Oxytocin and the modulation of pain experience: Implications for chronic pain management

doi:10.1016/j.neubiorev.2015.04.013

Neuroscience & Biobehavioral Reviews

Volume 55, August 2015, Pages 53-67

https://doi.org/10.1016/j.neubiorev.2015.04.013 Get rights and content

Highlights

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Pain phenomenology and factors which influence its perception are discussed.
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Acute and chronic pain are unique creatures, and should be treated as such.
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The diverse applications of oxytocin in clinical environments are highlighted.
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Methodological issues to consider for future research are evaluated.
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Overall, oxytocin has great potential as a modulator of pain experience.

Abstract

In an acute environment pain has potential protective benefits. However when pain becomes chronic this protective effect is lost and the pain becomes an encumbrance. Previously unheralded substances are being investigated in an attempt to alleviate the burden of living with chronic pain. Oxytocin, a neuropeptide hormone, is one prospective pharmacotherapeutic agent gaining popularity. Oxytocin has the potential to modulate the pain experience due to its ubiquitous involvement in central and peripheral psychological and physiological processes, and thus offers promise as a therapeutic agent. In this review, we discuss previous effective applications of oxytocin in pain-free clinical populations and its potential use in the modulation of pain experience. We also address the slowly growing body of literature investigating the administration of oxytocin in clinical and experimentally induced pain in order to investigate the potential mechanisms of its reported analgesic actions. We conclude that oxytocin offers a potential novel avenue for modulating the experience of pain, and that further research into this area is required to map its therapeutic benefit.

Section snippets

Overview

Pain is truly a double-edged sword. Under most circumstances it serves to protect us, whereas at other times it can be severely disabling. Both the context and duration of painful events dictate the way we react to pain and heavily influence our perception of painful events. The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (Loeser and

Nociceptors

Peripheral neurons that respond to noxious stimulation and detect potentially damaging stimuli are called nociceptors (Basbaum and Jessell, 2000). There are two main types of nociceptive fibres: the thinly myelinated A-delta (Aδ) neurons, which transmit information about acute and localised pain with fast conduction speeds; and the unmyelinated C fibres which signal more widespread pain, with slower conduction speeds (Campbell and Meyer, 2006). Nociceptors can be specific to a particular type

Overview

Oxytocin is a nonapeptide hormone primarily synthesised within the magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus in the brains of mammals (Sofroniew and Weindl, 1981). Magnocellular neurons transport oxytocin from the hypothalamic nuclei to the posterior pituitary gland, where the hormone is then released into the peripheral circulation (Fig. 1; Carter et al., 2007, Uvnas-Moberg and Petersson, 2004). With an evolutionary precursor, vasotocin, responsible

Pain phenomenology

Throughout history there have been numerous models of pain perception, beginning with Descartes’ model in the 17th century (Descartes and Schuyl, 1662). Descartes proposed that pain transmission occurred via a series of tubes and gates. Sensory cues, such as placing your bare foot near an open flame, would “tug” on a tube within the body. The “tug” would open a gate between the tube and the brain, which would allow “animal spirits” to flow through the tubes to the brain and elicit a motor

Cognitive processing: attention

Pain is a highly subjective and complex experience that shows a non-linear relationship between nociceptive input and pain experience (Wiech and Tracey, 2009). Many cognitive processes have been found to influence pain perception and nociceptive processing within the human brain (Wiech et al., 2008). Attention can amplify behavioural and physiological responses to relevant events while attenuating responses to irrelevant events (Corbetta and Shulman, 2002). For example, attentional focus on a

Oxytocin administration

Over the last two decades, the heuristic interest of oxytocin has grown exponentially due to the hormone's potential ability to improve social skills of individuals with autism spectrum disorders (Guastella et al., 2010), reduce activation of the amygdala in social anxiety (Labuschagne et al., 2010), and to alleviate psychiatric conditions such as depression (Bakermans-Kranenburg and van Ijzendoorn, 2013). Attempts to administer oxytocin intravenously were short-lived because it does not

Definition, prevalence, burden and cause

There has been ongoing debate as to whether chronic pain should be classified as a disease on its own merit. Without doubt chronic pain has a severe impact on the general health, mood, and the socio-economic wellbeing of afflicted individuals (Elliott et al., 1999). Although chronic pain entails different pathophysiological processes to acute pain, defining chronic pain as a disease cannot be made without the presence of novel and unique pathophysiology (see Siddall and Cousins, 2004). Chronic

The utility of oxytocin in pain

Varying forms of evidence suggest that oxytocin may modulate pain experience. A recent systematic review provided a comprehensive analysis and synthesis of findings concerning the use of oxytocin as a potential analgesic agent (Rash et al., 2014). Examining results from both human and animal studies, as well as spinal cord samples, the authors concluded that most studies supported the hypothesis that oxytocin decreases sensitivity to noxious stimuli. However, it is critical to note that the

