Neuropeptide oxytocin enhances μ opioid receptor signaling as a positive allosteric modulator

Abstract

Oxytocin (OT) is a 9-amine neuropeptide that plays an essential role in mammalian labor, lactation, maternal bonding, and social affiliation. OT has been reported to exert an analgesic effect in both humans and animals, and the results of certain animal experiments have shown that the analgesic effect of OT is partially blocked by opioid receptor antagonists. To investigate the relationship between OT and μ opioid receptor (MOR), we evaluated how OT affects MOR in vitro by performing an electrical impedance-based receptor biosensor assay (CellKey™ assay), an intracellular cAMP assay, and a competitive receptor-binding analysis by using cells stably expressing human MOR and OT receptor. In both the CellKey™ assay and the intracellular cAMP assay, OT alone exerted no direct agonistic effect on human MOR, but treatment with 10 M OT markedly enhanced the MOR signaling induced by 10 M endomorphin-1, β-endorphin, morphine, fentanyl, and DAMGO. Moreover, in the competitive receptor-binding assay, 10 M OT did not alter the affinity of endomorphin-1 or morphine for MOR. These results suggest that OT could function as a positive allosteric modulator that regulates the efficacy of MOR signaling, and thus OT might represent a previously unrecognized candidate analgesic agent.

A New Lead Identification Strategy: Screening an sp3‐rich and Lead‐like Compound Library Composed of 7‐Azanorbornane Derivatives

“…Cell culture:H EK293 cells stably expressing each of TRP channels or ORs, and HEK293A cells stably expressing GHSR were constructed in our previous reports. [46][47][48] HEK293 cells and HEK293A cells were cultured in DMEM supplemented with 10 %FBS and penicillin (100 UmL À1 )a nd streptomycin (100 mg mL À1 )a t3 78Ci nahumidified incubator (5 %C O 2 ). To maintain the stable cell lines, geneticin (flag-MOR and myc-KOR:0 .7 mg mL À1 ;G HSR:0 .8 mg mL À1 ), hygromycin (T7-DOR:0 .25 mg mL À1 ), blasticidin (TRP channels: 0.01 mg mL À1 )o rz eocin (TRP channels:0 .2 mg mL À1 )w as added to the culture medium.…”

Endogenous oxytocin release in periaqueductal gray eases inflammatory pain through long term suppression of pain perception neurons in the spinal cord

“…When we try to interpret the OT-PAG analgesic system, an intriguing possibility is that OT achieves an analgesic effect via mu opioid receptors, which is also a G-protein coupled metabotropic receptor whose post synaptic current can last up to minutes. A recent study found that, although OT alone does not directly bind to the opioid-binding site of mu opioid receptor, OT strongly enhances the signaling of mu opioid receptor [22]. In addition to those studies using electric stimulation of PAG, mu opioid receptor agonist injection to PAG has also confirmed the descending analgesic pathway; PAG, RVM, and SC as follows.…”

The Role of Prenatal Melatonin in the Regulation of Childhood Obesity

“…However, recent data shows oxytocin to significantly suppress obesity, indicating wider roles in the regulation central and systemic processes [125]. It is also of note that oxytocin is a positive allosteric modulator of the µ-opioid receptor [126], thereby linking oxytocin effects to data showing the role of the µ-opioid receptor in obesity as well as in attachment, nociception, and reward. As melatonin can regulate hypothalamic oxytocin production in rodents [127], it requires investigation as to whether variations in circadian and local melatonin production are relevant to the modulation and development of the oxytocin system in the placenta and foetus.…”