^ abcPalmer CB, Meyrath M, Canals M, Kostenis E, Chevigné A, Szpakowska M (May 2022). "Atypical opioid receptors: unconventional biology and therapeutic opportunities". Pharmacology & Therapeutics. 233: 108014. doi:10.1016/j.pharmthera.2021.108014. PMID34624426. This is reinforced by the finding that blocking ACKR3 scavenging through administration of the modulator LIH383 leads to potentiation of dynorphin A effects on the classical opioid receptors, i.e. an increase in the inhibition of neuronal firing (Meyrath et al., 2020). Additionally, ACKR3 was recently shown to bind the natural analgesic molecule conolidine, further pointing to the involvement of this receptor in pain (Szpakowska et al., 2021). [...] Indeed, targeting ACKR3 with the highly specific small-molecule compound CCX771 was described to have, synergistically with ACTH, an anxiolytic-like effect on behavior in mice (Ikeda et al., 2013). Moreover, the effect of adrenorphin-derived small peptide LIH383, which blocks ACKR3 scavenging function, was recently addressed in an ex vivo rat locus coeruleus model where it potentiates the effect of endogenous opioids (Meyrath et al., 2020). [...] Systematic chemical modifications of conolidine resulted in an analogue compound, RTI-5152-12, with 15-fold improved potency towards ACKR3. Notably, conolidine and RTI-5152-12 function similarly to LIH383 and conolidine's analgesic activity was proposed to rely on the inhibition of the scavenging functions of ACKR3 increasing the availability of analgesia-inducing endogenous opioid peptides for the classical ORs.
^Sjöberg E, Meyrath M, Chevigné A, Östman A, Augsten M, Szpakowska M (2020). "The diverse and complex roles of atypical chemokine receptors in cancer: From molecular biology to clinical relevance and therapy". Advances in Cancer Research. Vol. 145. Elsevier. pp. 99–138. doi:10.1016/bs.acr.2019.12.001. ISBN978-0-12-820230-2. PMID32089166. Recently, LIH383, an octapeptide derived from an endogenous ACKR3 ligand, was also reported as a subnanomolar agonist of the receptor.
^ abcSowa JE, Tokarski K (December 2021). "Cellular, synaptic, and network effects of chemokines in the central nervous system and their implications to behavior". Pharmacological Reports. 73 (6): 1595–1625. doi:10.1007/s43440-021-00323-2. PMC8599319. PMID34498203. A recent elegant study has provided extensive evidence that ACKR3 is a chemokine receptor with the ability to bind opioid peptides; however, opioid binding did not trigger downstream signaling through this receptor [21]. Thus, it is suggested that ACKR3 serves scavenger functions for many opioids, especially enkephalins and dynorphins, by reducing their availability for their classical opioid receptors [21]. Accordingly, treatment with ACKR3 agonist LIH383, even at high concentration, did not produce any electrophysiological effect in PAG neurons, confirming the scavenging function of ACKR3 in this brain region.
^Zarca AM, Adlere I, Viciano CP, Arimont-Segura M, Meyrath M, Simon IA, et al. (March 2024). "Pharmacological Characterization and Radiolabeling of VUF15485, a High-Affinity Small-Molecule Agonist for the Atypical Chemokine Receptor ACKR3". Molecular Pharmacology. 105 (4): 301–312. doi:10.1124/molpharm.123.000835. PMID38346795.
