Mu- and Delta-Opioid Receptors Differentially Express and Modulate Inhibitory Interneurons in the Prefrontal Cortex

Authors

• CY Noh
• VS Tsai
• HE Yarur
• KA Zaghloul
• EN Ventriglia
• H Patel
• H Wang
• HA Tejeda

Abstract

The prefrontal cortex (PFC) plays a crucial role in goal-directed behavior and motivation, with deficits in this region leading to maladaptive behaviors. Similarly, endogenous opioids influence these behaviors and motivations, yet their precise distribution and activity within the PFC remains unclear. Additionally, interneuron cell populations are implicated in the regulation of PFC circuitry, but the regulation of opioid receptors on interneurons has not been established. This study employed RNAScope in-situ hybridization and whole-cell patch clamp to reveal the diverse somatic expression of opioid receptors across various interneuron and receptor populations.

In this project, we used channel rhodopsin (ChR2) virus in the PFC of MOR- and DOR-Cre mice to stimulate and record GABA release. This was achieved through blue light stimulation and electrophysiology, accompanied by bath applications of DOR agonist, Deltorphin II, and MOR agonist, DAMGO. Our results indicated that inhibitory currents induced by MOR+ axon terminal stimulation are modulated by both MOR and DOR activation, whereas those induced by DOR+ axon terminal stimulation are predominantly modulated by DOR activation.

Further experiments on non-human primate and human tissues highlight the interneuron specificity of MOR and DOR in mediating GABA inhibition. The differential inhibitory currents at the axon terminals of opioid receptors can be attributed to the specificity expression of these receptors between PV and SST interneurons. These insights identify potential drug targets for treating mental health disorders stemming from opioid dysregulation in the brain.

Scientific Focus Area: Neuroscience

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