The kappa opioid receptor modulates GABA neuron excitability and synaptic transmission in midbrain projections from the insular cortex

As an integrative hub, the insular cortex (IC) translates external cues into interoceptive states that generate complex physiological, affective, and behavioral responses. However, the precise circuit and signaling mechanisms in the IC that modulate these processes are unknown. Here, we describe a midbrain-projecting microcircuit in the medial aspect of the agranular IC that signals through the Gαi/o-coupled kappa opioid receptor (KOR) and its endogenous ligand dynorphin (Dyn). Within this microcircuit, Dyn is robustly expressed in layer 2/3, while KOR is localized to deep layer 5, which sends a long-range projection to the substantia nigra (SN). Using ex vivo electrophysiology, we evaluated the functional impact of KOR signaling in layer 5 of the IC. We found that bath application of dynorphin decreased GABA release and increased glutamate release on IC-SN neurons, but did not alter their excitability. Conversely, dynorphin decreased the excitability of GABA neurons without altering synaptic transmission. Pretreatment with the KOR antagonist nor-BNI blocked the effects of dynorphin in IC-SN neurons and GABA neurons, indicating that the changes in synaptic transmission and excitability were selectively mediated through KOR. Selective inhibition of IC GABA neurons using a KOR-derived DREADD recapitulated these effects. This work provides insight into IC microcircuitry and indicates that Dyn/KOR signaling may act to directly reduce activity of layer 5 GABA neurons. In turn, KOR-driven inhibition of GABA promotes disinhibition of IC-SN neurons, which can modulate downstream circuits. Our findings present a potential mechanism whereby chronic upregulation of IC Dyn/KOR signaling can lead to altered subcortical function and downstream activity. •KOR modulates a midbrain-projecting microcircuit in layer 5 of the insular cortex.•Dynorphin reduces GABA neuron excitability in layer 5 of the insular cortex.•Dynorphin increases excitatory drive in midbrain-projecting insular cortex neurons.•KOR DREADD inhibition of insula GABA neurons recapitulates the effects of dynorphin.•Insula projections release glutamate on substantia nigra GABA and dopamine neurons.