Clinical Oral Investigations

, Volume 21, Issue 7, pp 2363–2370 | Cite as

Opiorphin in burning mouth syndrome patients: a case-control study

Original Article



Opiorphin is a pentapeptide isolated from human saliva that suppresses pain from chemically induced inflammation and acute physical pain. Burning mouth syndrome (BMS) is a chronic condition of a burning sensation in the mouth, where no underlying dental or medical cause can be identified. We aimed to measure the level of opiorphin in whole unstimulated (UWS) and stimulated (SWS) saliva of patients with BMS.

Materials and methods

Originally developed and validated LC-MS/MS method was used for opiorphin quantification. Samples were obtained from 29 BMS patients and 29 age- and sex-matched controls.


The average concentration of opiorphin in UWS and SWS in the BMS group was 8.13 ± 6.45 and 5.82 ± 3.59 ng/ml, respectively. Opiorphin in BMS patients’ UWS was significantly higher, compared to the control group (t = 2.5898; p = 0.0122). SWS opiorphin levels were higher, but not significantly, in BMS patients than in controls.


Our results indicate that higher quantities of salivary opiorphin in BMS may be a consequence of chronic pain, but we cannot exclude that they occur as a result of emotional and behavioral imbalances possibly associated with BMS. To our knowledge, this is the first original article measuring opiorphin in a pain disorder.

Clinical relevance

Opiorphin may be a measurable biomarker for chronic pain, which could help in objectifying otherwise exclusively a subjective experience. Increased opiorphin could serve as a universal objective indicator of painful conditions. Since opiorphin may also reflect emotional and socio-relational imbalances occurring with BMS, it could as well represent a biomarker for BMS. Knowledge on opiorphin’s involvement in pain pathways could contribute to developing new clinical diagnostic methods for BMS.


Opiorphin Burning mouth syndrome Saliva Chromatography, Liquid Spectrometry, Mass 



We thank Lidija Brkljačić for her assistance with sample processing and LC-MS/MS analysis.

Compliance with ethical standards

Conflict of interest

Author Ivan Salarić declares that he has no conflict of interest. Author Maja Sabalić declares that she has no conflict of interest. Author Ivan Alajbeg declares that he has no conflict of interest.


The work was supported by the Croatian Science Foundation grant no. 3070 (“The role of oxidative stress and opiorphin in temporomandibular disorders,” PI: Assoc. Prof. Iva Alajbeg).

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Ethical Committee and with the 1964 Helsinki Declaration and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study. All pertaining data (de-identified medical data on study subjects, institutional ethical committee approval, copies of signed informed consent forms, laboratory results) can be obtained from the authors on request.


