Naloxone benzoylhydrazone activates Extracellular Signal-Regulated Protein Kinases and modulates Nociceptin Opioid Peptide Receptor activity

Naloxone benzoylhydrazone (NalBzoH) is often used as a nociceptin opioid peptide (NOP) receptor antagonist. However, NalBzoH is also a mixed μ antagonist/κ and δ opioid agonist and its actions at the NOP receptor range from an antagonist to partial agonist, depending on the effector response/system studied. We now report that NalBzoH activates endogenously expressed κ₃ opioid, but not NOP, receptors to stimulate extracellular signal-regulated protein kinases 1/2 and, subsequently, to mediate changes in the expression of tyrosine hydroxylase and G protein-coupled receptor kinase 2 in SH-SY5Y human neuroblastoma cells. Furthermore, pretreatment with NalBzoH produces homologous desensitization of the κ₃ opioid receptor as well as heterologous desensitization of the NOP receptor. In contrast, pretreatment with the NOP agonist, orphanin FQ/nociceptin (OFQ/N), desensitizes only NOP but not the NalBzoH response, suggesting the involvement of a receptor, distinct from NOP, in mediating the actions of NalBzoH in SH-SY5Y cells.