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, 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 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 and DOR agonists only reduced 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.Significance Statement This study investigates how opioids regulate brain circuits controlling pain and emotions. The claustrum, a brain region that processes sensory and emotional information, sends signals to the anterior cingulate cortex, a key area for pain perception and emotional regulation. By examining how opioid receptors influence these signals, the study reveals how each receptor type modulates circuit activity in distinct ways. These findings are important because they better our understanding of how different opioid receptor subtypes uniquely control different properties of synaptic transmission and brain circuit function, offering insights for developing targeted treatments for pain, emotional disorders, and opioid use disorder. This work advances our ability to understand and manipulate brain circuits involved in complex behaviors.
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