Oxytocin and Pain Perception: From Animal Models to Human Research

Highlights

• In rodents, oxytocin (OT) exerts analgesia acting on pain matrix structures.

• In humans, OT exerts effects on brain regions involved in pain processing, but OT-pain-pathways are not yet understood.

• Evidence for analgesic effects of oxytocin in humans is not as consistent as in animal models.

• In humans, OT might reduce pain perception by modulating emotional and cognitive aspects of the pain experience.

Abstract

An accumulating body of evidence suggests that the hypothalamic neuropeptide oxytocin (OT) has a modulatory effect on pain processing. Particularly strong evidence comes from animal models. Here, we review recent advances in animal research on the analgesic effects of OT and discuss possible target sites of OT within descending and ascending pain pathways in the brain. In addition to the spinal cord being a direct target of the neuropeptide, OT has also been shown to modulate the neuronal activity of limbic and cortical brain regions, which play a major role in the cognitive and emotional processing of pain. Human studies investigating the influence of OT on pain perception are less numerous and have revealed less consistent results. The human literature is therefore scanned thoroughly and different approaches to study the effects of OT on pain perception in humans are discussed. Moreover, we also address how OT might alleviate pain by influencing socio-emotional components in humans. We conclude that further investigating specific OT and OT-sensitive circuits, which modulate pain processing especially in primates, will improve our understanding of OT-analgesic effects. In human research, the increased use of neuroimaging and autonomic measures might help to bridge the gap to animal studies.

Introduction

Pain, as defined by the International Association for the Study of Pain (IASP), is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage” (http://www.iasp-pain.org/Taxonomy#Pain, Loeser and Treede, 2008). Thus, the experience of pain can be seen as a protective and survival mechanism since it triggers us to take action and seek for help, potential medical treatment and relief. Due to its complexity, it was impossible for researchers to merely believe in the existence of one single pain center in the brain. In 1989, Melzack introduced the Neuromatrix Theory, stating that there was not one single cortical region devoted to pain processing, but a complex brain network (Melzack, 1989, Melzack, 1999). From that time on, the tremendous development in brain imaging research in both animals and humans (Brooks and Tracey, 2005, Tracey, 2008, Borsook and Becerra, 2011, Morton et al., 2016) has provided further support for the idea of several interconnected brain areas which are consistently activated by a noxious stimulus.

Oxytocin (OT), an evolutionarily conserved neuropeptide, is synthesized within the paraventricular (PVN), the supraoptic (SON), and the accessory (AN) nuclei of the mammalian hypothalamus. Magnocellular OT neurons project to the posterior pituitary lobe and from there OT is released into the blood circulation (Swanson and Sawchenko, 1983). In addition, OT neurons simultaneously project to extrahypothalamic brain areas such as the amygdala, hippocampus, cerebral cortex, ventral tegmental area (VTA) and others (Insel et al., 1997, Gimpl and Fahrenholz, 2001, Kendrick, 2004, Ross and Young, 2009, Knobloch et al., 2012, Grinevich et al., 2016). Via release into the blood or/and the brain, OT exerts both central and peripheral actions to modulate a variety of social, emotional and non-social behaviors including pain (see reviews by Lee et al., 2009, Yang et al., 2013, Romano et al., 2015). Although OT is well conversed among species, its receptor (OTR) presents high levels of variability across species. In rodents OTR are prominently expressed in olfactory-related areas, whereas in primates OTRs were found in visual-related regions, such as the nucleus basalis Meynert and the superior colliculi (Freeman et al., 2014, Freeman and Young, 2016, Grinevich et al., 2016).

Due to the unique and multidimensional role of OT in a wide range of behaviors, the OTR has become a promising target for therapeutic interventions in pain. This is not surprising, because the central OT system plays a key neuromodulatory role in emotion, stress and anxiety for instance, which are well known to substantially influence pain perception (Apkarian et al., 2005, Apkarian, 2008, Hoeger Bement et al., 2010, Peters, 2015, Tracy et al., 2015). Thus, during the last decades, numerous studies (in animals and humans) have focused on the investigation of analgesic effects of OT (see reviews by Rash et al., 2014, Tracy et al., 2015, Xin et al., 2017). The purpose of the current review is not to merely summarize recently published findings in the topic, but to precisely discuss potential OT site actions (targets) in structures related to pain processing. Moreover, we review the literature on OT and pain in humans with respect to major caveats and challenges as studies in humans are less numerous and have revealed less consistent results than those in animals. As pain is a multidimensional phenomenon, we also discuss how OT can alleviate pain by modulating socio-emotional factors. Particularly in humans, OT effects on pain might strongly depend on the interplay between sensory, physiological, affective, cognitive and behavioral components. At the end of this review, we propose directions for further translational animal–human studies.