Main Research Findings

1) Oxytocin released through the stimulation of somatosensory organs induces overall well-being through the hypothalamic-pituitary-adrenal (HPA) axis.

2) Acute administration of the SSRI citalopram increased the level of plasma oxytocin, suggesting that oxytocin release is crucial to the pharmacological actions of SSRIs.

Selected Data

1) The research team of Ito et. Al examined the various beneficial effects related to the release of oxytocin. The effects of the peptide are derived from its ability to modify neural circuits in the central nervous system (CNS), the dorsal horn (DH), and the dorsal root ganglion (DRG). Oxytocin release regulates the vagal pathway and the autonomic nervous system while lowering blood pressure and cortisol levels and promoting anti-inflammatory and anti-stress effects. Recent research has reported that physical stimulation of somatosensory organs is able to induce enhanced levels of oxytocin.

Additional studies of pain relief have revealed that stimulation of both hairy and glabrous skin has the tendency to relieve joint and muscle pain. Patients presenting with tennis elbow experienced relief of symptoms after four treatments with pyramidal thorn patch- a technique used to mimic the feeling of a gentle touch. This allowed the researchers to hypothesize that stimulating gentle touch through the application of pyramidal thorn patches activates Merkel cells directly under the skin, in addition to the Merkel cell-neurite complexes present around hair follicles. Impulse signaling stimulated by a gentle touch is conveyed via A-beta fibers in order to alleviate the pain sensations originally delivered by C and Aδ fibers, an interaction that typically occurs in the DH or the DRG. From there, the reduced pain signal is sent to the CNS and results in reduced perception of pain. This lead the researchers to conclude that massage could be considered as an effective treatment to increase oxytocin release and decrease pain [1].

Pacinian corpuscles are present in glabrous skin and play a crucial role in responding to mechanical pressure, such as vibrational stimulation. Glabrous skin is typically found on the palms of the hand and the soles of the feet making these areas popular targets for various alternative medicine therapies. Tactile receptors are found in a multitude of different spots across the skin of the palms of the hands and soles of the feet, and are typically classified into fast- and slow-adapting response receptor types. The receptor types are classified based on the difference in mechanical impedance while numerous studies indicate that transient receptor potential (TRP) channels act as tactile receptors. TRP channels activated by extracellular and intracellular activity play many different physiological and pathological roles. TRPs are categorized into seven different groups: TRPC (canonical) TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin) TRPP (polycystin)m, TRPML (mucolipin), and TRPN (Drosophila NOMPC). When these channels are activated Na+ and Ca2+ enter into the cells and alter their physiological state. The channels tend to be activated in response to harmful stimuli, such as high temperature or UV radiation. However, it has been suggested that oxytocin release is increased in response to the activation of TRPM2 channels [1].

Oxytocin has also been shown to be released in states of relaxation, specifically, an emotion or mood stimulation of the brain contributing to relaxation, psychological stability, and reduction of stress responses. Due to the sense of emotional safety induced by oxytocin, the peptide has been shown to increase prosocial behaviors. Research investigating the effects of exogenously administered oxytocin revealed that central administration or nasal application of the peptide improves several social behaviors. Similar to the thought that stimulation of the glabrous skin through massage therapy induces oxytocin release, it is suggested that psychological mechanisms used for brain stimulation, such as mindfulness meditation, can enhance oxytocin release. That being said, the visual, olfactory, and auditory senses should be carefully examined for their ability to induce the psychological effect necessary for an increase in oxytocin.

Various imaging methods, such as MRI, EEG, and MEG have been used to attempt to view the effects of mindful meditation on the brain, however, the neural mechanisms remain unclear. Researchers have begun to use near-infrared spectroscopy (NIRS) in order to properly identify underlying brain mechanisms. In addition to a better view, NIRS is far more convenient to use in comparison to typical imaging examinations. It’s important to mention that oxytocin is typically linked to the placebo effect due to the main interactions that occur through glia-neuron interactions in the DH and DRG [1].

