Anti-stress Effect of Hypothalamic Oxytocin, Importance
of Somatosensory Stimulation and Social Buffering
Toku
Takahashi, Reji Babygirija, Kirk Ludwig
Toku Takahashi,
Reji Babygirija, Kirk Ludwig, Department of Surgery, Medical College of Wisconsin, and
Clement J Zablocki VA Medical Center, Milwaukee, Wisconsin, the United States
Correspondence to: Toku Takahashi, MD, PhD, Zablocki VA
Medical Center, 5000 West National Avenue, Milwaukee, WI 53295, the United States.
Email: ttakahashi@mcw.edu
Telephone: +1-4143842000 (ext. 41472)
Fax:
+1-414-382-5374
Received: February 27,
2015
Revised: May 2, 2015
Accepted: May 6, 2015
Published online: September 1, 2015
ABSTRACT
A
growing body of evidence suggests that stress stimuli, both acute and chronic,
promote different physiological mechanisms and neuroendocrine responses.
Oxytocin (OXT) is mainly synthesized in the paraventricular nucleus (PVN) and
supraoptic nucleus (SON) of the hypothalamus. Central OXT has an anxiolytic
effect and attenuates the hypothalamic–pituitary–adrenal (HPA) axis in response
to stress. Anti-stress effect of OXT has been explained by its inhibitory
effect on corticotropin releasing factor (CRF) expression at the PVN via GABAA
receptors. Repeated experience with the same stressor produces habituation, or
diminution of behavioral responses and HPA axis responses. Up-regulated OXT
expression in the PVN is involved in mediating habituation in response to
chronic homotypic stress in rats. In contrast to chronic homotypic stress, no
habituation is observed when rats are singly housed and received different
types of stressors for 7 days (chronic heterotypic stress). Increased CRF
expression and reduced OXT expression at the PVN are observed following chronic
heterotypic stress in singly housed rats. Thus, it is conceivable that stress
responses to chronic heterotypic stress would be diminished if endogenous OXT
expression is upregulated. Various manual therapies such as massage,
acupuncture and transcutaneous electrical nerve stimulation (TENS) involve the
stimulation of somatosensory neurons. OXT system is activated by manual
therapies. TENS increases OXT expression and decreases CRF expression at the
PVN following chronic heterotypic stress in singly housed rats. OXT has been
implicated in a number of social behaviors, including maternal care,
affiliation and social attachment. Social attachment is known to stimulate OXT
release in the hypothalamus in rats. A recent study demonstrates an increased
OXT expression following chronic heterotypic stress when rats are pair-housed.
Somatosensory stimulation is a promising treatment for stress-associated
diseases. A social interaction is also important to adapt to our daily life
stress.
© 2015 ACT. All
rights reserved.
Key words: Acupuncture; CRF; Hypothalamus; HPA axis; Social
interaction
Takahashi T, Babygirija R, Ludwig K. Anti-stress Effect
of Hypothalamic Oxytocin, Importance of Somatosensory Stimulation and Social
Buffering. International Journal of Neurology
Research 2015; 1(3):
96-101 Available from: URL:
http://www.ghrnet.org/index.php/ijnr/article/view/1090
editorial
1. Functional
GI disorders and stress
1-1. GI
dysmotility following acute stress: Functional gastrointestinal (GI)
disorders include functional dyspepsia (FD) and irritable bowel syndrome (IBS).
Functional GI disorders are common in the general population, with a reported
prevalence of 25-40%. The motor dysfunction of colon and visceral
hypersensitivity are considered especially important factors of functional GI
disorders[1,2]. Stress is highly associated with functional GI
disorders and GI symptoms may develop when we fail to adapt to various
stressors in our daily life.
Corticotropin
releasing factor (CRF) neurons are located in the PVN of the hypothalamus,
amygdala and locus coeruleus complex[3]. Acute restraint stress
stimulates CRF release, resulting in activation of the hypothalamic–pituitary–adrenal
(HPA) axis. Released CRF also influences GI motility via projecting to the
autonomic preganglionic neurons at the brain stem[4]. CRF-mediated
motor responses differ between the stomach and colon. Gastric emptying of solid
and liquid meals is delayed by acute restraint stress in rodents[5].
In contrast, acute restraint stress accelerates colonic transit in rats[6]
and mice[7].
