Pain manifestations in neuropsychiatric disorders (animal models and human

patients). The possible relevance of oxytocin

Iulia Antioch, Vasile Chirita, Roxana Chirita, Gabriel Ovidiu Oprisanu, Irina Dobrin, Alin

Ciobica

Iulia Antioch-PhD student, Department of Research, Faculty of Biology, "Alexandru Ioan Cuza"

University, Bd. Carol I, nr. 11, Iasi, 700506, Romania

Vasile Chirita -MD, PhD, senior psyhiatry, Onorary 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, assisstant 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, SplaiulIndependentei 54, 050094, Romania

Abstract

In the present mini-report we will describe some basic aspects regarding the current state of

knowledge for the pain sensibility and manifestations in most of the neuropsychiatric disorders,

as well as our previous experience in this understudied area of research. Moreover, considering

the ever increased interest in the pro-social and increased affiliation effects of intranasal
oxytocin, as a possible therapeutical agent in the specific neuropsychiatric disorders where a

social component is somehow affected, we will describe also if there is possible correlation

between pain perception, oxytocin and most of these neuropsychiatric manifestations.

Key-words: pain, neuropsychiatric disorders, oxytocin.

General considerations about pain

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 [1].

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 [2] and also, a

cognitive-evaluative side, which is known for the superior processes and memory involvement in

the occurrences of pain manifestations [3].

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 [4] 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 [7]. Considering that persons with schizophrenia come

under a high risk group for different underlined conditions that are not manifesting their classical

symptoms [8], 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 [9], others even found that the presence of pain manifestations were increased

in schizophrenia symptomatology [10].

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 subanesthetic 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 [14], which is in accordance to human individuals

reactions [10]. 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 [15]. On the other hand, on the same model of schizophrenic behaviour when it was

applied a neuropathic pain model, hyperalgesia was reported [15]. 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 [16]. 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 [19]. Even so, there are cases where it is sustained that pain manifestations

are no different than the ones found in non-demented subjects [20]. 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 [21].

Affective disorders include a group of mental diseases as anxiety, depression and bipolar

disorder [22]. As there is more and more data signalling 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 [23]. 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 [24], 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 [32]. 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 [37] and acknowledging that

oxytocin might have a beneficial influence on depression and anxiety [32-34] and even memory

enhancement proprieties [24], 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 [30] or as an enhancer of an old appointed

analgesic method represented by acupuncture [31], 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 [38]. Moreover, another study indicates
to a significant increase in pain tolerance and threshold when the persons were subjected to cold

pressor pain [39]. 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 [42], 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 reduction 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 [45] and also that stress is involved

in altering pain perception by increasing its manifestations [46], 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.

Acknowledgments

Iulia Antioch and Ciobica Alin 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.

References

1. Merskey H, Watson GD. The lateralization of pain. Pain. 1979; 7:271-280.

2. Westlund KN, Willis WD. The Rat Nervous System (Fourth Edition), 2015.
3. Melzack R, Casey KL. Sensory, motivational and central control determinants of pain:

A new conceptual model. In Kenshalo DR (ed): The Skin Senses, Springfield, IL, Charles

C. Thomas, 1968; 423-443.

4. Antioch I, Ciobica A, Paulet M, Bild V, Lefter R, Timofte D. Pain manifestations in

schizophrenia - clinical and experimental aspects in human patients and animal models.

Psychiatria Danubina. 2015; 27:142-152.

5. Becker A, Grecksch G, Zernig G, Ladstaetter E, Hiemke C, Schmitt U. Haloperidol

and risperidone have specific effects on altered pain sensitivity in the ketamine model of

schizophrenia. Psychopharmacology. 2009; 202:579-587.

6. Jochum T, Letzsch A, Greiner W, Wagner G, Sauer H, Bar KJ. Influence of

antipsychotic medication on pain perception in schizophrenia. Psychiatry Res. 2006;

142:151 156.

7. Kuritzky A, Mazeh D, Levi A. Headache in schizophrenic patients: A controlled study.

Cephalalgia, 1999; 19:725-727.

8. Stubbs B, Gaughran F, Mitchell AJ, De Hert M, Farmer R, Soundy A, Rosenbaum S,

Vancampfort D. Schizophrenia and the risk of fractures: a systematic review and

comparative meta-analysis. Gen Hosp Psychiatry 2015; 37:126-133.