2) A multitude of studies have examined the effects of oxytocin as an endogenous antidepressant/anxiolytic peptide hormone. The vast distribution of oxytocin receptors through the limbic forebrain areas indicates that oxytocin acts as a potent neuropeptide involved in both emotional and affective behavior. The 5-HT1A receptor agonists, buspirone and ipsapirone, of the new antidepressant/anxiolytic compound 5-hydroxytryptamine (5-HT) reported a significant increase in oxytocin levels through laboratory studies. A similar increase in oxytocin levels was observed following the administration of experimental drugs that stimulate the 5-HT2A/C receptors rather than 5-HT1B or 5-HT3 receptors. Based on the previous studies that outline the relationship between the 5-HT receptors and oxytocin release, the research team of Uvnäs-Moberg et. Al examined the antidepressant effects of increased oxytocin secretion in comparison to administration of SSRIs citalopram and zimeldine, considering that activation of the 5-HT1a and 5-HT2A/c receptors is crucial to the efficacy of these SSRIs.

The study utilized adult male Sprauge-Dawley rats weighing 280-320 grams. The subjects arrived in the laboratory 10 days prior to treatment in order to assimilate to their surroundings. The rats were housed five animals per cage and maintained under controlled conditions of temperature, humidity, and light-dark cycles. Both food and water were available to the test subjects ad libitum and all experimental procedures were approved by the Stockholm South Committee on Ethics of Animal Experimentation. Prior to the experimental protocol, oxytocin, somatostatin, gastrin, and cholecystokinin were all were immunoassayed followed by sample purification through the use of reversed-phase chromatography using C18 Waters SEP-PAK cartridges. The next step of the study was to add the proper antibody to the immunoassay in order to determine various levels of reactivity. Insulin was measured with a modified assay that utilized the M8309 antibody, porcine insulin, and the rat insulin standard.

The animals were either intraperitoneally injected once a day with 20 mg/kg of citalopram HBr, or 2 ml/kg of a saline vehicle, over an experimental period of 14 days. 24 hours after the last dose of citalopram was administered, the animals were given an acute subcutaneous injection of zimelidine 2 HCl, or 2 ml/kg of saline, once a day for 14 days. 24 hours after the last saline injection the subjects were administered a final subcutaneous injection of 20 mg/kg of zimelidine or a saline vehicle. 40-120 minutes after the final dose of either citalopram, zimelidine, or saline was given all animals were euthanized by way of decapitation. 5-7 ml of trunk blood was collected in ice-cold tubes containing aprotenin and heparin in order to centrifuge the sample and separate the plasma. Parametric description and analysis was completed according to standard procedure while statistical analysis was performed through two-way ANOVA.

Discussion

1) When applying the model of well-being induced by the paraventricular nucleus and the HPA axis, the research team found that when the paraventricular nucleus is activated, the release of oxytocin is increased. The researchers also hypothesized a positive feedback system that acts as an innate protect system and promotes the pain-induced increase in oxytocin. While pain analgesia tends to be modulated by oxytocin release in the DH and DRG, the peptide plays a more complex role throughout the CNS. Oxytocin regulates the neural circuits that correlate to various behaviors such as sexual behavior, maternal and partner behavior, pair and social bonding, grooming, nociception, sensory processing, and anxiety. In order to more accurately understand the multitude of effects of oxytocin in the CNS, it was theorized that oxytocin activated the HPA and paraventricular nucleus in addition to stimulating the release of NO. It is important to recognize the role of the HPA axis in stress management through the use of adrenocorticotropic hormone (ACTH) and cortisol. While extensive research regarding the relationship between the HPA axis and oxytocin still needs to be conducted, the research team of Ito et. Al mentioned that oxytocin tends to inhibit basal activity of the HPA axis and enhances activity of the axis during periods of high stress [1].

Figure 1: Actions and effects of the HPA axis-oxytocin-GABA-NO system.

The HPA axis is also activated by the amygdala and the paraventricular nucleus through psychological stimulation, such as mindfulness meditation, different emotions, and fragrances. That being said, the researchers suggested that if the HPA axis is activated by mood or emotions, then oxytocin release is thought to be significantly increased, resulting in an overall feeling of well-being. Additionally, the HPA axis is activated by stress via the locus coeruleus-norepinephrine or the hypothalamic-neurohypophyseal system. Oxytocin release via psychological stimulation into the blood from the posterior pituitary gland results in decreased stress. However, recent research indicates that if psychological stimulation does not result in sufficient oxytocin release then GABA and NO secreted from the parasympathetic nervous system are most likely stimulating the sympathetic nervous system.