Issues of complexity and future directions

Recall that pain can be viewed an experience of threat or danger. As we highlighted above, the physiological processes and responses associated with pain are somewhat similar to the responses observed in stress and fear. This is of importance as there are numerous similarities between the management of pain and normalising the processing of other socially and emotionally salient experiences of threat. This review has also given an overview of the involvement of oxytocin in experiences such as

Conclusions

There is a large body of research on both pain and oxytocin. Separately, these studies have greatly contributed to the way that we understand pain, and the numerous potential therapeutic applications of oxytocin. However, only a small portion of the literature overlaps, and very few studies have examined the utility of oxytocin in the management of chronic or procedural pain in humans. The financial and logistical complexities associated with research of this nature should not impede further

Conflict of interest

The authors have no conflict of interest to declare.

Role of the funding source

The conduct of this research project was funded by an Australian Research Council (ARC) Linkage Project Grant LP120200033, the Victorian Transport Accident Commission, and the School of Psychological Sciences, Monash University.

MJG is supported by a NHMRC Early Career Fellowship (Clinical).

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Citation Excerpt :
These limitations regarding analgesics aroused the interest of researchers to seek alternative and safer treatments to relieve pain (Spiller et al., 2009), and a substance that has stood out is oxytocin (OXT), a peptide hormone mainly produced in the hypothalamus and released both into peripheral circulation and centrally (Carter et al., 2008; Baribeau and Anagnostou, 2015). OXT plays a neuromodulatory role in processes linked to emotions, stress, and anxiety (Quirin et al., 2011; Bartz et al., 2011; MacDonald and Feifel, 2014) and has emerged as a promising therapeutic target due to its potential multidimensional action on pain (Tracy et al., 2015; Lussier et al., 2019). Oxytocinergic neurons are known to project themselves to key regions of the so-called “pain matrix”, which is composed of the somatosensory and cingulate cortex, prefrontal regions, thalamus, insula, and amygdala, and together process the perception of painful stimuli, information integration, and pain-related behavioral and emotional responses (Fenton et al., 2015; Boll et al., 2018; Zhang et al., 2019; Schneider et al., 2020).
Oxytocin (OXT) is a peptide hormone produced in the hypothalamus that plays a neuromodulatory role in emotion, stress, and anxiety. Due to its multidimensional role, OXT is a promising target for therapeutic interventions to treat pain.
Perform a systematic literature review, followed by a meta-analysis to identify the effects of intranasal OXT on the self-perception of clinical and experimental pain among human subjects.
A systematic review was conducted in the PubMed, PsycINFO, Scielo, Lilacs, and Web of Science databases, using the keywords Oxytocin, Pain, Analgesia, and Nociception.
Fifteen papers were included in the meta-analysis. None of the outcomes presented statistical significance in terms of the interventions' effect size: pain intensity (SMD = −0.02 (CI 95 %: −0.14 to 0.10; p = 0.76)) and pain unpleasantness (SMD = -0.15 (CI 95 %: −0.34 to 0.04; p = 0.12)). No meta-analysis was performed for pain threshold or tolerance because few papers address these outcomes.
There was no statistically significant effect of intranasal OXT administration on pain perception, considering equivalence limits between (−0.2 and 0.2). However, it must be considered that the study designs may not have been sensitive enough to detect minor analgesic effects of OXT, which, being weak, may also not be perceived at a conscious level. Additionally, OXT effects possibly depend on specific characteristics of the painful condition, such as pain complexity, intensity, and duration, contextual variables like the presence of social and affective support, and individual characteristics.
Neuroimaging genetics of oxytocin: A transcriptomics-informed systematic review
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The last couple of decades have witnessed a rapid accumulation of studies implicating oxytocin (OT) in several neurobiological underpinnings of human behaviour and their impairment in psychiatric illness. Specifically, a neuroimaging genetics approach is helping elucidate the impact of variations in OT pathway genes on the human brain. In this review, we provide the first systematic account and discussion of all previous findings arising from human neuroimaging (epi)genetic studies of OT-related genes. To improve our mechanistic interpretation of such findings, we used data from the Genotype-Tissue Expression project to explore the functional impact the genetic variations may have on the human transcriptome. As a result, we provide an up-to-date summary of brain circuits found to be impacted by OT-relevant (epi)genetic variability, map brain pathways linking OT genes to disease, and highlight several (epi)genetic factors that modulate brain responses to intranasal OT. Finally, we provide some suggestions we believe might improve future research in the field.
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Our previous study verified a sex difference of anti-hyperalgesia in rats and anti-allodynia in mice induced by intrathecal oxytocin (OT). In the model of intraplantar carrageenan-induced inflammatory hyperalgesia, intrathecal OT injection induced a substantial anti-hyperalgesia in male rats even at a low dose (0.125 nmol). In contrast, female rats only responded to an extremely high dose (1.25 nmol). This sex difference concurs with a lower expression of OT receptors and higher expression of insulin-regulated aminopeptidase (IRAP; OT degrading enzyme) in the spinal cords of female rats. In this study, we further determined the role of female hormones in this sex difference by using ovariectomized rats. Our results show that a low dose of intrathecal OT caused a significant anti-hyperalgesia effect in ovariectomized female rats, similar to that seen in male rats. Ovariectomy did not cause any change of paw edema except at the late stage of convalescence when compared with the sham-operated group. Ovariectomy-induced faster recovery from edema but did not affect the severity of hyperalgesia. Moreover, there was a similar amount of IRAP expression in ovariectomized and sham rats. When estradiol (E2) was given together with OT, OT-induced anti-hyperalgesia was abolished at the developmental stage of hyperalgesia in ovariectomized rats. These results show an inhibitory role of female hormones generated from ovaries (mainly estrogen) in the sex difference of anti-hyperalgesia induced by OT. This study suggests the feasibility of a novel OT-based remedy to treat hyperalgesia in men and in menopausal women no receiving hormonal supplements.
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Romantic rejection is an emotionally distressful experience profoundly affecting life, possibly leading to mental illness or suicide. Oxytocin (OT) is a neuropeptide widely implicated in reducing physical pain and negative emotions; however, whether OT has an effect on reducing intense social pain (e.g., romantic rejection) remains unknown. Here, we tested the effect of OT on social pain and investigated its role in the outcome evaluation phase of social decision-making.
Electroencephalographic recordings were obtained between August 2nd and October 20th, 2020 in Shenzhen University from 61 healthy participants in a double-blind, placebo-controlled study with a between-subject design. We defined frontal-midline theta oscillation as a neural signature of social pain and assessed self-reported pleasantness ratings for four possible romantic outcomes in an online speed-dating task.
In the placebo group, greater theta power was induced by romantic rejection, being associated with rejection distress. This pattern was not observed in the OT group, where romantic rejection induced significantly decreased theta power compared to the placebo group; in the OT group, there was no association between theta power and rejection distress. Furthermore, the frontal-midline theta oscillation could be source-localized to brain areas overlapping with the physical-social pain matrix (i.e., somatosensory cortex, anterior cingulate cortex, frontal pole, and supplementary motor area).
OT relieves social pain caused by romantic rejection, reflected in decreased frontal-midline theta oscillations and a diminished connection between theta power and rejection distress. These findings can help understand and harness OT’s pain-reducing effect on social pain.

