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Science, Medicine, and the Anesthesiologist

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Anesthesiology September 2024, Vol. 141, A13–A15.

Distinct μ-opioid ensembles trigger positive and negative fentanyl reinforcement. Nature 2024; 630:141–8. PMID: 38778097

The potent µ-opioid receptor (µOR)–specific agonist, fentanyl, has devastating consequences on public health, increasing opioid addiction-related deaths. Fentanyl is highly addictive, with robust withdrawal symptoms leading to negative reinforcement behaviors where individuals retake the drug to avoid withdrawal effects. However, the neurobiologic mechanisms underlying fentanyl positive and negative reinforcement remain to be described. This study, using sophisticated biologic approaches alongside behavioral analysis, involved conducting innovative experiments to address this gap. Increased neuronal activity in the central amygdala (CeA) was observed during precipitated withdrawal in fentanyl-treated animals. Oprm1, expressed in a distinct neuronal population in CeA, was found to modulate fentanyl withdrawal when deleted. Retrograde viral tracing indicated that CeA primarily projected to the bed nucleus of the stria terminalis and the parabrachial lateral nucleus, associated with aversive and pain-related processes, respectively. Monitoring neural activities associated with positive and negative reinforcement revealed that fentanyl reduced GABAergic neuronal activity while increasing dopamine activity in the ventral tegmental area (VTA). Deleting µOR in VTA abolished dopamine neuronal activity but did not prevent fentanyl withdrawal. Additionally, increased µOR neuron activity in CeA was observed during withdrawal. Optogenetic manipulation of VTAGABA or CeAMOR neurons, combined with operant behavior, confirmed their roles in fentanyl positive and negative reinforcement, respectively.

Take home message: The study sheds light on distinct brain neural circuits for fentanyl positive and negative reinforcement. These findings may help in improving the management of opioid addiction by specifically targeting those brain circuits for reducing both the rewarding and aversive aspects of fentanyl addiction.

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