Genetic and Molecular Insights Linking Mood Disorders and Pain
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Keywords

pain
mood disorders
arthritis
biomarkers

How to Cite

Bogdanova, S., Dimitrov, S., Gerganov, G., Markov, M., Kabakchieva, P., & Benkova-Petrova, M. (2026). Genetic and Molecular Insights Linking Mood Disorders and Pain. Rheumatology (Bulgaria), 34(1), 43-64. https://doi.org/10.35465/7825v194

Abstract

Pain has been a constant companion of humankind since the dawn of time. As a sensory perception, it is a complex, multidimensional phenomenon and an integral part of human life. It is always a personal experience influenced by numerous endogenous and exogenous factors. Since pain is an unpleasant sensation, it is always associated with an emotional component. In addition to being personal, it is also a multifaceted experience, and its perception and awareness change throughout a person’s life. Pain can lead to impulsive behavior, affecting decision-making and self-control. As a universal and complex phenomenon in the animal world, it has fascinated scientists, clinicians, and philosophers for centuries. It goes beyond simple sensory perception and encompasses a multidimensional experience that includes not only the recognition of harmful stimuli but also cognitive and behavioral responses. This multifaceted nature of pain makes it a subject of great interest and research in various fields, including neurology, psychology, and clinical medicine.

DOI: https://doi.org/10.35465/7825v194
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References

1. Bogdanova S. Musculoskeletal pain in patients with COVID-19. Rheumatology (Bulgaria). 2022 Aug 24;30(2):3-17.

2. Богданова С. Болка, настроение и връзката помежду им; изд. Стено, 2025

3. James S. Human pain and genetics: Some basics. Br. J. Pain. 2013;7:171–178.

4. Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD. Writing a narrative biomedical review: considerations for authors, peer reviewers, and editors. Rheumatol Int [Internet]. 2011 Nov;31(11):1409–17. Available from: https://doi.org/10.1007/s00296-011-1999-3

5. Hashimoto K, Shimizu E, Iyo M. Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Brain Res Rev. 2004 May;45(2):104-14

6. Hashimoto K. Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci. 2010 Aug;64(4):341-57.

7. Xiong HY, Hendrix J, Schabrun S, Wyns A, Campenhout JV, Nijs J, Polli A. The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation. Biomolecules. 2024 Jan 5;14(1):71.

8. Woolf CJ, Ma QP, Allchorne A, Poole S. Periphreal cell types contributing to the hyperalgesic action of nerve growth factor in inflammation. J Neurosci 1996;16:2716-2723.

9. Ateaque S, Merkouris S, Barde YA. Neurotrophin signalling in the human nervous system. Front. Mol. Neurosci. 2023;16:1225373.

10. Duman RS, Monteggia LM. A Neurotrophic Model for Stress-Related Mood Disorders. Biol. Psychiatry. 2006;59:1116–1127.

11. Martinowich K, Manji H, Lu B. New insights into BDNF function in depression and anxiety. Nat. Neurosci. 2007;10:1089–1093.

12. Seidel MF, Hügle T, Morlion B, Koltzenburg M, Chapman V, Maassen Van Den Brink A, Lane NE, Perrot S, Zieglgänsberger W. Neurogenic inflammation as a novel treatment target for chronic pain syndromes. Exp Neurol. 2022;356;114108.

13. Smith MA, Makino S, Kim SY, Kvetnansky R. Stress increases brain-derived neurotropic factor messenger ribonucleic acid in the hypothalamus and pituitary. Endocrinology 1995; 136: 3743–3750.

14. Hwang JP, Tsai SJ, Hong CJ, Yang CH, Lirng JF, Yang YM. The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with geriatric depression. Neurobiol. Aging 2006; 27: 1834–1837.

15. Borroni B, Archetti S, Costanzi C et al. Role of BDNF Val66Met functional polymorphism in Alzheimer's disease-related depression. Neurobiol. Aging 2009; 30: 1406–1412

16. Licinio J, Dong C, Wong ML. Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response. Arch. Gen. Psychiatry 2009; 66: 488–497.

