Active Mental Health Lungs & Breathing

From novel biology to clinical strategy: Targeting the M5-muscarinic acetylcholine receptor in opioid addiction

Funder Wellcome Charity-funded
Associated organisations University of Glasgow · Vanderbilt University Europe PMC affiliations are not treated as award recipients or mapped locations.
Funding £5.0M
Period Oct 2024 — Sept 2029

In plain English

AI plain-English summary

Opioid addiction hijacks the brain’s reward circuitry, and a team of researchers is now targeting a specific receptor—the M5-muscarinic acetylcholine receptor—to block that hijacking at its source. In the US, more than 4% of adults misuse prescription opioids; in the UK, roughly half of adults in substance-abuse treatment are opioid-dependent. Current treatments are limited, and no existing drug targets the M5-receptor’s role in reward-seeking behaviour. The researchers have shown in preclinical models that blocking this receptor reduces both the acquisition of opioid self-administration and cue-triggered relapse. The problem is that nobody understands how the M5-receptor actually works within the brain’s mesocorticolimbic reward circuitry—a fundamental gap that prevents these findings from becoming medicines. This project brings together two leading muscarinic-receptor groups to map that mechanism using genetic and pharmacological tools. If they succeed, the work could lead to a new class of drugs that prevent opioid misuse from taking hold and lower the risk of relapse after treatment. This is fundamental biology with a direct clinical target: a deeper understanding of a single receptor could reshape how addiction is treated.

View original technical description
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.

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Researchers

Andrew Tobin (EPMC Awardee)Carrie Jones (EPMC Awardee)

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Original classification

Discovery Award

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