Targeting Mu Opioid Receptor Neurons of the Habenula to Limit Naloxone Aversion

Opioid use disorder is a chronic relapsing condition that continues to rise worldwide. Naloxone, an opioid antagonist, reverses overdose but triggers strong negative affect. The neuronal circuits underlying these aversive effects remain unclear. We previously identified mu opioid receptor-expressing habenular neurons (Hb-MOR) as key encoders of negative emotional states and hypothesized that they also mediate naloxone aversion.

We combined behavioral models of naloxone aversion with in vivo fiber photometry to monitor Hb-MOR activity in opioid-naïve and -dependent mice. Causality was tested through chemogenetic silencing of Hb-MOR neurons. Finally, we targeted GPR139, an anti-opioid orphan receptor enriched in the habenula, to pharmacologically modulate naloxone responses.

In opioid-naïve mice, high-dose naloxone induced conditioned place aversion (CPA) and increased Hb-MOR neuron activity, both of which were prevented by chemogenetic inhibition. In dependent animals, low-dose naloxone was sufficient to activate Hb-MOR neurons and produce CPA. Silencing Hb-MOR neurons abolished these effects and alleviated somatic withdrawal signs, indicating enhanced sensitivity of these neurons in dependence. Targeting GPR139 provided a therapeutic approach: The GPR139 antagonist JD-1 reduced Hb-MOR responses to naloxone and attenuated both somatic and affective withdrawal symptoms in morphine-dependent mice.

Hb-MOR neurons are key to naloxone-induced aversion and withdrawal. Pharmacological modulation of GPR139 represents a promising strategy to limit adverse effects associated with naloxone and opioid withdrawal.