17. Pan W, Banks WA, Fasold MB, Bluth J, Kastin AJ. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology 1998; 37: 1553–1561

18. Pittenger C, Sanacora G, Krystal JH. The NMDA receptor as a therapeutic target in major depressive disorder. CNS Neurol. Disord. Drug Targets 2007; 6: 101–115

19. Williams F.M., Spector T.D., MacGregor A.J. Pain reporting at different body sites is explained by a single underlying genetic factor. Rheumatology. 2010;49:1753–1755

20. Martinowich K, Manji H, Lu B. New insights into BDNF function in depression and anxiety. Nature neuroscience. 2007 Sep;10(9):1089-93.

21. Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology. 2008 Jan;33(1):88-109.

22. Pittenger C, Sanacora G, Krystal JH. The NMDA receptor as a therapeutic target in major depressive disorder. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders). 2007 Apr 1;6(2):101-15.

23. Yu F.H., Catterwall W.A. Overview of the voltagegated sodium channel family. Genome Biol. 2003;4:207

24. Williams F.M., Spector T.D., MacGregor A.J. Pain reporting at different body sites is explained by a single underlying genetic factor. Rheumatology. 2010;49:1753–1755

25. Xie T., Ho S.L., Ramsden D. Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. Mol. Pharmacol. 1999;56:31–38

26. Lachman, H., Papolos, D., Saito, T., Yu, Y., Szumlanski, C. L., & Weinshilboum, R. M. (1996). Human catechol-O-methyltransferase pharmacogenetics: Description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics, 6, 243–250.

27. Šanjug J, Kuna K, Goldštajn MŠ, Dunkić LF, Carek A, Negovetić Vranić D. Relationship between COMT Gene Polymorphism, Anxiety, and Pain Perception during Labour. J Clin Med. 2023 Sep 29;12(19):6298

28. Hosák, L. (2007). Role of COMT gene Vall58Met polymorphism in metal disorders: A review. European Psychiatry, 22, 276–281

29. Chen J., Lipska B. K., Halim N., Ma Q. D., Matsumoto M., Melhem S., Weinberger D. R. (2004). Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): Effects on mRNA, protein, and enzyme activity in postmortem human brain. American Journal of Human Genetics, 75, 807–821.

30. Tunbridge, E. M., Harrison, P. J., & Weinberger, D. R. (2006). Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biological Psychiatry, 60, 141–151.

31. Meyer-Lindenberg, A., Kohn, P. D., Kolachana, B., Kippenhan, S., McInerney-Leo, A., Nussbaum, R., Berman, K. F. (2005). Midbrain dopamine and prefrontal function in humans: Interaction and modulation by COMT genoytype. Nature Neuroscience, 8, 594–596.

32. Drabant, E. M., Hariri, A. R., Meyer-Lindenberg, A., Munoz, K. E., Mattay, V. S., Kolachana, B. S., Weinberger, D. R. (2006). Catechol O-methyltransferase Val158Met genotype and neural mechanisms related to affective arousal and regulation. Archives of General Psychiatry, 63, 1396–1406.

33. Harrison, P. J., & Tunbridge, E. M. (2008). Catechol-O-methyltransferase (COMT): A gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology, 33, 3037–3045.

34. Taylor S. Association between COMT Val158Met and psychiatric disorders: A comprehensive meta‐analysis. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2018 Mar;177(2):199-210.

35. Oroszi G, Goldman D (2004). Alcoholism: genes and mechanisms. Pharmacogenomics 5: 1037–1048.

36. Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L et al (1998). Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci USA 95: 9608–9613.

37. Slavich, G. M., Tartter, M. A., Brennan, P. A. & Hammen, C. Endogenous opioid system influences depressive reactions to socially painful targeted rejection life events. Psychoneuroendocrinology 49, 141–149 (2014).

