Activation of MOR and DOR results in opposite behavioural fear responses with activation of DOR being anxiolytic8 and activation of MOR being anxiogenic10. The cellular basis for these opposing actions of opioid receptors is likely complex and occurs at multiple sites. At a cellular level, we have shown there is anatomical specificity of the endogenous opioid action at MOR and DOR in the Im. We suggest this could provide a basis for understanding the opposite actions of MOR and DOR activity on anxiety. In the Im, endogenously released opioids act via DOR to reduce the strength of BLA synaptic inputs. While this reduced excitatory drive from the BLA could decrease Im outputs to target neurons, it is also possible that it could allow Im neurons to be more strongly influenced by other inputs, such as those from the cortex that carry more complex/contextual information3154. Thus, a DOR-mediated shift in strength of synaptic inputs could contribute to DOR-mediated anxiolytic processes such as fear extinction (Fig. 7b). Distinct from this, the endogenous opioid actions at MOR directly inhibit Im neuronal excitability and through this, likely reduce their activation by all synaptic inputs. This in turn, would reduce Im-dependent GABA release onto target neurons such as the CeM16 and disinhibit CeM output to promote fear learning. Thus endogenous opioids acting via postsynaptic MOR to reduce Im excitability, maybe a feature of MOR-mediated anxiogenic processes such as fear learning. This differential pharmacology of endogenously released opioids in the Im could have important consequences. First, the net effect of endogenous opioid actions could change if one receptor sub-type was altered by a physiological55, pathophysiological state or pharmacological treatment56. Second, it raises some interesting therapeutic possibilities. If the desired therapeutic strategy is to enhance endogenous opioid action at both DOR and MOR, this could be achieved by inhibition of peptidases57. Alternatively, if enhancing the activity of only one receptor is desired, a PAM, such as shown in this study, could be utilized45.