Excitatory Synaptic Transmission Is Differentially Modulated by Opioid Receptors along the Claustrocingulate 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 are poorly understood. This study investigates the effects of opioid receptor activation on glutamatergic signaling in CLA→ACC circuitry using spatial transcriptomics, brain slice electrophysiology, optogenetics, and pharmacological approaches in mice of both sexes. Our results demonstrated that excitatory synaptic transmission generated by the CLA onto Layer 5 pyramidal (L5 PYR) cells 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 and DOR agonists only reduced slower, longer-latency recurrent excitatory responses. These findings provide new insights into how opioid receptors regulate the claustrocingulate circuit and demonstrate the distinct, receptor-specific modulation of synaptic transmission within this network.