Impact of individual differences in the development of opioid dependence

Opioid use disorder (OUD) is a chronic relapsing brain disease characterized by compulsion to seek and take the drug despite adverse consequences that has recently risen epidemic proportion becoming a global health problem. Opioids belong to a class of highly addictive narcotics used for pain management in a number of acute and chronic medical conditions; however their abuse leads to tolerance, dependence and risk of overdose. By binding opioid receptors in many areasof the brain involved in the reward circuitry, they are able to induce an increased release of dopamine into the Nucleus Accumbens creating positive reinforcements and pleasurable feelings. Not all people who experienced drugs become addicted: in fact it is a pathological response generated only in a subset of individuals with a vulnerable phenotype that pre-exists the first exposure to the addictive substance. This intrinsic predisposed state derives from a combination of biological, genetic and environmental factors that, taken together, make an individual more prone than others, to precipitate into the addiction cycle. Following the presentation of the research background in Chapter 1, in Chapter 2 my study is focused on the role of stress in facilitating heroin seeking and taking. The Marchigian Sardinian alcohol preferring (msP) rats is a validated animal model selected for excessive alcohol drinking and high sensitivity to stress due to the dysregulation of the HPA axis and an over expression of the opioid receptor system: considering their vulnerable phenotype, we set out to compare heroin taking and motivation between male and female msP rats and their non-selected Wistar counterparts. Results of the heroin/response and heroin/breakpoint curve showed that msP line consumed a higher amount of heroin and a higher motivation to work for the drug compared with controls. We had demonstrated that the msP rat line could be a valid preclinical model of stress- induced vulnerability to poly-drug abuse. Stress, however, is only one factor that contributes to enhancing the risk to develop OUD: in Chapter 4 I extend my investigation on addiction vulnerability taking into consideration all the individual differences that could be involved in red to better characterize the heroin-addictive behavior of vulnerable and resilient phenotypes. For this purpose we selected as animal model the NIH_ Heterogeneous stock rats, an outbred line that best mimics the individual variability of the human population. Data collected from the behavioral screening allow us to clusterize the overall population in three different phenotype ( vulnerable, intermediate and resilient) and also compare their heroin predisposition with innate behavioral trait ( basal locomotor activity, anxiety, pain and heroin analgesic sensitivity) in order to investigate if they could be predictive of a vulnerable or resilient phenotype. In Chapter 3 and 5, I approached the OUD study from a pharmacological point of view:nowadays, approved OUD treatment are based on the maintenance therapy with the use of long-acting opioid agonists, like methadone and buprenorphine whose efficacy is limited by adverse side effects like abuse liability, tolerance and respiratory depressions. I investigate the role of the MOP and NOP concomitant stimulation in reducing heron seeking and taking with a promising candidate Cebranopadol, already in clinical trials for the treatment of chronic and acute pain, that is characterized by a nano molar affinity for both these receptors. The NOP agonism is not only responsible for its reduced abuse potential but has also anxiolytic effects and made this drug particularly interesting in coping with stressful conditions, acting as a functional antagonist of the CRF1 receptor system. For these reasons, I explored the effects of Cebranopadol pretreatment in reducing heroin self-administration and motivation for heroin in male and female msP rats. From the results emerged that Cebranopadolsucceeded in counteracting heroin related behaviors both in male and female, but also that gender is a factor that has to be taken into account in the valuation of the effectiveness of a therapy approach. On this point, in the last Chapter, I investigated how the pharmacological response can vary depending on the individual. For this purpose, I used part of the previously characterized HS rats that were treated with Cebranopadol to evaluate its effect on heroin self-administration and cue-induced reinstatement. Results allow us to identify a subgroup of non-responder animals, that reflect the necessity also in human society, to fine tune individualized therapy depending on the genetic traits of each patient.