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Low catechol-O-methyltransferase and stress potentiate functional pain and depressive behavior, especially in female mice.
Pain 2020; 161(2):446-458PAIN

Abstract

Low levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, and stress, which potentiates catecholamine release from sympathetic nerves, are fundamental to chronic functional pain syndromes and comorbid depression, which predominantly affect females. Here, we sought to examine the independent and joint contributions of low COMT and stress to chronic functional pain and depression at the behavioral and molecular level. Male and female C57BL/6 mice received sustained systemic delivery of the COMT inhibitor OR486 over 14 days and underwent a swim stress paradigm on days 8 to 10. Pain and depressive-like behavior were measured over 14 days, and brain-derived neurotrophic factor (BDNF; a factor involved in nociception and depression) and glucocorticoid receptor (GR; a stress-related receptor) expression were measured on day 14. We found that stress potentiates the effect of low COMT on functional pain and low COMT potentiates the effect of stress on depressive-like behavior. The joint effects of low COMT and stress on functional pain and depressive-like behavior were significantly greater in females vs males. Consistent with behavioral data, we found that stress potentiates COMT-dependent increases in spinal BDNF and low COMT potentiates stress-dependent decreases in hippocampal BDNF in females, but not males. Although low COMT increases spinal GR and stress increases hippocampal GR expression, these increases are not potentiated in the OR486 + stress group and are not sex-specific. These results suggest that genetic and environmental factors that enhance catecholamine bioavailability cause abnormalities in BDNF signaling and increase risk of comorbid functional pain and depression, especially among females.

Authors+Show Affiliations

Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States.Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States.Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States.Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States. Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea.Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States.Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States.Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States.Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31972854

Citation

Zhang, Xin, et al. "Low catechol-O-methyltransferase and Stress Potentiate Functional Pain and Depressive Behavior, Especially in Female Mice." Pain, vol. 161, no. 2, 2020, pp. 446-458.
Zhang X, Kanter K, Chen J, et al. Low catechol-O-methyltransferase and stress potentiate functional pain and depressive behavior, especially in female mice. Pain. 2020;161(2):446-458.
Zhang, X., Kanter, K., Chen, J., Kim, S., Wang, Y., Adeyemi, C., ... Nackley, A. G. (2020). Low catechol-O-methyltransferase and stress potentiate functional pain and depressive behavior, especially in female mice. Pain, 161(2), pp. 446-458. doi:10.1097/j.pain.0000000000001734.
Zhang X, et al. Low catechol-O-methyltransferase and Stress Potentiate Functional Pain and Depressive Behavior, Especially in Female Mice. Pain. 2020;161(2):446-458. PubMed PMID: 31972854.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Low catechol-O-methyltransferase and stress potentiate functional pain and depressive behavior, especially in female mice. AU - Zhang,Xin, AU - Kanter,Katie, AU - Chen,Jiegen, AU - Kim,Seungtae, AU - Wang,Yaomin, AU - Adeyemi,Clementine, AU - OʼBuckley,Sandra C, AU - Nackley,Andrea G, PY - 2020/1/24/entrez PY - 2020/1/24/pubmed PY - 2020/1/24/medline SP - 446 EP - 458 JF - Pain JO - Pain VL - 161 IS - 2 N2 - Low levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, and stress, which potentiates catecholamine release from sympathetic nerves, are fundamental to chronic functional pain syndromes and comorbid depression, which predominantly affect females. Here, we sought to examine the independent and joint contributions of low COMT and stress to chronic functional pain and depression at the behavioral and molecular level. Male and female C57BL/6 mice received sustained systemic delivery of the COMT inhibitor OR486 over 14 days and underwent a swim stress paradigm on days 8 to 10. Pain and depressive-like behavior were measured over 14 days, and brain-derived neurotrophic factor (BDNF; a factor involved in nociception and depression) and glucocorticoid receptor (GR; a stress-related receptor) expression were measured on day 14. We found that stress potentiates the effect of low COMT on functional pain and low COMT potentiates the effect of stress on depressive-like behavior. The joint effects of low COMT and stress on functional pain and depressive-like behavior were significantly greater in females vs males. Consistent with behavioral data, we found that stress potentiates COMT-dependent increases in spinal BDNF and low COMT potentiates stress-dependent decreases in hippocampal BDNF in females, but not males. Although low COMT increases spinal GR and stress increases hippocampal GR expression, these increases are not potentiated in the OR486 + stress group and are not sex-specific. These results suggest that genetic and environmental factors that enhance catecholamine bioavailability cause abnormalities in BDNF signaling and increase risk of comorbid functional pain and depression, especially among females. SN - 1872-6623 UR - https://www.unboundmedicine.com/medline/citation/31972854/Low_catechol-O-methyltransferase_and_stress_potentiate_functional_pain_and_depressive_behavior,_especially_in_female_mice L2 - http://dx.doi.org/10.1097/j.pain.0000000000001734 DB - PRIME DP - Unbound Medicine ER -