38. Nelson AM, Battersby AS, Baghdoyan HA, Lydic R. Opioid-induced decreas- es in rat brain adenosine levels are re- versed by inhibiting adenosine deami- nase. Anesthesiology 2009; 111:1327-1333.

39. Riley J, Ross JR, Rutter D, Wells AU, Goller K, du Bois R, Welsh K. No pain relief from morphine? Individual varia- tion in sensitivity to morphine and the need to switch to an alternative opioid in cancer patients. Supportive Care in Cancer 2006; 14:56-64.

40. Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology. 2000 Apr 1;22(4):370-9.

41. Hannestad J, DellaGioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology. 2011 Nov;36(12):2452-9.

42. Oh S.B., P.B. Tran, S.E. Gillard, R.W. Hurley, D.L. Hammond, R.J. Miller Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons J Neurosci, 21 (2001), pp. 5027-5035

43. Brydon L., C. Walker, A. Wawrzyniak, D. Whitehead, H. Okamura, J. Yajima, et al. Synergistic effects of psychological and immune stressors on inflammatory cytokine and sickness responses in humans Brain Behav Immun, 23 (2009), pp. 217-224

44. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor á promoter on transcriptional activation. Proc Natl Acad Sci U S A 1997;94:3195–9.

45. Kroeger KM, Carville KS, Abraham LJ. The− 308 tumor necrosis factor-α promoter polymorphism effects transcription. Molecular immunology. 1997 Apr 1;34(5):391-9.

46. Jun TY, Pae CU, Chae JH, Bahk WM, Kim KS, Serretti A. Possible association between–G308A tumour necrosis factor-α gene polymorphism and major depressive disorder in the Korean population. Psychiatric genetics. 2003 Sep 1;13(3):179-81.

47. Gao Z, Yuan H, Sun M, Wang Z, He Y, Liu D. The association of serotonin transporter gene polymorphism and geriatric depression: a meta-analysis. Neuroscience letters. 2014 Aug 22;578:148-52.

48. Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Archives of general psychiatry. 2011 May 2;68(5):444-54.

49. Mohammad‐Zadeh LF, Moses L, Gwaltney‐Brant SM. Serotonin: a review. Journal of veterinary pharmacology and therapeutics. 2008 Jun;31(3):187-99.

50. Kenna, G. A., Roder-Hanna, N., Leggio, L., Zywiak, W. H., Clifford, J., Edwards, S., Swift, R. M. (2012). Association of the 5-HTT gene-linked promoter region (5-HTTLPR) polymorphism with psychiatric disorders: review of psychopathology and pharmacotherapy. Pharmacogenomics and Personalized Medicine, 5, 19–35

51. Brunton LL, Knollmann BC, Hilal-Dandan R, editors. Goodman & Gilman's the pharmacological basis of therapeutics. New York, NY, USA:: McGraw-Hill Education; 2018.

52. Heils A, Teufel A, Petri S, Stober G, Riederer P, et al: Allelic variation of human serotonin transporter gene expression. J Neurochem. 1996, 66: 2621-2624.

53. Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Archives of general psychiatry. 2011 May 2;68(5):444-54.

54. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR, Hamer DH, Murphy DL. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996 Nov 29;274(5292):1527-31.

55. Munafò MR, Brown SM, Hariri AR. Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biological psychiatry. 2008 May 1;63(9):852-7.

56. Heinz A, Braus DF, Smolka MN, Wrase J, Puls I, Hermann D, Klein S, Grüsser SM, Flor H, Schumann G, Mann K. Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nature neuroscience. 2005 Jan 1;8(1):20-1.

57. Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nature neuroscience. 2005 Jun 1;8(6):828-34

58. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003 Jul 18;301(5631):386-9.

59. Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ. Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Molecular psychiatry. 2002 Dec;7(10):1115-9.