  1. 1.
    Wisner A, Dufour E, Messaoudi M, Nejdi A, Marcel A, Ungeheuer MN, Rougeot C (2006) Human opiorphin, a natural antinociceptive modulator of opioid-dependent pathways. Proc Natl Acad Sci U S A 103:17979–17984CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Rougeot C, Robert F, Menz L, Bisson JF, Messaoudi M (2010) Systemically active human opiorphin is a potent yet non-addictive analgesic without drug tolerance effects. J Physiol Pharmacol 61:483–490PubMedGoogle Scholar
  3. 3.
    Javelot H, Messaoudi M, Garnier S, Rougeot C (2010) Human opiorphin is a naturally occurring antidepressant acting selectively on enkephalin-dependent delta-opioid pathways. J Physiol Pharmacol 61:355–362PubMedGoogle Scholar
  4. 4.
    Popik P, Kamysz E, Kreczko J, Wróbel M (2010) Human opiorphin: the lack of physiological dependence, tolerance to antinociceptive effects and abuse liability in laboratory mice. Behav Brain Res 213:88–93CrossRefPubMedGoogle Scholar
  5. 5.
    Yang QZ, SS L, Tian XZ, Yang AM, Ge WW, Chen Q (2011) The antidepressant-like effect of human opiorphin via opioid-dependent pathways in mice. Neurosci Lett 489:131–135CrossRefPubMedGoogle Scholar
  6. 6.
    Tian XZ, Chen J, Xiong W, He T, Chen Q (2009) Effects and underlying mechanisms of human opiorphin on colonic motility and nociception in mice. Peptides 30:1348–1354CrossRefPubMedGoogle Scholar
  7. 7.
    Kamysz E, Sałaga M, Sobczak M, Kamysz W, Fichna J (2013) Characterization of the effects of opiorphin and sialorphin and their analogs substituted in position 1 with pyroglutamic acid on motility in the mouse ileum. J Pept Sci 19:166–172CrossRefPubMedGoogle Scholar
  8. 8.
    Dufour E, Villard-Saussine S, Mellon V, Leandri R, Jouannet P, Ungeheuer MN, Rougeot C (2013) Opiorphin secretion pattern in healthy volunteers: gender difference and organ specificity. Biochem Anal Biochem 2:136. doi: 10.4172/2161-1009.1000136 Google Scholar
  9. 9.
    Rougeot C (2014) Opiorphin peptide derivatives as potent inhibitors of enkephalin-degrading ectopeptidases. US patent US8642729 B2Google Scholar
  10. 10.
    Al-Saffar MT, Al-Sandook TA, Y-Taha M (2013) A possible new concept in the mechanism of action of local anesthesia. Am J Med Biol Res 1:134–137CrossRefGoogle Scholar
  11. 11.
    Headache Classification Subcommittee of the International Headache Society (2013) The international classification of headache disorders: 3rd edition. Cephalalgia 33:629–808CrossRefGoogle Scholar
  12. 12.
    Zakrzewska JM, Forssell H and Glenny AM (2005) Interventions for the treatment of burning mouth syndrome. Cochrane Database Syst Rev CD002779. doi: 10.1002/14651858.CD002779
  13. 13.
    Scala A, Checchi L, Montevecchi M, Marini I, Giamberardino MA (2003) Update on burning mouth syndrome: overview and patient management. Crit Rev Oral Biol Med 14:275–291CrossRefPubMedGoogle Scholar
  14. 14.
    Grushka M, Ching V, Epstein V (2006) Burning mouth syndrome. Adv Othorinolaryngol 63:278–287Google Scholar
  15. 15.
    Forsell H, Jääakeläinen S, Tenovuo O, Hinkka S (2002) Sensory dysfunction in burning mouth syndrome. Pain 99:41–47CrossRefGoogle Scholar
  16. 16.
    Hagelberg N, Forsell H, Rinne JO, Scheinin H, Taiminen T, Aalto S, Luutonen S, Någren K, Jääskeläinen S (2003) Striatal dopamine D1 and D2 receptors in burning mouth syndrome. Pain 101:149–154CrossRefPubMedGoogle Scholar
  17. 17.
    Nagler RM, Hershkovich O (2004) Sialochemical and gustatory analysis in patients with oral sensory complaints. J Pain 5:56–63CrossRefPubMedGoogle Scholar
  18. 18.
    Granot M, Nagler RM (2005) Association between regional idiopathic neuropathy and salivary involvement as the possible mechanism for oral sensory complaints. J Pain 6:581–587CrossRefPubMedGoogle Scholar
  19. 19.
    Jääskeläinen SK (2012) Pathophysiology of primary burning mouth syndrome. Clin Neurophysiol 123:71–77CrossRefPubMedGoogle Scholar
  20. 20.
    Sabalić M, Brkljačić L, Salarić I, Alajbeg I, Jerić I, Nemet I (2012) Salivary opiorphin as a potential marker of oral disease. Book of abstracts of the 11th Biennial Congress of the European Association of Oral Medicine. Oral Dis 18(1, SI):21Google Scholar
  21. 21.
    Brkljačić L, Sabalić M, Salarić I, Jerić I, Alajbeg I, Nemet I (2011) Development and validation of a liquid chromatography-tandem mass spectrometry method for the quantification of opiorphin in human saliva. J Chromatogr B Analyt Technol Biomed Life Sci 879:3920–3926CrossRefPubMedGoogle Scholar
  22. 22.