There are two
distinct CRF receptors, subtype 1 (CRF type1) and subtype 2 (CRF
type2). The different motor patterns between the upper and lower gut
are mediated via different CRF receptors. Delayed gastric emptying induced by
acute restraint stress is mediated via central CRF2 receptors[5].
In contrast, accelerated colonic transit induced by acute restraint stress is
mediated via central CRF1 receptors in rats[6].
Acute
restraint stress stimulates central CRF2 receptors and sympathetic pathway,
resulting in delayed gastric emptying[5] (Figure 1), while acute
restraint stress stimulates central CRF1 receptors and
parasympathetic pathways (vagal nerve and pelvic nerve), resulting in
acceleration of colonic transit in rats[6] (Figure 1).
As CRF1
receptors are expressed in the myenteric plexus of the rat colon, it has been
suggested that stress-induced acceleration of colonic transit is mediated via
peripheral CRF receptors[8], in addition to the central CRF
receptors. However, a clinical trial demonstrated that peripheral
administration of a selective CRF1 receptor antagonist (pexacerfont)
failed to affect colonic transit and bowel function in IBS patients[9],
indicating that peripheral CRF1 receptors are not involved in
mediating colonic dysmotility in IBS patients. Although the motor responses to
acute restraint stress differ between upper and lower GI tract, it should be
noted that both responses are mediated via the same neuropeptide of the CNS,
which is CRF.
1-2. Anti-stress effect off
OXT following acute stress: Oxytocin (OXT) is mainly produced in neurons
originating in the paraventricular nucleus (PVN) and supraoptic nucleus (SON)
of the hypothalamus. Besides female reproductive functions, OXT is also known
for its anti-stress and anti-anxiety effects[10]. OXT attenuates HPA
axis in response to stress[10]. Delayed gastric emptying and
accelerated colonic transit induced by acute restraint stress are abolished by
intracerebroventricular (icv)-injection of OXT in rats[11,12].
Anti-stress
and anti-anxiety effects of OXT are mediated by its inhibitory effect on CRF
mRNA expression[13]. The inhibitory effect of OXT on CRF expression
may not have a direct effect on CRF neurons, because the majority of neuronal
responses to OXT are excitatory. GABAergic neurons are located in the immediate
surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN
have been shown to inhibit CRF synthesis via GABAA receptors[14].
A recent study demonstrated that the inhibitory effect of OXT on CRF mRNA
expression is mediated by GABAA receptors at the PVN[15]
(Figure 2). In the central amygdala, others also showed that OXT enhances
GABAergic transmission through an increased frequency of the inhibitory
postsynaptic currents[14].
Central-injection
of OXT, but not peripheral-injection of OXT, significantly improves delayed
gastric emptying induced by acute restraint stress in mice[16] and
rats[11]. Similarly, water avoidance stress-induced acceleration of
colonic motility is attenuated by central, but not peripheral, administration
of OXT[17]. Microdialysis study showed a significant increase of
central OXT, but not peripheral OXT, in response to chronic stress[18].
Thus, central OXT plays a predominant role in regulating stress-induced GI dysmotility.
Although OXT and its receptors are expressed on the smooth muscle cells,
enteric neurons and intestinal epithelium of the GI tract[19],
peripheral OXT may not have a major role in attenuating stress responses.
1-3. Habituation of GI motility
following chronic homotypic stress: Repeated experience with the same
stressor produces habituation, or diminution of behavioral responses and HPA
axis responses. Delayed gastric emptying and accelerated colonic transit observed
in acute stress are restored to normal levels following repeated stress loading
(chronic homotypic stress) for 5 days in rats[20] and mice[16].
Restored gastric emptying following chronic homotypic stress is reversed by
icv-injection of OXT antagonists[11]. OXT knockout (KO) mice fails
to restore gastric emptying[21] and colonic transit[7]
following chronic homotypic stress. These suggest that central OXT is involved
in mediating the adaptation mechanism in response to chronic homotypic stress.
Up-regulated OXT expression at the PVN inhibits CRF expression, resulting in
reduced HPA axis activity and restoration of GI motility following chronic
homotypic stress[11] (Figure 3b).
The mechanism
of upregulated OXT expression at the hypothalamus following chronic homotypic
stress remains unclear. It has been shown that noradrenergic and serotonergic
transmission plays important roles in neuroendocrine stress responses.
