Brain hijack by opiates: focus on the corticotropin-releasing factor system – BIOSCIENCE

Opiate use disorders (OUD) are chronic, relapsing, diseases with a major health and socio-economic impact worldwide. To date, they are treated mainly by substitutive opioid receptor agonists, such as methadone and buprenorphine. However, the latter opiate therapy is often ineffective, increasingly misused and induces dependence, posing health and regulatory challenges difficult to solve. Novel treatments are thus urgently needed but their development heavily relies on the elucidation of the neural substrates underlying OUD.
Likewise other substances of abuse, opiates dramatically narrow behavior towards substance-oriented activities, to the detriment of naturally rewarding activities, such as social interaction or eating. Closely related brain systems might mediate the rewarding and motivational properties of substances of abuse, food and social behavior. Thus, substances of abuse might hijack brain systems underlying activities essential to species survival, to deviate behavior towards addictive-like substance seeking and intake.
The corticotropin-releasing factor (CRF) system might mediate substance use disorders. Notably, we previously reported crucial, but often opposite, roles for the two known CRF receptor types (CRF1 and CRF2) in brain and behavioral alterations associated with chronic opiate or cocaine administration and withdrawal. Thus, elucidation of the specific role for each of the two known CRF receptor types might be crucial to develop effective therapy for substance use disorders. However, to date the role of the CRF system in opiate-driven motivational states and loss of interest for naturally rewarding activities remains largely unknown.
Thus, by a multidisciplinary integrated strategy, including advanced behavioral, genetic and pharmacological studies in mice, our project aims at identifying the specific role for the CRF1 and the CRF2 receptor in opiate-induced brain reward, substance seeking and intake, sociability deficits and loss of motivation to eat.
Our research project will be developed through four different specific tasks. First, whole-body CRF1 or CRF2 receptor-deficient mice will be tested in clinically-oriented behavioral paradigms assessing the rewarding, motivational and social behavior effects of morphine, the main opiate substance. Then, using lentiviral-based systems of RNA interference, further genetic studies will investigate the specific role for the CRF1 and the CRF2 receptor in brain regions implicated in the addictive-like properties of substances of abuse. Moreover, studies will examine CRF receptor-dependency of brain dopamine and oxytocin alterations underlying behavioral disorders induced by morphine. Finally, pharmacological studies will assess the therapeutic potential of currently available or newly developed compounds preferentially targeting the CRF1 or the CRF2 receptor. In particular, to foster a possible clinical use, the latter experiments will be carried out using molecules that readily cross the blood-brain barrier and can thus be administered peripherally, and preferentially orally. Notably, throughout all tasks of the present project, a decision tree will be followed based on the most promising results obtained step by step.
Thus, the combined multidisciplinary research approaches proposed herein might shed light on the brain mechanisms underlying behavioral disorders induced by opiate substances. Moreover, since our work focuses on cell membrane receptors, our results might foster knowledge that could be easily translated into pharmacology research. Notably, the investigation of non-opioid brain systems as therapeutic targets might lead to treatments devoid of abuse and dependence potential. This could, in the short/medium term, encourage the active involvement of public health services and private pharmaceutical companies into pre-clinical and clinical research on OUD and, in the longer term, lead to effective medical therapy for these devastating diseases.