Pain manifestations in neuropsychiatry disorders (animal models and human patients). The possible relevance of oxytocin.
Pain is an undesirable experience that all people encounter at least once in their lifetime. There have been postulated several interpretations in the attempt to define this complex and yet not fully elucidated phenomenon known as pain.
At the present moment the definition that is generally accepted is given by the International Association for the Study of Pain (IASP) which advocates that pain is 'an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage' .
The definition itself indicates that this event is not a pure sensory experience but also a perception, element which implies the need of a cognitive processing.
Therefore, it can be noted that pain manifestation is composed of multiple sides such as: a sensory-discriminative side, responsible for locating and/or marking the intensity of pain; a motivational-affective side, representing the emotional reactions that pain creates  and also, a cognitive-evaluative side, which is known for the superior processes and memory involvement in the occurrences of pain manifestations .
This multifaceted event that pain contours to be gives it a complex outlook and difficult to quantify qualities, shaped to be a highly selective individual experience.
PAIN MANIFESTATIONS IN NEUROPSYCHIATRIC DISORDERS--CLINICAL AND ANIMAL MODELS
Most of the current studies following pain manifestations point to an impaired perception of pain in the context of neuropsychiatric disorders. Knowing that pain is already a difficult event to assess accompanied by a high rate of subjectivity, introducing neuropsychiatric disorders in the disputed point, acknowledged for their severe mental impairments, makes assessment of pain an even more difficult task to achieve.
However, pain manifestations were followed in different psychiatric conditions, either in clinical environment or partially replicated in laboratory conditions. In schizophrenia, a renowned severe debilitating mental illness, the limited number of clinical studies involving human patients recorded in this context showed that pain manifests distinctively in these individuals. As our group previously reviewed  the array of reactions encountered in patients suffering from schizophrenia vary from lack of pain sensitivity pointed out by a majority of clinical investigations [5,6], to no significant differences between healthy volunteers and persons diagnosed with this mental condition . Considering that persons with schizophrenia come under a high risk group for different underlined conditions that are not manifesting their classical symptoms , as for example the presence of painless myocardial infarction which under normal circumstances is considered a medical emergency causing a great deal of pain, the need of following pain in this mental disorder is imperiously necessary. Although there were researches that did not uncover a difference between pain perception in patients with schizophrenia and their healthy peers , others even found that the presence of pain manifestations were increased in schizophrenia symptomatology .
Another way to investigate specific disease features is by employing animal models. It was observed that by administering glutamate antagonist like ketamine specific schizophrenia symptoms are replicated. In this way, it was created an animal model of schizophrenia by administering ketamine in sub-anesthetic dosages [11-13]. The ketamine--induced animal model of schizophrenia appears to manifest increased pain tolerance, results similar to the ones registered in human patients suffering from schizophrenic disorder. Our laboratory also tested thermal pain thresholds in the ketamine-induced animal model of schizophrenia and results indicated to an increased pain sensitivity , which is in accordance to human individuals reactions . There are also other animal models utilized to create schizophrenia symptoms in laboratory animals, for instance by administering neonatal intracerebroventricular of quinolinic acid and N-acetyl-aspartyl-glutamate. In these models there were also observed modification in the nociceptive perception, a higher thermal pain threshold being recorded. Nonetheless, there were not logged any significant changes in acute mechanical nociception and neither in the formalin test . On the other hand, on the same model of schizophrenic behaviour when it was applied a neuropathic pain model, hyperalgesia was reported . Therefore, the same contradictory results manifest also in animal models of schizophrenia, making the subject of pain in the context of schizophrenic disorder an interesting pursuit to follow.
Alzheimer's disease (AD) is another severe neuropsychiatric condition characterized by neurodegeneration leading to loss of short term memory, as a main symptom. Besides the specific features that accompany this disorder, several studies indicate that alteration of pain perception both acute and chronic is encountered in patients with dementia . The situation of pain manifestations is similar somehow to the one described in the schizophrenic disorder, because perception of pain ranges from lack of it to hypersensitivity [17, 18] as our group anterior demonstrated . Even so, there are cases where it is sustained that
pain manifestations are no different than the ones found in nondemented subjects . An interesting observation is that patients suffering from AD might express their discomfort caused by pain features differently by utilizing behavioural traits such as agitation, aggression, pacing, wandering and sleep disturbances .
Affective disorders include a group of mental diseases as anxiety, depression and bipolar disorder . As there is more and more data signaling the strong bond between pain and psychiatric conditions, affective disorders are not excluded from this pain disturbance phenomenon. In the case of depression it appears that the relationship between pain and the psychiatric manifestation is bidirectional, clinical studies indicating to a 50% rate and more expose risk for persons suffering from chronic pain to be also diagnosed with depression, as in the report of Bair et al., 2003. In the same time, individuals experiencing multiple painful encounters are 3 to 5 time more plausible to struggle with depression as well compared to those without painful events, as demonstrated by Magni et al., 1993. A somehow comparable situation is unfolding in the case of anxiety also (Gerrits et al., 2015). Moreover, an association between anxiety and depression is recorded in people undergoing pain events (Williams et al., 2012). In addition, a remarkable connection between pain and bipolar disorder (BD) has been observed in the clinical studies, notable being that people diagnosed with BD also feel more pain, as previously showed by Fornaro and Stubbs, 2015.