Hypothalamic magnocellular neurons receive input from A1 and A2
noradrenergic neurons in the medulla oblongata. A variety of stressful stimuli
activate medullary noradrenergic neurons, which stimulate OXT release from the
PVN via alpha1 adrenergic receptors.
Serotonergic
(5-HT) neurons originating in the dorsal and median raphe nucleus project to
the PVN. 5-HT is able to stimulate OXT neurons via 5-HT1A, 5-HT2A
and 5-HT2c receptors. OXT release is also regulated via histamine,
glutamate, opioids and dopamine (DA)[22]. It needs to be studied
whether upregulation of OXT following chronic homotypic stress is mediated via
adrenergic, serotonergic, or other receptors.
1-4. Mal-adaptation
(non-habituation) following chronic heterotypic stressl: In modern
society, individuals encounter various types of physical, mental and social
stress on a daily basis. To replicate complex stress exposure in humans, rats
are loaded different types of stressors for 7 consecutive days (chronic
heterotypic stress). In contrast to chronic homotypic stress, delayed gastric
emptying and accelerated colonic transit are still observed following chronic
heterotypic stress[11,12].
As mentioned
above, central CRF plays a dominant role in response to acute stress. However,
it is not well established whether CRF is still involved in mediating responses
to chronic heterotypic stress. It has been shown that vasopressin (VP) plays a
role during the adaptation to chronic stress and that VP may be the principal
modulator of the HPA axis in response to chronic stress. Accelerated colonic
transit and delayed gastric emptying following chronic heterotypic stress are
antagonized by CRF1 receptor antagonists and CRF2
receptor antagonists, respectively[12]. In addition, icv-injection
of VP receptor antagonists have no significant effects on GI dysmotility
following chronic heterotypic stress. These suggest that central CRF receptors
play a major role in mediating GI dysmotility following chronic heterotypic
stress. Lower OXT expression and higher CRF expression at the PVN are observed
following chronic heterotypic stress[11]. These indicate that
chronic heterotypic stress fails to adapt GI dysmotility due to hypersecretion
of CRF and impaired OXT expression at the PVN (Figure 3c).
2. Anti-stress
effects of somatosensory stimulation
2-1. Effects of
somatosensory stimulation on GI motility: It has been demonstrated that
somatic afferents from the skin and muscle are involved in the control of
various autonomic functions, including GI motility in rats and humans. The
spinal–supraspinal pathways responsible for somatosensory stimulation mainly
comprise the posterior column pathway and spinothalamic pathway. Most
peripheral thick myelinated afferent fibers activated by the discriminative
touch and sense of vibration enter the ipsilateral dorsal column-medial
lemniscus tract (posterior column pathway) and emerge into the contalateral
spinothalamic pathway. In contrast, the thinly myelinated or unmyelinated
afferent fibers activated by pain and temperature are carried up by the
contalateral spinothalamic tract to supraspinal levels (spinothalamic pathway).
These impulses are further relayed to the thalamus, and ultimately sent to the
primary somatosensory cortex. In addition, these impulses are also relayed to
other brain areas, including the brain stem, periaqueductal gray (PAG) and hypothalamus,
via collateral connections[23] (Figure 4).
Various manual
therapies, including massage, acupuncture and transcutaneous electrical nerve
stimulation (TENS), involve the stimulation of somatosensory neurons.
Acupuncture involves the insertion of thin needles into the skin and underlying
muscle layer. Inserted acupuncture needles are often stimulated by electricity
under various frequencies of 1-100 Hz (electroacupuncture; EA). In contrast to
acupuncture, TENS is a non-invasive procedure, in which electrodes are placed
on the skin and stimulated by electricity.
Acupuncture
has been used for treating various GI diseases, including gastroparesis,
functional dyspepsia (FD), irritable bowel syndrome (IBS), constipation and
diarrhea[24]. Recent study showed that TENS applied to the
acupuncture points (transcutaneous-EA; TEA) at the hands and lower legs
improves GI symptoms in patients with FD[25]. Effects of acupuncture
on GI motility is mediated via the CNS levels, not the spinal levels. Acupuncture-induced
gastric relaxations were almost completely abolished by spinal transection.