    World Health Organization (2014) WHO Collaborating Centre for Drug Statistics Methodology, ATC classification index with DDDs. Available at:
  23. 23.
    World Health Organization (1992) International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10). Geneva: WHO. Version for 2015. Available at:
  24. 24.
    Netto FO, Diniz IM, Grossmann SM, de Abreu MH, do Carmo MA, Aguiar MC (2011) Risk factors in burning mouth syndrome: a case-control study based on patient records. Clin Oral Investig 15:571–575CrossRefPubMedGoogle Scholar
  25. 25.
    Gurvits GE, Tan A (2013) Burning mouth syndrome. World J Gastroenterol 19:665–672CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Bergdahl M, Bergdahl J (1999) Burning mouth syndrome: prevalence and associated factors. J Oral Pathol Med 28:350–354CrossRefPubMedGoogle Scholar
  27. 27.
    Lopez-Jornet P, Molino Pagan D, Andujar Mateos P, Rodriguez Agudo C, Pons-Fuster A (2015) Circadian rhythms variation of pain in burning mouth syndrome. Geriatr Gerontol Int 15:490–495. doi: 10.1111/ggi.12303 CrossRefPubMedGoogle Scholar
  28. 28.
    Morris KE, St Laurent CD, Hoeve RS, Forsythe P, Suresh MR, Mathison RD, Befus AD (2009) Autonomic nervous system regulates secretion of anti-inflammatory prohormone SMR1 from rat salivary glands. Am J Physiol Cell Physiol 296:C514–C524CrossRefPubMedGoogle Scholar
  29. 29.
    Heckmann SM, Heckmann JG, HiIz MJ, Popp M, Marthol H, Neundörfer B, Hummel T (2001) Oral mucosal blood flow in patients with burning mouth syndrome. Pain 90:281–286CrossRefPubMedGoogle Scholar
  30. 30.
    Ran HH, Zhang R (2011) Renin-angiotensin system modulates vasoreactivity through a mechanism of oxidative stress. Sheng Li Ke Xue Jin Zhan 42:117–120PubMedGoogle Scholar
  31. 31.
    Fang Y, Li S, Zhou H, Tian X, Lv S, Chen Q (2014) Opiorphin increases blood pressure of conscious rats through renin-angiotensin system (RAS). Peptides 55C:47–51CrossRefGoogle Scholar
  32. 32.
    Tian XZ, Chen Y, Bai L, Luo P, XJ D, Chen Q, Tian XM (2015) Effects and underlying mechanisms of human opiorphin on cardiovascular activity in anesthetized rats. Eur J Pharmacol 749:32–38CrossRefPubMedGoogle Scholar
  33. 33.
    Salort-Llorca C, Mínguez-Serra MP, Silvestre FJ (2008) Drug-induced burning mouth syndrome: a new etiological diagnosis. Med Oral Patol Oral Cir Bucal 13:E167–E170PubMedGoogle Scholar
  34. 34.
    Mathison R, Davison JS, Befus AD (1994) Neuroendocrine regulation of inflammation and tissue repair by submandibular gland factors. Immunol Today 15:527–532CrossRefPubMedGoogle Scholar
  35. 35.
    Mathison RD, Davison JS, St Laurent CD, Befus AD (2012) Autonomic regulation of anti-inflammatory activities from salivary glands. Chem Immunol Allergy 98:176–195CrossRefPubMedGoogle Scholar
  36. 36.
    Mathison RD, Davison JS, Befus AD, Gingerich DA (2010) Salivary gland derived peptides as a new class of anti-inflammatory agents: review of preclinical pharmacology of C-terminal peptides of SMR1 protein. J Inflamm (Lond) 7:49CrossRefGoogle Scholar
  37. 37.
    Rosinski-Chupin I, Huaulme JF, Rougeot C, Rougeon F (2001) The transcriptional response to androgens of the rat VCSA1 gene is amplified by both binary and graded mechanisms. Endocrinology 142:4550–4559CrossRefPubMedGoogle Scholar
  38. 38.
    Woda A, Dao T, Gremeau-Richard C (2009) Steroid dysregulation and stomatodynia (burning mouth syndrome). J Orofac Pain 23:202–210PubMedGoogle Scholar
  39. 39.
    Kim HI, Kim YY, Chng JY, Ko JY, Kho HS (2012) Salivary cortisol, 17β-estradiol, progesterone, dehydroepiandrosterone, and α-amylase in patients with burning mouth syndrome. Oral Dis 18:613–620CrossRefPubMedGoogle Scholar
  40. 40.
    Trombelli L, Mandrioli S, Zangari F, Saletti C, Calura G (1992) Oral symptoms in the climacteric. A prevalence study. Minerva Stomatol 41:507–513PubMedGoogle Scholar
  41. 41.
    Srivastava A, Wang J, Zhou H, Melvin JE, Wong DT (2008) Age and gender related differences in human parotid gland gene expression. Arch Oral Biol 53:1058–1070CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Department of Oral and Maxillofacial SurgeryUniversity of Zagreb School of Dental Medicine University Hospital DubravaZagrebCroatia
  2. 2.Department of Craniofacial Development and Stem Cell Biology, Guy’s HospitalKing’s College LondonLondonUK
  3. 3.Department of Oral MedicineUniversity of Zagreb School of Dental Medicine and University Hospital Centre ZagrebZagrebCroatia

Personalised recommendations