{
  "abstract": "Oxytocin, often referred to as the love hormone, is a neuropeptide composed of nine amino acids produced in the hypothalamus and released into the bloodstream from the posterior pituitary gland. Its receptor, the oxytocin receptor, plays a crucial role in various physiological and psychological processes, including social bonding, reproductive behaviours, and pain modulation (Arrowsmith and Wray, 2014). This report explores the effects of oxytocin receptor activation, presents the differences between the two available oxytocin receptor agonists (oxytocin and carbetocin), and focuses on pain modulation as one of several central nervous system (CNS) effects. History The discovery of oxytocin dates back to 1906 when Sir Henry Dale first isolated it from the posterior pituitary gland.(Dale, 1909) The American biochemist Vincent du Vigneaud was awarded the Nobel Prize for Chemistry in 1955 for the isolation and synthesis of the two, closely related hormones oxytocin and vasopressin.(du Vigneaud et al., 1953) The oxytocin receptor, a member of the G-protein-coupled receptor family, was identified in the 1990s. Biology Oxytocin’s functions are primarily facilitating childbirth by promoting uterine contractions and milk ejection during lactation.(Arrowsmith and Wray, 2014) However, its influence is not confined to obstetrics; it also significantly impacts the cardiovascular system and the CNS.(Froemke and Young, 2021; Rosseland et al., 2013) Endogenously produced oxytocin is released directly into the CNS and, in addition, acts as a blood-borne hormone. This means that oxytocin acts as both a neurotransmitter and a hormone. Theoretically, the two drugs available that have oxytocin receptor effects are expected to have no CNS effects as they cannot pass the blood-brain barrier. However, even if the drugs are not supposed to pass the blood-brain barrier, studies indicate some CNS effects after nasal spray and intravenous injection.(Fathabadipour et al., 2022) Intrathecal oxytocin has been studied in animal and human studies with documented effects on pain.(Eisenach et al., 2023a) Stimulation of the oxytocin receptor leads to different effects depending on the cell type. Systemic vascular resistance is reduced due to a relaxation of smooth muscle cells in the vessels, but the uterine smooth muscle cells contract. Oxytocin also has some stimulating effect on the vasopressin receptors, leading to an anti-diuretic effect, which, combined with excessive water drinking or glucose infusion, probably has led to many cases of severe hyponatremia.(Moen et al., 2009; SINGHI et al., 1985) This is the reason why we stopped giving oxytocin together with glucose many years ago. The effects of oxytocin in the CNS are multifaceted. Oxytocin has been shown to modulate various neurobiological processes, including anxiety, stress response, and social behaviour. The oxytocin system interacts with other neurotransmitter systems, including dopamine, serotonin, and norepinephrine, to regulate mood and emotional states. Furthermore, oxytocin’s anxiolytic and antidepressant effects have been explored, suggesting its potential therapeutic applications in anxiety and mood disorders. Oxytocin receptor stimulation may affect autism spectrum disorder, and differences in the oxytocin receptor gene are associated with autism.(Jacob et al., 2007) One of the more intriguing effects of oxytocin is its potential for pain relief. Research has shown that oxytocin receptor agonists can play an analgesic role by modulating pain pathways in the brain and spinal cord, reducing the perception of pain.(Gutierrez et al., 2013) This effect may be mediated through the inhibition of pain pathways and the modulation of excitatory and inhibitory signals in the spinal cord, suggesting new avenues for pain management. Oxytocin Receptor Agonists (ORA) There are two ORAs available: carbetocin and oxytocin. Carbetocin is a synthetic derivative of oxytocin, with a slight modification in its molecular structure intended to increase the duration of the drug’s effect.(Jaffer et al., 2022) It produces long-acting uterine contractions post-delivery, thereby mitigating postpartum haemorrhage. Carbetocin efficacy is comparable to the combination of oxytocin and methergine, but it has fewer side effects,(Jaffer et al., 2022) and less crossover stimulation of vasopressin receptors.(Arrowsmith and Wray, 2014) Another interesting feature is that carbetocin, unlike oxytocin, is temperature stable. In many countries, keeping cool storage of drugs is difficult, making oxytocin inactive.(Widmer et al., 2018) Pain Management ORA may have promising potential as a non-opioid therapy in treating acute post-surgical pain, but also in chronic pain syndromes, especially those that are resistant to conventional analgesics.(Mekhael et al., 2023) The analgesic properties of ORA may have significant implications for pain management strategies. The postpartum period, more so than pregnancy, offers protection against chronic hypersensitivity following peripheral nerve injury in rats, and this protection may be attributed to oxytocin signaling in the CNS during the postpartum period.(Gutierrez et al., 2013) ORA may protect against persistent pain, which raises interesting perspectives for the prevention of chronic pain.(Sun and Pan, 2019) Recently, intrathecal oxytocin was tested for pain relief in hip replacement surgery. The oxytocin group did not experience a decrease in worst daily pain, but they did have faster recovery and reduced opioid use.(Eisenach et al., 2023b) Intravenously administered carbetocin showed antinociceptive effects on experimental pain in healthy male volunteers compared with placebo.(Biurrun Manresa et al., 2021) Reported postoperative pain severity was inversely correlated with plasma oxytocin levels measured 1 hour and 24 hours after cesarean delivery.(Ende et al., 2019) Furthermore, carbetocin has been shown to reduce post-caesarean pain compared with oxytocin.(Bekkenes et al., 2023) Still, clinical studies investigating the analgesic effects of ORAs are few. Conclusion Oxytocin and its receptor system play a multifaceted role within the CNS, influencing not only peripheral physiological processes but also exerting profound effects on social behaviour, emotional regulation, and pain. The exploration of ORA in neurobiology paves the way for novel therapeutic applications. 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  "authors": [
    {
      "affiliations": [
        "Dep of Research and Deelopment, Division of Emrgencies and Critical Care, Oslo University Hospital, Oslo, Norway"
      ],
      "name": "Leiv Arne Rosseland"
    }
  ],
  "title": "FT40 Role of oxytocin",
  "uid": "0f55665a-2076-51d1-a17f-a47d6d17251a"
}