Overall, the research team concluded that the HPA axis and oxytocin work together in order to promote well-being through psychological stimulation such as mindfulness meditation, the placebo effect, or familiar fragrances. fMRI examinations were used following intranasal administration of oxytocin as well as after psychological stimulation in order to confirm the effects oxytocin has on well-being. NIRS was also used successfully in order to observe and analyze the dynamic patterns present in response to increased levels of oxytocin. An ultrasensitive ELISA assay is currently being developed in order to detect trace amounts of oxytocin in the blood, saliva, and urine. The use of the ELISA assay and NIRS will most accurately confirm the hypothesis formulated by Ito et. Al [1].

2) Results of the study conducted by Uvnäs-Moberg et. Al reported that administration of the SSRI, citalopram, leads to a significant increase in plasma oxytocin levels. Additionally, 14 days of treatment with the drug did not result in a higher tolerance to its effects, nor were there any long-term chances in basal plasma oxytocin levels. The information revealed during this study solidified past research regarding the antidepressant and anxiolytic effects oxytocin elicits in animals. The role of oxytocin in depression and anxiety is also typically associated with social bonding and social learning. That being said, resolution of the negative psychosocial aspects related to depression and anxiety also assist in solidifying the data and concluding findings presented by the research team. The researchers also noted that SSRIs, such as citalopram, can potentially act as a potent treatment for forms of social phobia [2].

Figure 2: Changes in plasma oxytocin levels in response to treatment with citalopram or zimeldine.

Citalopram is described as a highly selective SSRI that elicits minimal effects on noradrenergic reuptake with weak affinity for serotonergic receptors. Because of the mechanism of action followed by the SSRI, the increase in plasma oxytocin levels was most likely related to the inhibition of neuronal serotonin reuptake. This pattern was also seen when the SSRI, zimeldine, was administered to the subjects as well. However, the drug is not structurally related to citalopram. Following treatment with the SSRI there is a potential for enhanced synaptic availability of serotonin, specific at 14 cloned 5-HT receptor subtypes.

This is important to mention considering a significant increase in plasma oxytocin levels was reported in response to stimulation of the 5-HT1A and 5-HT2A/C receptors. Additionally, the research team reported that the 5-HT1A and 5-HT2A/C receptor agonists, 8-OH-DPAT, DOI, and MK-212, all affect plasma oxytocin levels in a different manner. For example, the effects of DOI and MK-212 both display sensitization, while tolerance tends to build to the effects of 8-OH-DPAT. When looking at all three agonists, the researcher team concluded that the different mechanisms are involved in the systemic response to the SSRIs. Based on these results further research should be conducted exploring the possibility of newly characterized 5-HT receptors [2].

The researchers also examined the effects of the SSRIs on plasma levels of CCK, gastrin, somatostatin, and insulin. Citalopram administration resulted in an increase in plasma levels of CCK, however, this effect was not seen after repeated administration of the SSRI. Zimeldine did not elicit any statistically significant effects on the release of CCK, however, acute administration of the drug led to effects similar to that of acute administration of citalopram. There was also a marked decrease in plasma somatostatin levels after acute treatment with citalopram; the same phenomenon was not reported about subchronic treatment (14 days). While there was speculation regarding the relationship between oxytocin interaction with CCK and somatostatin, the research team was able to conclude that there were no links between the peptides when citalopram was consistently administered. It is important to mention that gastrin and insulin did not experience any significant changes, however, plasma insulin levels tended to increase in response to an acute dose of zimeldine, following subchronic treatment with citalopram.

Overall, the research team was able to conclude that oxytocin release is closely linked to treatment with SSRIs. That being said, further research should be conducted regarding the exact mechanism through which the expression of oxytocin elicits beneficial effects on the antidepressant and anxiolytic actions of drugs like citalopram and zimeldine. Results of the study also found that oxytocin regulates both the autonomic nervous system and various behavioral aspects in both male and female test subjects. For example, the animals experienced lowered blood pressure and antinociceptive effects for approximately 3 weeks after a single injection of oxytocin [2].

Disclaimer

**LAB USE ONLY**
*This information is for educational purposes only and does not constitute medical advice. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).

Citations

[1] Ito E, Shima R, Yoshioka T. A novel role of oxytocin: Oxytocin-induced well-being in humans. Biophys Physicobiol. 2019 Aug 24;16:132-139. doi: 10.2142/biophysico.16.0_132. PMID: 31608203; PMCID: PMC6784812.

[2] Uvnäs-Moberg K, Bjökstrand E, Hillegaart V, Ahlenius S. Oxytocin as a possible mediator of SSRI-induced antidepressant effects. Psychopharmacology (Berl). 1999 Feb;142(1):95-101. doi: 10.1007/s002130050867. PMID: 10102788.

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