Network and Cellular Effects of the Mu Opioid Receptor in Cortical Interneurons

The µ opioid receptor (µOR) exerts a powerful excitatory effect in cortical circuits and cultured neurons by promoting glutamatergic activity after binding endogenous or exogenous opioids. While most research indicates that the receptor does this by decreasing activity or output of GABAergic interneurons that inhibit glutamate-releasing Pyramidal Neurons, other experiments suggest that the µOR directly upregulates excitatory Pyramidal Neurons instead. Thus, the cellular target of cortical opioid agonists remains unclear, and the µOR’s net excitatory mechanisms are not fully understood. Consequently, utilizing electrophysiology to detect µOR responses to the specific agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin (DAMGO) has yielded incomplete information on its effects. This receptor has been shown to modulate both αDTX sensitive and insensitive currents in thalamic neurons to exert its effects, but this has not been investigated in cortical neurons. Here, we utilized a combination of calcium-imaging and patch-clamp electrophysiology in cultured rat neocortical neurons to investigate the network and cellular effects of the µOR to understand its mechanisms and their consequences. With our experiments testing its effects on spontaneous calcium oscillations, we found that the µOR exerts its net excitatory effects through inhibition of GABAergic interneurons. Our separate set of studies using patch-clamp electrophysiology reveals that the µOR has multiple inhibitory effects on firing frequency and action potential kinetics, including αDTX-sensitive and insensitive ones. Thus, opioids suppress GABAergic interneurons to promote net excitation in cortical circuits. Collectively, these findings promote our understanding of effects of endogenous or exogenous opioids on cortical networks, as well as provide robust analyses of the electrophysiological effects of the µOR which could provide insight into further studies of this receptor on cortical neurons