Korean J Physiol Pharmacol.  2017 Jul;21(4):361-370. 10.4196/kjpp.2017.21.4.361.

Effects of tianeptine on symptoms of fibromyalgia via BDNF signaling in a fibromyalgia animal model

• Lee H
• Im J
• Won H
• Nam W
• Kim YO
• Lee SW
• Lee S
• Cho IH
• Kim HK
• Kwon JT
• Kim HJ

• KMID: 2384449
• DOI: http://doi.org/10.4196/kjpp.2017.21.4.361

Abstract

Previous reports have suggested that physical and psychological stresses may trigger fibromyalgia (FM). Stress is an important risk factor in the development of depression and memory impairments. Antidepressants have been used to prevent stress-induced abnormal pain sensation. Among various antidepressants, tianeptine has been reported to be able to prevent neurodegeneration due to chronic stress and reverse decreases in hippocampal volume. To assess the possible effect of tianeptine on FM symptoms, we constructed a FM animal model induced by restraint stress with intermittent cold stress. All mice underwent nociceptive assays using electronic von Frey anesthesiometer and Hargreaves equipment. To assess the relationship between tianeptine and expression levels of brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and phosphorylated cAMP response element-binding protein (p-CREB), western blotting and immunohistochemistry analyses were performed. In behavioral analysis, nociception tests showed that pain threshold was significantly decreased in the FM group compared to that in the control group. Western blot and immunohistochemical analyses of medial prefrontal cortex (mPFC) and hippocampus showed downregulation of BDNF and p-CREB proteins in the FM group compared to the control group. However, tianeptine recovered these changes in behavioral tests and protein level. Therefore, this FM animal model might be useful for investigating mechanisms linking BDNF-CREB pathway and pain. Our results suggest that tianeptine might potentially have therapeutic efficacy for FM.

Keyword

Animal model; BDNF; Fibromyalgia; Pain; Tianeptine

MeSH Terms

Animals*
Antidepressive Agents
Behavior Rating Scale
Blotting, Western
Brain-Derived Neurotrophic Factor*
Cyclic AMP Response Element-Binding Protein
Depression
Down-Regulation
Fibromyalgia*
Hippocampus
Immunohistochemistry
Memory
Mice
Models, Animal*
Pain Measurement
Pain Threshold
Prefrontal Cortex
Risk Factors
Sensation
Stress, Psychological
Antidepressive Agents
Brain-Derived Neurotrophic Factor
Cyclic AMP Response Element-Binding Protein

Figure

• 

  Fig. 1 Corticosterone concentration changes after stressful paradigm. Corticosterone secretion was induced by restraint stress in FM mice (n=7 per group). Corticosterone level was expressed in concentration of pg/ml. Data are presented as means±SEM (*p<0.05 vs. CON; †p<0.05 vs. FM). FM, Fibromyalgia animal model; CON, non-FM animal model; FM-TIA, Tianeptine administered FM model.

• 

  Fig. 2 Effect of tianeptine on immobility time in mice subjected to tail suspension test. The total duration of immobility during a 6-min period was measured (n=7 per group). Data are presented as means±SEM (*p<0.05 vs. CON; †p<0.05 vs. FM). FM, Fibromyalgia animal model; CON, non-FM animal model; FM-TIA, Tianeptine administered FM model.

• 

  Fig. 3 Effect of tianeptine on nociceptive response via tail flick test in FM model. Latency time of tail flicking away from radiant heat was scored (n=7 per group). Comparison was made between Con and FM groups. Data are presented in second as means±SEM (*p<0.05 vs. CON; †p<0.05 vs. FM). FM, Fibromyalgia animal model; CON, non-FM animal model; FM-TIA, Tianeptine administered FM model.

• 

  Fig. 4 Effect of tianeptine on nociceptive response in FM model. (A) Results of the right hind paw. (B) Results of the left hind paw. Thermal pain threshold was assessed via plantar test (n=7 per group). Graphs are shown in means±SEM of response frequency to heat stimulation (*p<0.05 vs. CON; †p<0.05 vs. FM). PWL, paw withdrawal time; FM, Fibromyalgia animal model; CON, non-FM animal model; FM-TIA, Tianeptine administered FM model.

• 

  Fig. 5 Effect of tianeptine on nociceptive response in FM model using digital von Frey. (A) Results of the right hind paw. (B) Results of the left hind paw. Withdrawal responses to von Frey filaments from both hind paws were counted and then expressed as an average in gram (n=7 per group). Comparison was made between CON and FM groups. Data are presented as means±SEM (*p<0.05 vs. CON; †p<0.05 vs. FM). PWT, paw withdrawal threshold; FM, Fibromyalgia animal model; CON, non-FM animal model; FM-TIA, Tianeptine administered FM model.

• 

  Fig. 6 Western blot analysis of BDNF, p-CREB, and CREB in mPFC. (A) Expression levels of BDNF, p-CREB, and CREB were detected by western blot analysis using anti-β-tubulin antibody as an internal control. Graph demonstrating the ratio of p-CREB or BDNF to Tubb. (B~D) Quantitative analysis of western blot results for BDNF, pCREB, CREB expression levels in the medial prefrontal cortex (*p<0.05 vs. CON; †p<0.05 vs. FM). FM, Fibromyalgia animal model; CON, non-FM animal model; FM-TIA, Tianeptine administered FM model.

• 

  Fig. 7 Western blot analysis of BDNF, p-CREB, and CREB in hippocampus. (A) Expression levels of BDNF, CREB, and CREB were detected by western blot analysis using anti-β-tubulin antibody as an internal control. Graph demonstrating the ratio of p-CREB or BDNF to Tubb quantified using ImageJ software. (B~D) Quantitative analysis of western blot results of BDNF, pCREB, an CREB in the hippocampus (*p<0.05 vs. CON; †p<0.05 vs. FM). FM, Fibromyalgia animal model; CON, non-FM animal model; FM-TIA, Tianeptine administered FM model.

• 

  Fig. 8 Patterns of p-CREB expression across the hippocampus in the FM model and tianeptine-administered FM model group. (A) Immunohistochemistry analysis showing p-CREB immunoreactivity in the hippocampus. Confocal microscopy image showed immunofluorescent staining for p-CREB (anti-p-CREB, red, Cy3) with DAPI (blue) in CA3 region of hippocampus. Scale bar, 50 µm. (B) Optical densities of p-CREB signals in immunostained hippocampus sections (*p<0.05 vs. CON; †p<0.05 vs. FM). (C) Confocal microscopy image showing immunofluorescent staining for CREB (anti-CREB, red, Cy3) with DAPI (blue) in the hippocampus. Scale bar, 50 µm. (D) Optical densities of CREB signals in immunostained hippocampus sections (*p<0.05 vs. CON; †p<0.05 vs. FM). Quantitative measurements of p-CREB, CREB, BDNF, and β-tubulin proteins were obtained using ImageJ software (http://imagej.nih.gov/ij). HIPP, hippocampus; FM, Fibromyalgia animal model; CON, non-FM animal model; FM-TIA, Tianeptine administered FM model; p-CREB, phospho CREB; CREB, cAMP response element-binding protein.

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