[논문]Citral-induced analgesia is associated with increased spinal serotonin, reduced spinal nociceptive signaling, and reduced systemic oxidative stress in arthritis

Mota, Clarissa M.D.; Rodrigues-Santos, Caroline; Carolino, Ruither O.G.; Anselmo-Franci, Janete A.; Branco, Luiz G.S.

doi:10.1016/j.jep.2019.112486

Citral-induced analgesia is associated with increased spinal serotonin, reduced spinal nociceptive signaling, and reduced systemic oxidative stress in arthritis

Journal of ethnopharmacology, v.250, 2020년, pp.112486 -

Mota, Clarissa M.D. (Department of Physiology, School of Medicine of Ribeirã) , Rodrigues-Santos, Caroline (o Preto, University of Sã) , Carolino, Ruither O.G. (o Paulo) , Anselmo-Franci, Janete A. (Department of Morphology, Physiology and Basic Pathology, School of Dentistry of Ribeirã) , Branco, Luiz G.S. (o Preto, University of Sã)

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Abstract Ethnopharmacological relevance Citral (3,7-dimethyl-2,6-octadienal) is the main component of Cymbopogon citratus (DC) Stapf, an herb with analgesic properties. Arthritic pain is the main unpleasant component of rheumatoid arthritis. The pharmacological approaches used to treat arthritic pain are often accompanied by adjuvant drugs or non-pharmacological treatments, showing a constant need in identifying new efficient analgesic drugs. Aim of the study To test the hypothesis that citral, which is a monoterpenoid compound with therapeutic properties, reduces nociception, spinal pro-nociceptive and pro-inflammatory signaling, and systemic oxidative stress in arthritic rats. Materials and methods Complete Freund's adjuvant (CFA) was administrated in the left knee joint of rats. Oral treatment with citral was performed during eight days and mechanical allodynia was monitored during the period of treatment to evaluate the analgesic effect of citral. We assessed the levels of serotonin (5-hydroxytryptamine, 5-HT) in the lumbar dorsal horn of the spinal cord (DHSC) and the profiles of expression of the glycogen synthase kinase-3β (GSK3β), which is a 5-HT-regulated intracellular protein, and of the stress-activated protein kinase (SAPK)/jun N-terminal kinase (JNK) in the DHSC. Plasma levels of superoxide dismutase (SOD) were assessed as an indicator of oxidative stress. Results Administration of CFA induced mechanical allodynia associated with reduced spinal GSK3β phosphorylation, increased spinal SAPK/JNK phosphorylation, and increased plasma SOD levels. Oral administration of citral reversed mechanical allodynia, increased endogenous spinal 5-HT levels, reduced spinal SAPK/JNK phosphorylation, and reduced plasma SOD levels. Conclusion Citral shows anti-nociceptive effects in an animal model of arthritic pain by modulating spinal nociceptive signaling. Highlights Citral reversed mechanical allodynia in arthritic rats. Citral increased endogenous levels of spinal 5-HT in arthritic rats. Citral reduced spinal SAPK/JNK phosphorylation in arthritic rats. Citral prevented CFA-induced increase in systemic oxidative stress. Graphical abstract Neurochemical mechanisms involved in citral-induced analgesia in arthritis. (A) Complete Freund's adjuvant (CFA)-induced arthritis reduces spinal serotonin metabolism in the lumbar dorsal horn of the spinal cord ipsilateral to the injured joint, as indicated by the reduction in the spinal levels of the main metabolite of serotonin (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA). Moreover, there is a reduction in glycogen synthase kinase-3β (GSK3β) phosphorylation, which is a 5-HT-regulated intracellular protein, and an increase in stress-activated protein kinase (SAPK)/jun N-terminal kinase (JNK) phosphorylation. Systemically, arthritis increases plasma superoxide dismutase levels, which indicate an increase in plasma reactive oxygen species (ROS). Together, the alteration of the molecules described and certainly many other aspects contribute to a scenario of increased central sensitization and chronic arthritic pain. (B) During arthritis, chronic treatment with citral increases spinal 5-HT and regulates spinal 5-HT metabolism (i.e., 5-HIAA levels), prevents CFA-induced increase in spinal GSK3β phosphorylation and reduces CFA-induced increase in SAPK/JNK phosphorylation, and reduces plasma ROS. Here, we propose that the increase in 5-HT signaling in the spinal cord combined with the reduction of spinal SAPK/JNK phosphorylation and the reduction of systemic oxidative stress are the anti-nociceptive mechanisms by which citral causes analgesia. [DISPLAY OMISSION]

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Citral-induced analgesia is associated with increased spinal serotonin, reduced spinal nociceptive signaling, and reduced systemic oxidative stress in arthritis

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