Exogenous opioids activate a potassium conductance in Im neurons16 and in many other brain regions4647. However, it is not known whether endogenously released opioids can activate this potassium conductance. Given the strong endogenous opioid regulation in Im neurons (current findings), their very high MOR expression21 and that 60% of MOR receptors are in postsynaptic dendritic compartments3435, we wondered whether endogenously released opioids could directly regulate Im neurons. We have already shown ME is well placed to regulate synaptic transmission (Fig. 1c–e), but we also found ME immunoreactivity in multiple terminals converging onto large dendrites (Fig. 5a) within Im, suggesting ME directly acts at postsynaptic sites. Indeed, exogenous ME (30 μM) produced an outward current in all neurons (37.5±4.1 pA, n=20) that could be readily reversed either after washout (n=16) or by CTAP (n=4; Fig. 5b). Current–voltage analysis before and during ME indicates activation of a potassium conductance as the reversal potential of the ME-induced current was close to the potassium reversal potential (MErev: −103.2±1.4 mV, n=9; Ek: −104.9 mV, calculated with the Nernst equation; Fig. 5c). In addition, bath application of the KIR 3.1/3.4 antagonist tertiapin Q (300 nM) for 5 min prior to application of ME significantly reduced the ME current (ME+tertiapin 7.4±1 pA, n=5, ME alone 37.5±4.1 pA, n=20; P<0.002, unpaired t-test). This is consistent with findings from mouse Im neurons where the MOR agonist DAMGO activated a potassium conductance and induced a hyperpolarization16. To test whether endogenously released opioids also activate this potassium conductance in Im neurons, we applied the peptidase inhibitor cocktail and observed an outward current in the majority of Im neurons (8/9), which was fully reversed by CTAP (n=4) or naloxone (n=5, Fig. 5d,f). While these peptidase inhibitor-induced currents occurred without any electrical stimulation, the highly variable amplitude (Fig. 5d,f) suggested spontaneous activity of cells in the slice could be influencing the size of the endogenous opioid response. Consistent with this, we found that when we electrically stimulated the BLA (10–20 stimuli at 150 Hz), PIs induced a larger, more consistent outward current, which again was fully reversed by CTAP (n=1) or naloxone (n=3; Fig. 5e,f). These data indicate that in the Im, endogenous opioids are readily released in response to spontaneous or stimulated synaptic activity and act postsynaptically to induce an outward potassium conductance. Given the input resistance of Im neurons (643.9±101.5 MΩ, n=13), the endogenous opioid current with and without stimulation would be expected to hyperpolarize the Im neurons by 24.2±2.7 and 10.1±3.8 mV, respectively.