The use of human iN cells enables the study of synaptic perturbations that may be involved in addiction and reward pathogenesis. We observed increased sensitivity in D40 MOR iNs to the MOR-specific agonist, DAMGO, in a number of patient-derived and gene-edited iN cells. We also tested another MOR agonist, opiate morphine, and observed similar responses which we observed with the synthetic opioid peptide DAMGO. Our data indicate that MOR activation affects the frequency of spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSCs) but not their amplitudes. These data suggest that the MOR is expressed at the presynaptic inhibitory nerve terminals to exert presynaptic modulation. It is traditionally believed that in synaptic physiology, a change in the frequency of events (and not the amplitude) is due to a presynaptic alteration of neurotransmitter release. Modulation of the number of events is likely a consequence of a change in presynaptic release of neurotransmitter. This result could be explained by differences seen in N-linked glycosylation of human MOR which could impact agonist binding affinity and/or receptor trafficking 51 .
