Oxytocin Is a Positive Allosteric Modulator of κ-Opioid Receptors but Not δ-Opioid Receptors in the G Protein Signaling Pathway

Abstract

Oxytocin (OT) influences various physiological functions such as uterine contractions, maternal/social behavior, and analgesia. Opioid signaling pathways are involved in one of the analgesic mechanisms of OT. We previously showed that OT acts as a positive allosteric modulator (PAM) and enhances μ-opioid receptor (MOR) activity. In this study, which focused on other opioid receptor (OR) subtypes, we investigated whether OT influences opioid signaling pathways as a PAM for δ-OR (DOR) or κ-OR (KOR) using human embryonic kidney-293 cells expressing human DOR or KOR, respectively. The CellKeyTM results showed that OT enhanced impedance induced by endogenous/exogenous KOR agonists on KOR-expressing cells. OT did not affect DOR activity induced by endogenous/exogenous DOR agonists. OT potentiated the KOR agonist-induced Gi/o protein-mediated decrease in intracellular cAMP, but did not affect the increase in KOR internalization caused by the KOR agonists dynorphin A and (-)-U-50488 hydrochloride (U50488). OT did not bind to KOR orthosteric binding sites and did not affect the binding affinities of dynorphin A and U50488 for KOR. These results suggest that OT is a PAM of KOR and MOR and enhances G protein signaling without affecting β-arrestin signaling. Thus, OT has potential as a specific signaling-biased PAM of KOR.

Neurobiology of Loneliness, Isolation, and Loss: Integrating Human and Animal Perspectives

“…The influence of OT on other systems appears to be widespread, as it not only interacts with 5-HT and DA, but also directly influences CRH and opioid activity. To list a few examples: OTRs expressed on serotonin (5-HT) terminals in the NAc are critical for social motivation (Dölen et al, 2013), OTR activation in the VTA is necessary for social reward in male and female Syrian hamsters (Borland et al, 2019), OT modulates HPA activity and CRH release via interaction with GABA-A receptors in the PVN (Smith et al, 2016), and OT binds to Mu opioid receptors as a positive allosteric modulator and directly influences anxietylike behavior associated with chronic pain (Meguro et al, 2018;Miyano et al, 2021). Finally, the social salience hypothesis of OT proposes that OT regulates the salience of social stimuli and increases sensitivity to social cues depending on context and individual factors (reviewed in Shamay-Tsoory and Abu-Akel, 2016).…”

Opioid Ligands Addressing Unconventional Binding Sites and More Than One Opioid Receptor Subtype

“…In an in vitro study, the neuropeptide oxytocin enhanced the activity of several μOR agonists, exhibiting probe dependence, without having any agonist effect on its own, a profile consistent with μOR PAMs [104] . A more recent study suggested that oxytocin also acts as a biased PAM towards the G‐protein pathway at the κOR but not the δOR [105] . Other recently discovered allosteric ligands of μOR, through combination of in vivo and in silico studies, include compound 1 , an allosteric agonist and compound 2 , a PAM [106] …”

“…[104] A more recent study suggested that oxytocin also acts as a biased PAM towards the G-protein pathway at the kOR but not the δOR. [105] Other recently discovered allosteric ligands of μOR, through combination of in vivo and in silico studies, include compound 1, an allosteric agonist and compound 2, a PAM. [106] Overall, structurally dissimilar compounds have proven able to modulate the OR activity through binding to its allosteric site.…”

Oxytocin and oxygen: the evolution of a solution to the ‘stress of life’

“…In addition, OT can indirectly influence the function of other receptors. For example, OT serves as a positive allosteric regulator of opioid receptors [ 68 , 69 ]. In addition, OT regulates gaseous transmitters, including hydrogen sulfide (H 2 S), nitric oxide (NO) and CO 2 , with generally protective effects on tissues throughout the body [ 26 , 27 ].…”