9. Stubbs B, Mitchell AJ, De Hert M, Correll CU, Soundy S, Stroobants M, Vancampfort

D: The prevalence and moderators of clinical pain in people with schizophrenia:A

systematic review and large scale meta-analysis. Schizophrenia Research 2014; 160:18.

10. Strassnig M, Brar JS, Ganguli R: Body mass index and quality of life in community-

dwelling patients with schizophrenia. Schizophr Res. 2003; 62:7376.

11. Becker A, Peter B, Schroeder H, MannT, Huether G, Grecksch G. Ketamine-induced

changes in rat behaviour: a possible animal model of schizophrenia. Prog

Neuropsychopharmacol Biol Psychiatry 2003; 27:687-700.

12. Becker A, Grecksch G: Ketamine-induced changes in rat behaviour: a possible

animal model of schizophrenia. Test of predictive validity. Prog Neuropsychopharmacol

Biol Psychiatry 2004; 28: 1267-1277.

13. Becker A, Grecksch G, Schroeder H: Pain sensitivity is altered in animals after

subchronic ketamine treatment. Psychopharmacology (Berl) 2006; 189:237-247.

14. Antioch I. Pain phenomenon in schizophrenia. Berlin Psychiatry Summer School-

oral presentation 2015.

15. Frank M, Vaculn S, Yamamotov A, Stastn F,Bubenkov-Valeov V, Rokyta R.

Pain perception inneurodevelopmental animal models of schizophrenia. Physiol Res.

2010; 59:811-9.

16. Farrell MJ, Katz B, Helme RD. The impact of dementia on the pain experience. Pain.

1996; 67:7-15.

17. Rainero I, Vighetti S, Bergamasco B, Pinessi L, Benedetti F. Autonomic responses

and pain perception in Alzheimer`s disease. European Journal of Pain. 2000;4:267-274.

18. Jensen-Dahm C., Werner M.U., Dahl J.B., Staehelin Jensen T, Ballegaard M., Hejl

Anne-Mette, Waldemar G.. Quantitative sensory testing and pain tolerance in patients

with mild to moderate Alzheimer disease compared to healthy control subjects. Pain.

2014; 155:1439-1445
19. Antioch I, Ciobica A, Bild V, Anton E, Timofte D. Current knowledge of pain

involvement in Alzheimer`s disease. Annals of the Alexandru Ioan Cuza University

Sect. II a., Genetics and Molecular Biology 2015;16(1):27-36.

20. Pickering G, Jourdan D, Dubray C. Acute versus chronic pain treatment in

Alzheimer's disease. Eur J Pain. 2006; 10:379-84.

21. Coehen-Mansfiel J, Thein K, Marx MS. What are the barriers to performing

nonpharmacological interventions for behavioural symptoms in the nursing home? J Am

Med Dir Assoc. 2012; 13:400-405.

22. O`Shea Brian. Textbook of Psychological Medicine Fifth Edition, The College of

Psychiatry of Ireland 2010; pp.379.

23. Barberis C, Tribollet, E. Vasopressin and oxytocin receptors in the central nervous

system. Crit. Rev. Neurobiol. 1996; 10:119154.

24 . McEwen BB. The role of vasopressin and oxytocin in memory processing. Elsevier

Science, Amsterdam 2004; vol. 50.

25. Ciobica Alin, Balmus Ioana Miruna, Padurariu Manuela. Is oxytocin relevant for the

affective disorders? Acta Endocrinologica. 2016; 12 (1):65-71.

26. Padurariu Manuela, Prepelita Raluca, Ciobica Alin, Dobrin Romeo, Timofte Daniel,

Stefanescu Cristinel, Chirita Roxana. The concept of suicide: neurophysiological/genetic

theories and possible oxytocin relevance. Neurophysiology. 2016; 8(4):312-321.

27. Manuela Padurariu, Alin Ciobica. Understanding the Importance of Oxytocin in

Depression. Nobel Medicus. 2017

28. Ebstein RP, Israel S, Lerer E, Uzefovsky F, Shalev I, Gritsenko I, Riebold M,

Salomon S, Yirmiya N. Arginine vasopressin and oxytocin modulatehuman social

behavior. Ann. N. Y. Acad. Sci. 2009; 1167:87102.