Acupuncture-induced gastric relaxations are reduced by spino-medullary
transection, but not by ponto-medullary transection, suggesting that the reflex
center of acupuncture-induced gastric relaxations is located in the medulla[26].
Acupuncture regulates colonic motility and transit in rats via stimulating
autonomic neurons in rats[27]. These suggest that acupuncture alters
GI motility via the pathways of somaotosenory - spinal cord - autonomic
neurons. Finally, released acetylcholine (Ach), catecholamine (CA), or other
neurotransmitters from the enteric nervous system (ENS) regulates GI motility[26,27].
Thus, it is unlikely that acupuncture primarily stimulates ENS.
2-2. Anti-stress effect of TENS and
EA: Animal studies demonstrated that TENS and EA improve various
stress-induced physiological responses. GI dysmotility (delayed gastric
emptying and accelerated colonic transit) induced by acute restraint stress was
restored by EA at the lower legs in rats[28]. EA stimulates
parasympathetic activity and inhibits sympathetic activity under the acute
restraint stress loading in rats[29]. EA is shown to attenuate
stress-induced defecation reduce CRF expression at the hypothalamus in the rat
IBS model[30].
2-3.Anti-stress effects of TENS are
mediated via OXT: In humans, post-traumatic stress disorder (PTSD) is marked by
deficits in anxiety, stress regulation and in social functioning. Traumatic
stress in the normal individual results in activation of the sympatho-adrenal
system causing a rise in noradrenaline/adrenaline, and activation of the HPA
system resulting in elevated cortisol levels.
OXT has unique
effects of decreasing background anxiety without affecting learning and memory
of a specific traumatic event in rats. Increased OXT neurotransmission during
traumatic events is likely to prevent the formation of aversive memories. When
OXT is centrally administered prior to fear conditioning or extinction training,
fear expression and facilitated fear extinction are decreased in rats[31].
OXT may be effective in PTSD through a reduction of fear response and an
increase of social functioning. Toth
proposed that OXT treatment before fear extinction training is a comparable
time point for psychotherapy in PTSD patients[32].
Various types
of somatosensory stimulation (massage, EA, thermal stimulation, vibration, and
afferent sciatic nerve stimulation can increase OXT levels in plasma and
cerebrospinal fluid in anesthetized rats[33]. These raise the
possibility that TENS may act on OXT neurons at the hypothalamus. GI
dysmotility induced by chronic heterotypic stress is significantly improved by
TENS in rats, which is abolished by icv-injection of OXT antagonists+. TENS
increases the number of OXT-immunopositive cells and decreased
CRF-immunopositive cells at the PVN following chronic heterotypic stress[34].
These suggest that TENS activates hypothalamic OXT neurons via the
spinothalamic pathway (Figure 5). Activated OXT neurons inhibit CRF expression,
resulting in the attenuation of stress responses of GI tract.
Clinical
trials demonstrated that acupuncture is effective for treating the patients
with PTSD. People diagnosed with PTSD were randomized to either an empirically
developed acupuncture treatment or a CBT group. Compared with CBT, acupuncture
provided significant effects on PTSD[35].
3. Anti-stress
effects of social buffering
3-1 Anti-stress effects of social buffering following chronic
heterotypic stress: Social activity is related to beneficial effects on
the cardiovascular, endocrine, and immune systems. Social connectedness may
have stress-buffering effects. It is important for us to feel connected, to be
trusted and loved. Feeling connected to others increases psychological and
physical well-being and decreases the risk of depression and physical ailments.
People with a higher quality of social relationships show a lower risk of
death, while social isolation has been shown as a major risk factor for
mortality. Social activities and psychological coping styles reduce the
deleterious effects of stress and thus reduce the risk of disease in a
non-specific way[36,37]. Unfortunately, our society is becoming
increasingly isolated and distrustful. It seems that technological, economical,
and social changes have developed less trustworthiness among us.
OXT plays an
important role in the ability to form social attachments including parental
care, pair bonding and social memory. In humans, intranasal administration of
OXT (OXT spray) increases trusting behavior[38]. The social
interaction of daily life as well as a positive environment continuously
activates the system of OXT release in both males and females[39].
Social attachment (social buffering) has been shown to stimulate OXT release in
the hypothalamus in rodents[10].
