PT - JOURNAL ARTICLE AU - Gabrielle C Gregoriou AU - Sahil D Patel AU - Bryony L Winters AU - Elena E Bagley TI - Neprilysin controls the synaptic activity of neuropeptides in the intercalated cells of the amygdala AID - 10.1124/mol.119.119370 DP - 2020 Jan 01 TA - Molecular Pharmacology PG - mol.119.119370 4099 - http://molpharm.aspetjournals.org/content/early/2020/06/29/mol.119.119370.short 4100 - http://molpharm.aspetjournals.org/content/early/2020/06/29/mol.119.119370.full AB - Endogenous opioids peptides in the amygdala regulate many of our behaviours and emotional responses. In particular, the endogenous opioid enkephalin plays a significant role in regulating amygdala activity, but its action is strongly limited by peptidases which degrade enkephalin into inactive fragments. Inhibiting peptidases maybe an attractive method to enhance endogenous opioid signalling, however we do not know which specific peptidase/s to target. Using inhibition of glutamate release onto the intercalated cells of the amygdala as an assay for enkephalin activity, we applied specific peptidase inhibitors to determine which peptidase/s regulate enkephalin signalling in this region. Thiorphan (10μM), captopril (1μM) or bestatin (10μM) were used to inhibit the activity of neprilysin, angiotensin-converting enzyme or aminopeptidase N respectively. In rat brain slices containing the intercalated cells, we found that inhibition of glutamate release by a submaximal concentration of enkephalin was doubled by application of all three peptidase inhibitors combined. Then, we tested inhibitors individually and found that inhibition of neprilysin alone could enhance enkephalin responses to the same extent as inhibitors of all three peptidases combined. This indicates neprilysin is the predominant peptidase responsible for degrading enkephalins in the intercalated cells of the amygdala. This differs from the striatum, locus coeruleus and spinal cord, where multiple peptidases metabolise enkephalin. These data highlight the importance of knowing which specific peptidase/s control opioid actions in the relevant neural circuit and how they change in disease states, to allow rationale choices of drugs targeting the specific peptidase of interest.SIGNIFICANCE STATEMENT Endogenous opioids modulate many of our emotional and behavioural responses. In the amygdala they modulate our pain, fear and addictive behaviours. Their actions are terminated when they are catabolised into inactive fragments by at least 3 different peptidases. In this study we found that neprilysin selectively controls endogenous opioid concentrations at synapses in the intercalated cells of the amygdala. This peptidase may be a target for regulation of endogenous opioid modulation of amygdala mediated emotional and behavioural responses.