An endogenous opioid circuit determines state-dependent reward consumption

mu-Opioid peptide receptor (MOPR) stimulation alters respiration, analgesia and reward behaviour, and can induce substance abuse and overdose(1-3). Despite its evident importance, the endogenous mechanisms for MOPR regulation of consummatory behaviour have remained unknown(4). Here we report that endogenous MOPR regulation of reward consumption in mice acts through a specific dorsal raphe to nucleus accumbens projection. MOPR-mediated inhibition of raphe terminals is necessary and sufficient to determine consummatory response, while select enkephalin-containing nucleus accumbens ensembles are engaged prior to reward consumption, suggesting that local enkephalin release is the source of the endogenous MOPR ligand. Selective modulation of nucleus accumbens enkephalin neurons and CRISPR-Cas9-mediated disruption of enkephalin substantiate this finding. These results isolate a fundamental endogenous opioid circuit for state-dependent consumptive behaviour and suggest alternative mechanisms for opiate modulation of reward.

Automated summary

The study reveals that mu-opioid peptide receptor regulates reward consumption in mice through a specific pathway from the dorsal raphe to the nucleus accumbens. Inhibition of raphe terminals by MOPR is crucial for determining consummatory response. Activation of enkephalin-containing nucleus accumbens ensembles prior to reward consumption suggests that local enkephalin release is the source of the endogenous MOPR ligand.