From novel biology to clinical strategy: Targeting the M5-muscarinic acetylcholine receptor in opioid addiction (360G-Wellcome-307319_Z_23_Z)

The world is facing an opioid crisis of epidemic proportion. Within the United States >4% of the adult population currently misuse prescription opioid analgesics whilst in the UK, of adults receiving treatment for substance abuse, ~50% abuse opioids. Whilst current treatments remain limited, there is an immediate need for a novel target mechanism to prevent opioid misuse and opioid-use-disorder (OUD). Our preliminary data demonstrates that inhibition of the M5-receptor, one of five members of the muscarinic-acetylcholine receptor family, can significantly decrease acquisition of opioid self- administration and reduce cue-induced reinstatement of opioid-agonist drug seeking in preclinical models of relapse. The barrier to progressing these findings to effective medicines for opioid-misuse and OUD is an almost complete lack of understanding of the mode-of-action of the M5-receptor in the mesocorticolimbic reward circuitry. This proposal addresses this barrier by bringing together two of the world’s strongest muscarinic-receptor research groups to apply novel genetic and pharmacological approaches in a programme aimed at revealing unappreciated fundamental biology of the M5-receptor in the reward-seek circuitry. By investigating this in the context of opioid addiction models this programme aims to discover breakthrough therapeutic approaches to reducing acquisition of misuse of prescribed opioids and reduce the risk of relapse.