Age-dependent opioid withdrawal: the role of μ-opioid receptor expressing neurons in the medial habenula

Abstract

Opioid abuse is a prevalent health and social issue that causes severe physical and psychological consequences affecting people of all ages and backgrounds. The recent global surge in adolescent opioid abuse is cause for concern, especially with the rise of increasingly popular and potent synthetic opioids such as fentanyl and emphasises the need to explore the link between adolescent and adult opioid addiction. Withdrawal is a critical indicator of addiction that perpetuates drug-seeking behaviour and relapse as a negative reinforcer, characterised by negative affective states and substantial discomfort during abstinence from opioids. Rodent models have presented evidence that the severity of withdrawal experienced during adulthood is potentiated by previous adolescent exposure to opioids. However, the neural mechanisms underlying opioid withdrawal during adolescence, and potentiation of withdrawal severity during re-exposure in adulthood remain unknown. This literature review aims to summarise current behavioural studies that consider adolescent and adult rodents in opioid withdrawal and to review the emerging research suggesting that μ-Opioid Receptor (MOR) expressing neurons in the Medial Habenula (MHb) are essential for orchestrating opioid withdrawal symptoms. We first explore the role of MOR expressing MHb (MHb-MOR) neurons in mediating aversive states caused by opioid withdrawal and opioid-induced long-term neuroadaptations in MORs. We then focus on the possibility that MHb-MOR neurons play a role in modulating the potentiation of withdrawal symptoms experienced by adult rodents that are re-introduced to opioids following prior exposure during adolescence, though considering MOR desensitisation. Two experiments are proposed in light of these discoveries, which would expand on our understanding of MHb-MOR neuron functions in the context of adolescent opioid withdrawal and opioid re-exposure during adulthood. By furthering our knowledge of opioid withdrawal specific circuitry, we hope to expand on the current scientific narrative around developing more effective and age-related treatment and intervention strategies for opioid abuse.