Is Oxytocin "Nature's Medicine"?

Abstract

Oxytocin is a pleiotropic, peptide hormone with broad implications for general health, adaptation, development, reproduction, and social behavior. Endogenous oxytocin and stimulation of the oxytocin receptor support patterns of growth, resilience, and healing. Oxytocin can function as a stress-coping molecule, an anti-inflammatory, and an antioxidant, with protective effects especially in the face of adversity or trauma. Oxytocin influences the autonomic nervous system and the immune system. These properties of oxytocin may help explain the benefits of positive social experiences and have drawn attention to this molecule as a possible therapeutic in a host of disorders. However, as detailed here, the unique chemical properties of oxytocin, including active disulfide bonds, and its capacity to shift chemical forms and bind to other molecules make this molecule difficult to work with and to measure. The effects of oxytocin also are context-dependent, sexually dimorphic, and altered by experience. In part, this is because many of the actions of oxytocin rely on its capacity to interact with the more ancient peptide molecule, vasopressin, and the vasopressin receptors. In addition, oxytocin receptor(s) are epigenetically tuned by experience, especially in early life. Stimulation of G-protein-coupled receptors triggers subcellular cascades allowing these neuropeptides to have multiple functions. The adaptive properties of oxytocin make this ancient molecule of special importance to human evolution as well as modern medicine and health; these same characteristics also present challenges to the use of oxytocin-like molecules as drugs that are only now being recognized. SIGNIFICANCE STATEMENT: Oxytocin is an ancient molecule with a major role in mammalian behavior and health. Although oxytocin has the capacity to act as a "natural medicine" protecting against stress and illness, the unique characteristics of the oxytocin molecule and its receptors and its relationship to a related hormone, vasopressin, have created challenges for its use as a therapeutic drug.

Fig. 1.

The descent of the neuropeptide ligand and receptor systems through evolutionary time, adapted from Grinevich et al. (2016). Beginning approximately 700 million years ago (MYA), the ancestral peptide and its receptor predate mammals and indeed vertebrates. Both peptide and receptor underwent two rounds of genome duplication approximately 550 MYA. These systems eventually consisted of mesotocin (MS), the mesotocin receptor (MSR), vasotocin (VT), and three vasotocin receptors (VTRs). At the emergence of mammals approximately 200 MYA, the vasotocin peptide and receptor evolved into their modern forms, consisting of AVP and its three receptors (AVPR1A, AVPR1B, and AVPR2). Modern mammalian oxytocin (OXT) and its receptor (OXTR) first evolved approximately 100 MYA.

Fig. 2.

Processing of the oxytocin molecule and its targets. After conversion from the prohormone form, oxytocin exists in an extended form with three extra amino acids. The conversion from extended OXT to oxytocin consisting of nine amino acids occurs with maturation of the hypothalamus in neurotypical individuals. It is not known how this extended form interacts with receptors. In their canonical nine–amino acid forms, both oxytocin and vasopressin bind and act as agonists to both OXTR and AVPR1A, although oxytocin has a higher affinity for OXTR than the AVPR1A, as denoted by the thicker arrow. Oxytocin also acts as an agonist to the pain-sensing transient receptor potential vanilloid-1 (TRPV1) receptor and as a positive allosteric modulator at the MOR. After degradation by IRAP, the C-terminal tail is cleaved from oxytocin to form MIF-1, which can both inhibit MOR and act as an allosteric modulator on the D2 subtype of dopamine receptors (D₂R). Oxytocin can also be degraded by other as of yet unspecified peptidase activity into a linear form that stimulates activity of the α-2 type adrenoreceptors (α2ARs). Conventional arrow = agonist; circle-tipped arrow = positive allosteric modulator; block-tipped arrow = antagonist.

Fig. 3.

The effects of oxytocin and vasopressin can be context-dependent. Sensitivity of the AVPR1A or OXTR to either oxytocin or vasopressin may be altered by a history of adversity or by positive experiences, especially during early life. For example, as illustrated here, arousal or stress may increase the release of oxytocin and/or increase sensitivity of AVPR1A to oxytocin [reviewed Carter (2017)].

Fig. 4.

Oxytocin acts as an anti-inflammatory molecule for the nervous system in the presence of stressors. For the developing brain, oxytocin confers neuroprotection in the presence of a stressor by inhibiting the release of proinflammatory cytokines by microglia by decreasing oxidative stress exposure and by protecting mitochondrial function. For the adult brain, oxytocin confers similar neuroprotection in the presence of a stressor by inhibiting the release of proinflammatory cytokines by microglia, by decreasing oxidative stress exposure, by protecting mitochondrial function, and by increasing antioxidant capacity. Moreover, similar to its inhibition of microglia-mediated inflammatory cascades, oxytocin inhibits macrophage-mediated proinflammatory cascades outside of the central nervous system during an immune challenge with LPS. Although oxytocin mediates many aspects of social behavior and cognition, the known social and cognitive functions that oxytocin protects in the presence of inflammation are shown here for the developing and adult brain. Inflammatory cascades are shown in purple and oxytocin signaling is shown in red. All of oxytocin’s protective effects shown here are believed to be mediated by oxytocin binding to the OXTR. COX-2, cyclooxygenase-2; GPx, glutathione peroxidase; GSH, reduced glutathione; GSSG, oxidized glutathione; HMGB1, high-mobility group box 1.

Fig. 5.

Oxytocin acts as an anti-inflammatory molecule for the gastrointestinal system in the presence of stressors. For the developing gut, oxytocin confers protection in the presence of a stressor by inhibiting the activation of proinflammatory cascades by activating the UPR^ER and by enhancing autophagy. For the adult gut, oxytocin confers protection in the presence of a stressor by inhibiting proinflammatory cascades by inhibiting enteric glia and NF-κB signaling by activating the UPR^ER by enhancing autophagy and by decreasing oxidative stress. Although oxytocin mediates many aspects of social behavior and cognition after stress-aggravated colitis, oxytocin has been shown to decrease anxiety-like behavior (Cetinel et al., 2010). Inflammatory cascades are shown in purple, and oxytocin signaling is shown in red. All of oxytocin’s protective effects shown here are believed to be mediated by oxytocin binding to the OXTR. CCR5, C-C chemokine receptor-5; GSH, reduced glutathione; LDH, lactate dehydrogenase; MDA, malondialdehyde; MPO, myeloperoxidase.