Striatal µ-Opioid Receptor Activation Triggers Direct-Pathway GABAergic Plasticity to Induce Negative Affect

Abstract

SUMMARYWithdrawal from chronic opioid use often causes hypodopaminergic states and negative affect, which drives relapse. Direct-pathway medium spiny neurons (dMSNs) in the striatal patch compartment contain high levels of µ-opioid receptors (MORs). It remains unclear how chronic opioid exposure affects these MOR-expressing dMSNs and their striatopallidal and striatonigral outputs to induce negative emotions and relapse. Here, we report that MOR activation acutely suppressed GABAergic striatopallidal transmission in habenula-projecting globus pallidus neurons. Notably, repeated administrations of a MOR agonist (morphine or fentanyl) potentiated this GABAergic transmission. We also discovered that intravenous self-administration of fentanyl enhanced GABAergic striatonigral transmission and reduced the firing activity of midbrain dopaminergic neurons. Importantly, fentanyl withdrawal caused depression-like behaviors and promoted the reinstatement of fentanyl-seeking behaviors. These data suggest that chronic opioid use triggers GABAergic striatopallidal and striatonigral plasticity to induce a hypodopaminergic state, promoting negative emotions and leading to relapse.HighlightsRepeated administration of morphine potentiates IPSCdMSN◊GPh neurotransmission.Repeated administration of fentanyl potentiates IPSCdMSN◊SNc neurotransmission.Fentanyl withdrawal induces negative emotional states, which drive relapse.