GI dysmotility
following chronic heterotypic stress observed in singly-housed rats is restored,
when rats are housed by pair. Paired housing decreased CRF mRNA and increased
OXT mRNA expression at the PVN following chronic heterotypic stress[40,41].
These suggest that activation of OXT signaling via social interactions can
ameliorate the effects of stress on GI motility.
Amygdala is
stimulated by emotional arousal, such as affective words[42].
Amygdala is a source of efferent projections to the ventromedial hypothalamic
nucleus. Outputs of the MeA to the basal forebrain and hypothalamus orchestrate
the behavioral, autonomic, and neuroendocrine responses to conspecifics.
Received prosocial or trust behaviors may activate efferent output from the
amygdala to OXTergic systems.
Dopaminergic
(DAergic) fibers regulate OXT release from the PVN[43]. As there are
no direct projections from the MeA to the PVN[44], it is likely that
DAergic neurons are involved in relaying between MeA and PVN-OXT neurons. D2
receptors in the nucleus accumbens are important for the mediation of social
attachments in female voles[45]. Based on these observations, it is
likely that social buffering may activate the hypothalamic OXT neurons via the
MeA - DAergic pathways and D2 receptors (Figure 5).
It is
emphasized that a positive social interaction, which upregulates hypothalamic
OXT expression, is an important factor to overcome daily life stress and reduce
GI symptoms. Studies of humans and other social animals showed widespread
evidence of the beneficial effects of prosocial and altruistic behavior.
Numerous studies reveal protective effects of volunteering on mental and
physical health. Both consistency of volunteering over time and diversity of
participation are significantly related to well-being and self-reported health.
Participation in clubs and volunteer activities had a significant protective
effect on mortality. Piliavin insisted that “One does well by doing good”[46].
A positive
social interaction is bidirectional, involving both giving and receiving
empathy. A recent study showed that affiliative behavior toward others
attenuates stress responses of GI tract via up-regulating hypothalamic OXT
expression[41]. This suggests that giving affection and empathy to
others may be a key in upregulating hypothalamic OXT expression. As OXT is
linked to health promoting cardiovascular, analgesic, and anti-stress effects,
upregulated OXT expression would help to maintain our mental and physical
health.
“If you
want others to be happy, practice compassion. If you want to be happy, practice
compassion.” (Dalai Lama). Buddhist traditions have emphasized the
importance of cultivating connection and love toward others through techniques
such as loving-kindness meditation (LKM). A randomized clinical research has
demonstrated that the practice of LKM decreased chronic low back pain,
psychological distress, and anger[47]. Thus, performance of
religious thoughts provided the evidence that cultivating connection and social
interaction are key factors to maintain our well-being.
Intranasal OXT
administration reduces behavioral and endocrine responses to social stress,
mediates social buffering, attenuates the hyperactivity of amygdala to fearful
stimuli and improves social cognition and empathy[48]. Thus, a
pharmacological intervention in the OXT system can be a target for novel
therapeutic approaches.
However, we
cannot exclude the possibility that desensitization of OXT receptors and/or
downregulation of endogenous OXT synthesis may develop when OXT is administered
daily. A combination of intranasal OXT administration with TENS or social
interaction might provide new insights for a better treatment of GI dysmotility
and mental disorders associated with stress.
In conclusion,
it is proposed that TENS/acupuncture may promote anti-stress effects via
stimulating somatosensory pathway (bottom-up pathway). In contrast, social
buffering may promote anti-stress effects by stimulating brain activity and
throughout its network (top-down pathway). Both pathways finally activate the
OXT system at the hypothalamus (Figure 5). Upregulated OXT mediates anti-stress
effects. Thus, both pathways are beneficial in treating stress-associated
symptoms.
During the
process of maintaining the positive social interaction, both of giving and
receiving empathy, OXT system is upregulated in our brain. Especially, thinking
about helpless people and giving sympathy to them may upregulate hypothalamic
OXT expression, which promotes mental and physical health on the givers. It is
important to reconsider Buddhist traditions of cultivating connection and
compassion towards others in order to maintain our well-being.
CONFLICT OF INTERESTS
The authors have no conflicts of interest to declare.
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Peer reviewer: Janney
Sun, Editor-In-Chief, International Journal of Neurology Research, UNIT E, A1,
7/F, Cheuk Nang Plaza, 250 Hennessy Road, Wanchai, Hong Kong.
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