectly with the extinction showed by morphine-dependent animals. Moreover, Arc expression in the DG correlated strongly with the extinction of the CPA manifested by the group treated with the opiate. Finally, our results support the coordinated activity of some of these neuroplastic proteins for the extinction of morphine withdrawal memories in a regional-dependent manner. Present data provide evidence of differential expression and activity of synaptic molecules during the retrieval and extinction of aversive memories of opiate withdrawal in the amygdalar and hippocampal regions that will likely permit the development of therapeutic strategies able to minimize relapses induced by morphine withdrawal-associated aversive memories.
Highlights
Student’s t test revealed that the score of the morphine-treated rats that were sacrificed after the conditioned place aversion (CPA) test was significantly (t43 = 4.790, p < 0.0001) lower than the score of control animals sacrificed at the same time point (Figure 1B), indicating that the dose of naloxone administered for the conditioning elicited the aversive emotional state characteristic of morphine withdrawal in opiate-dependent rats but not in controls
Our experiments addressed the implication of mTORC1 on the retrieval of aversive memories of morphine withdrawal (CPA test) as well as on their extinction
In the basolateral amygdala (BLA), GluN1 levels were enhanced concomitantly with no alterations in mTOR activity, suggesting that this kinase did not participate in the recall of opiate withdrawal extinction memories
Summary
Opioids are the most effective drugs used for the management of moderate to high intensity acute and chronic pain. Their propensity to induce misuse and abuse exerts an important deterrent effect for their prescription [1]. Misuse of, and addiction to, prescription analgesic opioids was at the origin of the United States opioids crisis and, as a consequence, an increment in consumption of, first, synthetic analgesic opioids and, lately, illegal opioids such as heroin and illicit fentanyl, occurred [2]. An opioid crisis is present in Europe, where it has become a progressively harmful public health problem [3]
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