It is likely the endogenous opioids regulating Im neuronal activity are met- and leu-enkephalin. The endogenous opioid actions we have described are through MOR and DOR, both of which are potently and efficaciously activated by the enkephalins67. We describe this phenomenon in Im neurons of the amygdala, which express high levels of enkephalins2021 and the effects are terminated by peptidases, known to breakdown enkephalins38. β-Endorphin is the other major opioid peptide that acts at MOR and DOR but is expressed in Im neurons at much lower levels48 and is much less sensitive to peptidase degradation compared to enkephalin49. Although Im neurons have a low firing frequency in vivo (<0.1 Hz)29, subsequent orthodromic spike bursts29 or recurrent firing50 following synaptic stimulation or current injection could effectively release endogenous opioids. Indeed, our present findings support the premise that endogenous opioid release is activity dependent, however the intensity of this activity is much less than originally anticipated. Thus, within our working model (Fig. 7a), enkephalin is released in response to neuronal activity and this is likely from Im neurons, although it is possible that enkephalins are also released from BLA or CeA synaptic projections rather than from Im neurons alone.