29. Aoki Y, Yahata N, Watanabe T, Takano Y, Kawakubo Y, Kuwabara H et al..

Oxytocin improves behavioural and neuraldeficits in inferring others social emotions in

autism. Brain J. Neurol. 2014; 137:30733086.

30. Yang J, Yang Y, Chen JM, Liu WY, Wang CH, Lin BC. Central oxytocin enhances

antinociception in the rat. Peptides. 2007; 28(5):1113-9.

31. Yang J, Yang Y, Chen JM, Liu WY, Wang CH, Lin BC. Effect of oxytocin on

acupuncture analgesia in the rat. Neuropeptides. 2007; 41:285292.

32. Heinrichs M, von Dawans B, Domes G. Oxytocin, vasopressin, and human social

behavior. Frontiers in Neuroendocrinology. 2009; 30:548557.

33. Meyer-Lindenberg A, Domes G, Kirsch P, Heinrichs M. Oxytocin and vasopressin in

the human brain: social neuropeptides for translational medicine. Nature Reviews

Neuroscience. 2011; 12:524538.

34. Insel TR. The challenge of translation in social neuroscience: a review of oxytocin,

vasopressin, and affiliative behavior. Neuron. 2010; 65:768779.

35. Benoit M, Berrut G, Doussaint J, Bakchine S, Bonin-Guillaume S, Fremont P et al.

Apathy and depression in mild Alzheimers disease: a cross-sectional study using

diagnostic criteria. J. Alzheimers Dis. 2012; 31:325 334.

36. Olin JT, Schneider LS, Katz IR, Meyers BS, Alexopoulos GS, Breitner JC et al.

Provisional diagnostic criteria for depression of Alzheimers disease: description and

review. Expert Rev. Neurother. 2003; 3:99106.

37. Haller J, Kruk MR. Normal and abnormal aggression: human disorders and novel

laboratory models. Neurosci Biobehav Rev. 2006; 30:292303.

38. Wang YL, Yuan Y, Yang J, Wang CH, Pan YJ, Lu L et al. The interaction between

the oxytocin and pain modulation in headache patients. Neuropeptides. 2013; 47(2):93-7.

39. Rash JA, Campbell TS. The effect of intranasal oxytocin administration on acute cold

pressor pain: a placebo-controlled, double-blind, within-participants crossover

investigation. Psychosom Med. 2014; 76(6):422-9.

40. Singer T, Snozzi R, Bird G, Petrovic P, Silani G, Heinrichs M, Dolan RJ. Effects of

oxytocin and prosocial behavior on brain responses to direct and vicariously experienced

pain. Emotion. 2008; 8(6):781-91.

41. Mameli S, Pisanu GM, Sardo S, Marchi A, Pili A, Carboni M, Minerba L et al.

Oxytocin nasal spray in fibromyalgic patients. Rheumatol Int. 2014; 34(8):1047-52.

42. Tracy LM, Georgiou-Karistianis N, Gibson SJ, Giummarra MJ. Oxytocin and the

modulation of pain experience: Implications for chronic pain management. Neurosci

Biobehav Rev. 2015; 55:53-67.

43. Cardoso C, Kingdon D, Ellenbogen MA. A meta-analytic review of theimpact of

intranasal oxytocin administration on cortisol concentrations duringlaboratory tasks:

moderation by method and mental health. Psychoneuroendocrinology. 2014; 49:161170.

44. Parker KJ, Buckmaster CL, Schatzberg AF, Lyons DM. Intranasaloxytocin

administration attenuates the ACTH stress response in monkeys.

Psychoneuroendocrinology. 2005; 30:924929.

45. Agid O, Kohn Y, Lerer B. Environmental stress and psychiatric illness. Biomed

Pharmacother. 2000; 54(3):135-41.

 46. Heidari J , Mierswa T , Kleinert J , Ott I , Levenig C , Hasenbring M , Kellmann M.

Parameters of low back pain chronicity among athletes: Associations with physical and

mental stress. Physical Therapy in Sports. 2016; 21: 3137.

Corresponding author:

Ciobica Alin

"Alexandru Ioan Cuza" University

Faculty of Biology, Dept. of Research

B dul Carol I, 11

700506, Iasi, Romania

Tel :0040751218264; Fax 0040232201472;

E-mail : alin.ciobica@uaic.ro

Submission: 21 may 2017

Acceptance: 31 july 2017