OXYTOCIN IN THE CONTEXT OF NEUROPSYCHIATRIC DISORDERS
Oxytocin is a neuropeptide secreted by the paraventricular and supraoptic nuclei located in the hypothalamus . Most known functions of this element are attributed to uterine contractions during birth, the lactation reflex and recently explored functions such as cardiovascular regulation, learning, memory , but also beneficial impact on social behaviours in healthy and neuropsychiatric disorders [25-29] and surprisingly an influence in pain modulation [30-31].
There are other reports that describe oxytocin as a modulator of psychiatric symptomatology. For instance, some studies highlight the possible anxiolytic effects that oxytocin might possess . Also, considering that intranasal administration of oxytocin has an influence on emotional reactions and behaviours it created the idea of a potential action that oxytocin might have on mental conditions such as social anxiety disorder, autism and schizophrenia [33, 34]. Knowing that AD besides the main symptom of memory loss is accompanied by depressive traits [35, 36] and anxious behaviour  and acknowledging that oxytocin might have a beneficial influence on depression and anxiety [32-34] and even memory enhancement proprieties , it could become a strong future candidate in the therapy of dementia.
Thus, although there are several clinical and animal studies made on the matter of oxytocin effect in psychiatric disorders pointing to a positive outcome, there is still need of further researching the reactions of the interactions between psychiatric events and oxytocin efficacy.
OXYTOCIN AND ITS EFFECTS ON PAIN
Oxytocin, currently has gained another perspective once the possibility of utilizing it in the therapy of pain might become a viable option, considering the demonstrated role in pain modulation [30, 31]. Besides the increasing pain threshold proprieties of oxytocin in animal models tested in pain conditions either used by itself  or as an enhancer of an old appointed analgesic method represented by acupuncture , oxytocin presents analgesic proprieties also when employed in human subjects as highlighted by the few existing researches. In this way, it was demonstrated that by administering intranasal oxytocin in patients suffering from headaches, it might relieve headaches in a dose-dependent manner . Moreover, another study indicates to a significant increase in pain tolerance and threshold when the persons were subjected to cold pressor pain . However, there are still other reports that did not present any analgesic features when oxytocin was administered to the individuals experiencing either experimental or clinical pain [40, 41]. These various results have several reasons incriminated amongst them being the inconsistent sample sizes or the different pain states included in the evaluation , but nonetheless there is an obvious need of further researching the possibilities of this neuropeptide, oxytocin.
Considering that a possible mechanism incriminated in prosocial behaviour induced by oxytocin administration in both animal models and humans is due to re duction in stress activity opens new therapeutical possibilities [43, 44]. Adding up that stress amongst other elements is a contributing factor to the occurrence of psychiatric illnesses  and also that stress is involved in altering pain perception by increasing its manifestations , than it must not be overlooked the possibility of employing oxytocin as an agent which might have a beneficial role in both pain reduction and behavioural rehabilitation. Therefore, it is a really powerful potential candidate in the future therapy of pain and psychiatric symptomatology.
"Alexandru Ioan Cuza" University Faculty of Biology, Dept. of Research Bdul Carol I, 11 700506, Iasi, Romania Tel :0040751218264; Fax 0040232201472; E-mail : email@example.com
Submission: 21 May 2017
Acceptance: 31 July 2017
Iulia Antioch and Alin Ciobica are supported by a PN-II-RU-TE-2014-4-1886 grant called "A complex study regarding the relevance of oxytocin administration in some animal models of neuropsychiatric disorders", number 120 from 01/10/2015.
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Iulia Antioch--PhD student, Department of Research, Faculty of Biology, "Alexandru loan Cuza" University, Bd. Carol I, nr. 11, Iasi, 700506, Romania
Vasile Chirita--MD, PhD, senior psychiatry, Honorary Member of Romanian Academy
Roxana Chirita-MD, PhD, senior psychiatrist, professor, Gr.T.Popa University of Medicine and Pharmacy, Iasi, Socola Institute of Psychiatry Iasi
Gabriel Ovidiu Oprisanu-MD, Socola Institute of Psychiatry Iasi
Irina Dobrin-MD, PhD, senior psychiatrist, Assistant of professor, Gr.T.Popa University of Medicine and Pharmacy, Iasi, Socola Institute of Psychiatry Iasi
Alin Ciobica--Principal Researcher II, Department of Research, Faculty of Biology, "Alexandru Ioan Cuza" University, Bd. Carol I, nr. 11, Iasi, 700506, Romania
Center of Biomedical Research of the Romanian Academy, Iasi Branch, 700505, Iasi, Romania, The Academy of the Romanian Scientists, Bucharest, Splaiul Independentei 54, 050094, Romania
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|Author:||Antioch, Iulia; Chirita, Vasile; Chirita, Roxana; Ovidiu Oprisanu, Gabriel; Dobrin, Irina; Ciobica,|
|Publication:||Bulletin of Integrative Psychiatry|
|Date:||Sep 1, 2017|
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