Excitatory synaptic transmission is differentially modulated by opioid receptors along the claustro-cingulate pathway

The anterior cingulate cortex (ACC) plays a pivotal role in processing pain and emotion, communicating with both cortical and subcortical regions involved in these functions. The claustrum (CLA), a subcortical region with extensive connectivity to the ACC also plays a critical role in pain perception and consciousness. Both ACC and CLA express Kappa (KOR), Mu (MOR), and Delta (DOR) opioid receptors, yet whether and how opioid receptors modulate this circuit is poorly understood. This study investigates the effects of opioid receptor activation on glutamatergic signaling in CLA-ACC circuitry using spatial transcriptomics, slice electrophysiology, optogenetics, and pharmacological approaches in mice. Our results demonstrated that excitatory inputs generated by the CLA onto layer 5 pyramidal cells (L5 PYR) in the ACC are reduced by KOR, MOR, and DOR agonists. However, only KOR agonists reduce monosynaptic transmission from the CLA onto L5 ACC PYR cells, highlighting the unique role of KOR in modulating the CLA-ACC pathway. MOR agonists had a heterogeneous effect on optically-evoked excitatory postsynaptic currents (oEPSCs), significantly reducing longer-latency excitatory responses while only modestly inhibiting the short latency excitatory postsynaptic currents. DOR agonists only reduce slower, longer-latency recurrent excitatory responses. These findings provide new insights into how opioid receptors regulate the claustro-cingulate circuit and demonstrate the distinct, receptor-specific modulation of synaptic transmission within this network.