60. Aoki J, Ikeda K, Murayama O, Yoshihara E, Ogai Y, Iwahashi K. The association between personality, pain threshold and a single nucleotide polymorphism (rs3813034) in the 3′-untranslated region of the serotonin transporter gene (SLC6A4). Journal of Clinical Neuroscience. 2010 May 1;17(5):574-8.

61. Murphy DL, Fox MA, Timpano KR, Moya PR, Ren-Patterson R, Andrews AM, Holmes A, Lesch KP, Wendland JR. How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems. Neuropharmacology. 2008 Nov 1;55(6):932-60.

62. Schinka JA, Busch RM, Robichaux-Keene N. A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety. Molecular psychiatry. 2004 Feb;9(2):197-202.

63. Munafò MR, Brown SM, Hariri AR. Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biological psychiatry. 2008 May 1;63(9):852-7.

64. Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Archives of general psychiatry. 2011 May 2;68(5):444-54.

65. Henningsen P, Zimmermann T, Sattel H. Medically unexplained physical symptoms, anxiety, and depression: a meta-analytic review. Psychosomatic medicine. 2003 Jul 1;65(4):528-33.

66. Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J. International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacological reviews. 2005 Dec 1;57(4):411-25.

67. Dolphin AC. Calcium channel diversity: multiple roles of calcium channel subunits. Current opinion in neurobiology. 2009 Jun 1;19(3):237-44.

68. Moosmang S, Haider N, Klugbauer N, Adelsberger H, Langwieser N, Müller J, Stiess M, Marais E, Schulla V, Lacinova L, Goebbels S. Role of hippocampal Cav1. 2 Ca2+ channels in NMDA receptor-independent synaptic plasticity and spatial memory. Journal of Neuroscience. 2005 Oct 26;25(43):9883-92.

69. Bhat S, Dao DT, Terrillion CE, Arad M, Smith RJ, Soldatov NM, Gould TD. CACNA1C (Cav1. 2) in the pathophysiology of psychiatric disease. Progress in neurobiology. 2012 Oct 1;99(1):1-4.

70. Moon AL, Haan N, Wilkinson LS, Thomas KL, Hall J. CACNA1C: Association With Psychiatric Disorders, Behavior, and Neurogenesis. Schizophr Bull. 2018 Aug 20;44(5):958-965.

71. Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. The DISC locus in psychiatric illness. Molecular psychiatry. 2008 Jan;13(1):36-64.

72. Soldatov NM. Genomic structure of human L-type Ca2+ channel. Genomics. 1994 Jul 1;22(1):77-87.

73. Sklar P, Smoller JW, Fan J, Ferreira MA, Perlis RH, Chambert K, Nimgaonkar VL, McQueen MB, Faraone SV, Kirby A, De Bakker PI. Whole-genome association study of bipolar disorder. Molecular psychiatry. 2008 Jun;13(6):558-69.

74. Dao DT, Mahon PB, Cai X, Kovacsics CE, Blackwell RA, Arad M, Shi J, Zandi PP, O'Donnell P, Knowles JA, Weissman MM. Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans. Biological psychiatry. 2010 Nov 1;68(9):801-10.

75. Liu Y, Blackwood DH, Caesar S, de Geus EJ, Farmer A, Ferreira MA, Ferrier IN, Fraser C, Gordon-Smith K, Green EK, Grozeva D. Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder. Molecular psychiatry. 2011 Jan;16(1):2-4.

76. Jogia J, Ruberto G, Lelli-Chiesa G, Vassos E, Maierú M, Tatarelli R, Girardi P, Collier D, Frangou S. The impact of the CACNA1C gene polymorphism on frontolimbic function in bipolar disorder. Molecular psychiatry. 2011 Nov;16(11):1070-1.

77. Morii M, Ohka S, Nishizawa D, Hasegawa J, Nakayama K, Ebata Y, Soeda M, Fukuda KI, Yoshida K, Koshika K, Ichinohe T. The rs216009 single-nucleotide polymorphism of the CACNA1C gene is associated with phantom tooth pain. Molecular Pain. 2023 Jul 31;19:17448069231193383.

