Pain Processing: Examining the Role of Oxytocin

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A neuropeptide that has been evolutionarily conserved across species, oxytocin is synthesized within the hypothalamus.
A neuropeptide that has been evolutionarily conserved across species, oxytocin is synthesized within the hypothalamus.

The role of oxytocin (OT) in pain perception has been extensively studied, mainly in animal models; however, a limited number of studies have examined the analgesic effects of OT in humans. A review recently published in Neuroscience explores the evidence and findings that have uncovered OT sites of action along pain processing pathways.1

A neuropeptide that has been evolutionarily conserved across species, OT is synthesized within the paraventricular, supraoptic, and accessory nuclei of the hypothalamus. These magnocellular neurons send projections to the posterior lobe of the pituitary, where OT enters the bloodstream, and to other areas including the amygdala, hippocampus, cerebral cortex, and ventral tegmental area.

OT acts centrally and peripherally to modulate a range of social and nonsocial behaviors, emotion, and pain, the latter leading to an increasing focus on the OT receptor as a potential target for pain treatment. The present review identified more than 190 papers indicating analgesic effects of OT in rodents.

Among the notable recent findings, a 2016 study uncovered a new subset of approximately 30 parvocellular OT neurons in the paraventricular.2 These neurons were found to modulate nociception both directly, through the inhibition of spinal sensory neurons, and indirectly, through the release from supraoptic neurons in the periphery.

In a rodent study, induced acute pain led to the activation of parvocellular OT neurons, as well as to increased levels of OT in the plasma and the paraventricular; OT blocking resulted in hypersensitivity in those animals.3

Several key OT action sites in pain-related structures are highlighted here:

  • Cortex. Several cortical areas receive projections from OT neurons and express moderate levels of OT receptors; animal and human studies have shown activation of these areas (especially the cingulate and insular cortices) during acute pain and chronic pain (during which the medial prefrontal cortex was found to undergo morphological reorganization). No study to date has investigated the direct effects of OT on cortical pain processing, and the few brain imaging studies that have been conducted in humans found no evidence of OT-related cortical activation in response to induced pain.4-6
  • Amygdala. Human brain imaging studies have reported the modulation of blood oxygen level-dependent contrast imaging responses in the amygdala as a result of painful stimuli. In 1 rodent study, OT receptor-expressing interneurons were found in the lateral part of the central amygdala, and evoked OT release in this area led to reduced fear responses.7 "Because of the link between pain and fear/anxiety, as well as the known involvement of [central amygdala] in pain modulation, it is tempting to speculate that the analgesic OT domain may be located in the [central amygdala]," wrote the authors of the review.
  • Raphe nucleus. Intrathecally administered serotonin has been shown to mimic the effects of OT, as well as to enhance the antinociceptive effects of OT. A study published in 2009 indicated that serotonin release in the median raphe nucleus mediated by OT may have anxiolytic effects.8 Considering the somatosensory and emotional components of pain, as well as the association of anxiety and depression with chronic pain, additional research should explore the anxiolytic effects of OT and serotonin and their interaction.
  • Spine. An array of animal and human studies shows pronounced OT innervation around thoracic level 3 and lumbar levels 2 and 6. "Together, these data provide an anatomical support for a direct modulation of spinal cord neurons by OT, possibly affecting nociceptive and autonomic processing," emphasized the review authors.

In humans, it has been proposed that OT modulates a range of psychological factors that influence pain processing, including attention to pain, social support, and negatively valenced emotions. "All of these components are associated with neuronal activities in brain regions that have been shown to be modulated by OT administration in socio-emotional tasks," noted the review authors.

However, findings from the limited research on the link between OT and pain processing in humans have been mixed, with 10 of 17 studies supporting pain-modulating effects of OT.

The authors point to the following needs in bridging the gap between animal and human research:

  • Further insight into how and when intranasal OT reaches the brain
  • Clarification of optimal doses
  • An understanding of OT-sensitive circuits and their "interaction with ascending and descending pain pathways in both animals and humans"
  • Neuroimaging studies using autonomic pain markers
  • Consideration of the multidimensionality of pain processing in humans

"Particularly in humans, OT effects on pain might strongly depend on the interplay between sensory, physiological, affective, cognitive and behavioral components," they wrote. "Future studies should therefore also concentrate on indirect effects of OT on pain and examine benefits related to OT apart from its pure analgesic effects."

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References

  1. Boll S, Almeida de Minas AC, Raftogianni A, Herpertz SC, Grinevich V. Oxytocin and pain perception: From animal models to human research [published online September 28, 2017]. Neuroscience. doi:10.1016/j.neuroscience.2017.09.041
  2. Eliava M, Melchior M, Knobloch-Bollmann HS, et al. A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and Inflammatory pain processing. Neuron. 2016;89:1291-1304.
  3. Matsuura T, Kawasaki M, Hashimoto H, et al. Possible involvement of the rat hypothalamo-neurohypophysial/-spinal oxytocinergic pathways in acute nociceptive responses.  J Neuroendocrinol. 2016;28(6).
  4. Wang J-Y, Zhang H-T, Chang J-Y, Woodward DJ, Baccala LA, Luo F. Anticipation of pain enhances the nociceptive transmission 1136 and functional connectivity within pain network in ratsMol Pain. 2008:4:34.
  5. Orenius TI, Raij TT, Nuortimo A,  Näätänen P, Lipsanen J, Karlsson H. The interaction of emotion and pain in the insula and secondary somatosensory cortex. Neuroscience. 2017:349:185-94.
  6. Metz AE, Yau H-J, Centeno MV, Apkarian AV, Martina M. Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic painProc Natl Acad Sci USA. 2009;106(7):2423-2428.
  7. Knobloch HS, Charlet A, Hoffmann LC, et al. Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron. 2012;73(3):553-566.
  8. Yoshida M, Takayanagi Y, Inoue K, et al. Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in miceJ Neurosci. 2009;29:2259-2271.
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