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ReviewOxytocin and the modulation of pain experience: Implications for chronic pain management

Highlights

Abstract

Section snippets

Overview

Nociceptors

Overview

Pain phenomenology

Cognitive processing: attention

Oxytocin administration

Definition, prevalence, burden and cause

The utility of oxytocin in pain

Issues of complexity and future directions

Conclusions

Conflict of interest

Role of the funding source

Pain

Pain

Pain

Br. J. Anaesth.

Neurosci. Lett.

Cell

Biol. Psychol.

Pulm. Pharmacol. Ther.

Brain Res.

J. Pain

Lancet

Pain

Lancet Neurol.

Peptides

Neuron

Prog. Brain Res.

Pain

Pain

Pain

Horm. Behav.

Peptides

Pain

Lancet

Biol. Psychiatry

Neuropsychologia

Neurosci. Lett.

J. Psychosom. Res.

Regul. Pept.

Brain Res.

Psychoneuroendocrinology

J. Pain

Biol. Psychiatry

Psychoneuroendocrinology

Biol. Psychiatry

Neurosci. Lett.

Neuroscience

Biol. Psychiatry

Neuron

Oxytocin and female sexuality

Gynecol. Obstet. Invest.

Transcranial magnetic stimulation highlights the sensorimotor side of empathy for pain

Nat. Neurosci.

Sniffing around oxytocin: review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy

Transl. Psychiatry

Activity-dependent release of endogenous brain-derived neurotrophic factor from primary sensory neurons detected by ELISA in situ

J. Neurosci.

The perception of pain

Neuroscience: Exploring the Brain

The sites of origin brain stem neurotensin and serotonin projections to the rodent nucleus raphe magnus

J. Neurosci.

Reprint of the “Idea of a New Anatomy of the Brain,” with Letters, &c

J. Anat. Physiol.

Pain–autonomic interactions: a selective review

Clin. Auton. Res.

Pain–autonomic interactions

Neurol. Sci.

Endogenous opioid systems: current concepts and clinical correlations

Neurology

The role of oxytocin in relation to female sexual arousal

Gynecol. Obstet. Invest.

Review
Oxytocin and the modulation of pain experience: Implications for chronic pain management