78. Heyes S, Pratt WS, Rees E, Dahimene S, Ferron L, Owen MJ, et al. Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders. Prog Neurobiol. (2015) 134:36–54.

79. Dormer A, Narayanan M, Schentag J, Achinko D, Norman E, Kerrigan J, Jay G, Heydorn W. A Review of the Therapeutic Targeting of SCN9A and Nav1.7 for Pain Relief in Current Human Clinical Trials. J Pain Res. 2023 May 4;16:1487-1498.

80. Vargas-Alarcon G, Alvarez-Leon E, Fragoso JM, Vargas A, Martinez A, Vallejo M, Martinez-Lavin M. A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia. BMC Musculoskelet Disord. 2012 Feb 20;13:23

81. Chen CH, Huang YS, Fang TH. Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder. Int J Mol Sci. 2021 Dec 7;22(24):13189

82. Duan G, Guo S, ZhangY, YingY, Huang P, Wang Q, Zhang L, Zhang X, The Effect of SCN9A Variation on Basal Pain Sensitivity in the General Population: An Experimental Study in Young Women, The Journal of Pain, Volume 16, Issue 10, 2015, Pages 971-980

83. Leźnicka K, Pawlak M, Sawczuk M, Gasiorowska A, Leońska-Duniec A. SCN9A rs6746030 Polymorphism and Pain Perception in Combat Athletes and Non-Athletes. Genes. 2023; 14(3):733.

84. Kvernebo S. M., Grayson C., Stylianou I. M., Woloshen V., Radomski C., Mørk C., Kvernebo K., Genetic Variants in the SCN9A Gene are Detected in a Minority of Erythromelalgia Patients. Acta Dermato-Venereologica, 105, adv42022, (2025).

85. Matsubara T, Funato H, Kobayashi A, Nobumoto M, Watanabe Y. Reduced glucocorticoid receptor α expression in mood disorder patients and first-degree relatives. Biological psychiatry. 2006 Apr 15;59(8):689-95.

86. Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron. 2002 Mar 28;34(1):13-25.

87. Holsboer F. The corticosteroid receptor hypothesis of depression. Depression. 2013 Oct 15:219-43.

88. de Kloet E. Hormones, brain and stress. Endocrine regulations. 2003 Jun 1;37(2):51-68.

89. Webster MJ, Knable MB, O'grady J, Orthmann J, Weickert CS. Regional specificity of brain glucocorticoid receptor mRNA alterations in subjects with schizophrenia and mood disorders. Molecular psychiatry. 2002 Oct;7(9):985-94.

90. Felger JC, Lotrich FE. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience. 2013 Aug 29;246:199-229. doi: 10.1016/j.neuroscience.2013.04.060.

91. Greene CS, Penrod NM, Williams SM, Moore JH. Failure to replicate a genetic association may provide important clues about genetic architecture. PLoS One. 2009 Jun 2;4(6):e5639. doi: 10.1371/journal.pone.0005639.

92. Chatterjee N, Wheeler B, Sampson J, Hartge P, Chanock SJ, Park JH. Projecting the performance of risk prediction based on polygenic analyses of genome-wide association studies. Nat Genet. 2013 Apr;45(4):400-5, 405e1-3. doi: 10.1038/ng.2579.

93. Jiang S, Postovit L, Cattaneo A, Binder EB, Aitchison KJ. Epigenetic modifications in stress response genes associated with childhood trauma. Front Psychiatry. 2019 Nov 8;10:808. doi: 10.3389/fpsyt.2019.00808.

94. Tanaka M, Battaglia S. From biomarkers to behavior: mapping the neuroimmune web of pain, mood, and memory. Biomedicines. 2025;13(9):2226. doi: 10.3390/biomedicines13092226.

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Copyright (c) 2026 Simona Bogdanova, Stoimen Dimitrov, Georgi Gerganov, Miroslav Markov, Plamena Kabakchieva, Miroslava Benkova-Petrova (Author)

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