Oxytocin and the Limbic System

Oxytocin is the body’s most potent natural pain modifier and a regulator of anxiety, stress-coping, and sociality. It is a highly abundant neurohypophysial peptide that has a prevalent expression localized to magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei.7 Magnocellular oxytocin neurons of these nuclei innervate the forebrain and release the hormone into systemic circulation from the posterior pituitary in response to a variety of stimuli, including pain.78 The parvocellular oxytocin neurons project to the brainstem and spinal cord where the oxytocin modulates inflammation and pain processing, thus modulating the limbic system.7

There is some speculative evidence that the oxytocin from the paraventricular nuclei of the hypothalamus can reach the central amygdala. Oxytocin has been known to reduce amygdala activity and is believed to have a neurocomputational mechanism underlying social-value representation, suggesting that oxytocin may promote pro-sociality by modulating the amygdala.9*10 Administration of intranasal oxytocin has been shown to amplify the amygdala representation and increase prosocial behavior.

Oxytocin and Pain Management

With the continued rising concern surrounding the use of chronic opioids, oxytocin could prove to be an alternative pharmacotherapy, with the potential to modulate pain through both central and peripheral psychological and physiological processes (Figure 16.1).8 Oxytocin receptors are located at multiple sites in the brain and throughout the spinal cord, and endogenous stimulation of oxytocin has been shown to decrease pain sensitivity.11*12 The action of oxytocin’s visceral nociceptive effects include the dorsal horn neuronal response to noxious visceral stimulation. Neuronal projections from the hypothalamus to the receptors in the dorsal horn of the spinal cord prevent pain signals from reaching the brain.13 Oxytocin has been shown to indirectly reduce the activity of the spinal dorsal horn neurons following application of glutamate in rats.14 In addition to decreasing sensitivity to pain, oxytocin has also been shown induce a state of calmness, and lower serum cortisol, stress, and anxiety.15

Oxytocin is commonly know'n for its use in labor and delivery, where it binds to G-protein coupled cell surface receptors that are highly expressed in mammary glands and the myometrium. It also causes dilation of vascular smooth muscle, thus increasing renal, coronary, and cerebral blood flow. While parturition has been the primary utilization for oxytocin in pain management, it has also shown evidence of effects on chronic pain and may be useful in other disease states such as headache, constipation, irritable colon, fibromyalgia, and other deep tissue disorders.8*14*16-19

The role of oxytocin in pain has mostly been studied in animal models, but oxytocin is increasingly being investigated for pain management in humans. While the majority of research suggests that oxytocin decreases sensitivity to pain in animals, data on the association between oxytocin and pain processing in humans are limited and mixed. Additionally, oxytocin studies have typically focused on acute pain with less of a focus on chronic pain.

Oxytocin in pain modulation

FIGURE 16.1 Oxytocin in pain modulation.

Effect of Oxytocin on Pain via the Opioid and Cannabinoid Systems

Animal data suggest that oxytocin, in addition to binding to its own receptors, also has effects on opioid and cannabinoid receptors, both of which are known to relieve pain. Oxytocin has been shown to bind to opioid receptors, stimulating endogenous opioid release in the brain.20-22 In pre- clinical models, release of oxytocin from postsynaptic cells has been shown to increase intracellular calcium concentration, regulating the production of downstream endocannabinoids, which could be a plausible mechanism for its effects on cannabinoid receptors.23

Russo et al.23 conducted a study in mice using a carrageenan-induced hyperalgesia pain model to investigate the effect of oxytocin on peripheral pain and the inflammatory process, and its potential involvement in the cannabinoid and opioid systems. Oxytocin was administered centrally via the intracerebroventricular (icv) route and peripherally via intraperitoneal and intraplantar routes. Peripheral pain was induced by carrageenan injection into the mouse paw and pain was measured during a carrageenan-only period and then again when carrageenan was administered post-oxyto- cin treatment. Oxytocin, administered icv at the highest dose (30 ng/mouse), produced significant antihyperalgesic effects at both 3 and 6 hours post-dose. The antihyperalgesic effects were not present at 24 hours post-dose. Another set of experiments demonstrated that the antihyperalgesic effects of oxytocin icv occurred in a dose-dependent manner. Oxytocin did not show any effect in reducing paw edema. Intraperitoneal and intraplantar injections did not reduce carrageenan- induced hyperalgesia.

Protein expression of inflammatory (COX-2, iNOS) and algesiogenic (nNOS) enzymes was evaluated in the spinal cord 3 hours post-carrageenan insult, and then again after the administration of icv oxytocin, to explore the effects of oxytocin on the inflammatory process. Carrageenan alone significantly increased the expression of COX-2, iNOS, and nNOS. Oxytocin administration significantly reduced nNOS expression but did not modify COX-2 or iNOS levels. Results were consistent with what was seen with the pain model, a reduction in pain but a lack of effect on edema. Direct involvement of the oxytocin receptor was confirmed using a specific receptor antagonist, which produced significant inhibition of oxytocin’s antihyperalgesic effects.

The involvement of the cannabinoid system in oxytocin-induced antihyperalgesic effects was also explored with the use of specific CB, and CB2 antagonists. Results showed that the antihyperalgesic effect of oxytocin was significantly reversed when used in conjunction with the CB, antagonist but not the CB2 antagonist.

Naloxone was used to explore the effect of oxytocin on the opioid system. When administered alone, naloxone did not exert any significant effect on mechanical hyperalgesia. When used in conjunction with oxytocin, oxytocin’s antihyperalgesic effects were significantly reversed at 3 hours but not 6 hours post-administration. Researchers were able to further elucidate the involvement specifically of the p and к receptors in oxytocin-induced antihyperalgesic effects through the use of opioid receptor subtype antagonists. The concomitant administration of oxytocin, naloxone, and the CB, antagonist produced the most significant reversion of oxytocin’s antihyperalgesic effects, supporting the concept that both systems are involved with oxytocin’s effects.23

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