Opioid receptors are G protein-coupled receptors (GPCRs) expressed by the central nervous system and immune cells that play a central role in reward processing, euphoria and analgesia, but also in stress, anxiety and depression. The family of opioid receptors consists of four classical receptors: mu (µ or MOR), delta (d or DOR), kappa (¿ or KOR) and the nociception receptor (NOP, or orphanin FQ receptor). These receptors are the targets of painkillers for the treatment of moderate, acute or chronic pain as well as for depression. Although efficient drugs like codeine and morphine exist, the use of these drugs is often associated with tolerance, dependence and various adverse effects or misusage. We have recently identified the atypical chemokine receptor ACKR3/CXCR7 as a new key regulator of the opioid system. Our data demonstrate that ACKR3, in contrast to the known opioid receptors, does not signal in response to opioid peptides but rather acts as a scavenger, regulating their local and/or systemic concentrations and thus availability for the classical opioid receptors. This discovery adds a novel level of complexity to the opioid system but also opens a new avenue for the development of alternative, potentially safer drugs to treat pain and depression by modulating/restoring the normal levels of endogenous opioids. To this end, we developed a small highly potent (subnanomolar) and selective peptide modulator of ACKR3 called LIH383.During this project, we wish to evaluate the potential of ACKR3 as a new opioid receptor and of LIH383 as its new highly active modulator and to define the best path to valorize these complementary discoveries.