Modulation of Brain-derived Neurotrophic Factor Expression by Physical Exercise in Reserpine-induced Pain-depression Dyad in Mice

Abstract

Pain accompanied by depressive symptoms is a common reason for seeking medical assistance, and many chronic pain patients experience comorbid depression. The brain-derived neurotrophic factor (BDNF) is a well-known neurotrophin expressed throughout the nervous system, playing a crucial role in neuronal growth and neuroplasticity. This study aimed to examine the effects of exercise on BDNF expression in the nervous system and reserpine (RSP)-induced pain-depression dyad. RSP (1 mg/kg) was subcutaneously administered once daily for three days in mice. The exercise was performed using a rota-rod tester for seven consecutive days following RSP administration. Pain responses were evaluated using von Frey filaments, and depression-like behaviors were assessed through forced swimming and open field tests. Immunofluorescence staining was performed to examine the changes in BDNF expression in the dorsal root ganglion (DRG), spinal cord, and hippocampus. Administration of RSP reduced mechanical paw withdrawal threshold, increased immobility time in the forced swimming test, and decreased movement in the open field test. The immunoreactivity of BDNF was increased in the DRG and spinal dorsal regions, and decreased in the hippocampus after RSP administration. Physical exercise significantly reduced the RSP-induced mechanical hypersensitivity and depression-like behaviors. In addition, exercise suppressed not only the increased expression of BDNF in the DRG and spinal dorsal regions but also the decreased expression of BDNF in the hippocampus induced by RSP administration. These findings suggest that repetitive exercise could serve as an effective and non-invasive treatment option for individuals experiencing both pain and depression by modulating BDNF expression.

Keywords: Brain-derived neurotrophic factor; Depression; Exercise; Pain; Reserpine.

Fig. 1

Effects of different intensity (15 or 30 RPM) of exercise on the reserpine (RSP, 1 mg/kg)-induced pain and body weight variation in mice. (A, B) Physical exercise performed using a rota-rod tester at an intensity of 15 or 30 RPM inhibited the RSP-induced reduction of the paw withdrawal threshold (A). Area under curve was analyzed in control, RSP-treated, and RSP-treated exercised (15 or 30 RPM) groups (B). (C, D) The RSP-treated exercised (30 RPM) group of mice display lower body weight variation (%) relative to control mice (C). Area under the curve was analyzed and shown in D. (E) The number of falls in rota-rod tester during exercise was increased in the exercised group at an intensity of 30 RPM. n=5~7 mice/group. *p<0.05, **p<0.01, ***p<0.001 vs Control; ^#p<0.05, ^##p<0.01, ^###p<0.001 vs RSP; ^††p<0.01 vs RSP+EXR15.

Fig. 2

Effects of different intensity (15 or 30 RPM) of exercise on the reserpine (RSP, 1 mg/kg)-induced depression-like behaviors in mice. (A) Physical exercise performed using a rota-rod tester at an intensity of 15 or 30 RPM inhibited the RSP-induced increased immobility time (sec) during the forced swimming test. (B~D) Representative images for visualization of the path of movement during the open field test (B). The RSP-treated exercised (15 RPM) group of mice showed a significant increase in the total moved distance (C) and the number of crossings in the box during the open field test (D). n=5~7 mice/group. *p<0.05, **p<0.01, ***p<0.001 vs Control; ^#p<0.05, ^##p<0.01 vs RSP; ^†p<0.05, ^††p<0.01 vs RSP+EXR30.

Fig. 3

Effects of physical exercise (15 RPM), gabapentin (GBP, 50 mg/kg), and fluoxetine (FLU, 10 mg/kg) on BDNF immunoreactivity in the DRG, spinal cord, and hippocampus of reserpine (RSP, 1 mg/kg)-treated mice. (A~F) Physical exercise at an intensity of 15 RPM inhibited the RSP-induced changes in BDNF-immunoreactive area in the DRG (A, B), spinal cord dorsal horn (C, D), and hippocampus (E, F). Administration of GBP or FLU suppressed the RSP-induced modulation of BDNF expression, but less effectively than physical exercise. White dotted lines in C indicate the laminae I-V in the spinal cord dorsal horn, and those in E indicate the hippocampal subfields CA1 and the dentate gyrus (DG). Scale bar=20 µm. n=5~7 mice/group. ***p<0.001 vs Control; ^#p<0.05, ^###p<0.001 vs RSP; ^†p<0.05 vs RSP+GBP; ^‡p<0.05, ^‡‡p<0.01, ^‡‡‡p<0.001 vs RSP+FLU.

Fig. 4

Effects of physical exercise (15 RPM), gabapentin (GBP, 50 mg/kg), and fluoxetine (FLU, 10 mg/kg) on the reserpine (RSP, 1 mg/kg)-induced pain and body weight variation in mice. (A, B) Not only physical exercise at an intensity of 15 RPM but also GBP or FLU administration inhibited the RSP-induced reduction of the paw withdrawal threshold, but FLU was less effective than physical exercise and GBP administration (A). Area under curve was analyzed in control, RSP-treated, RSP-treated exercised (15 RPM), RSP and GBP-treated, RSP and FLU-treated groups (B). (C, D) There was no difference in body weight variation (%) between control and experimental groups (C). Area under the curve was analyzed and shown in D. n=10~14 mice/group. ^###p<0.001 vs RSP; ^‡‡‡p<0.001 vs RSP+FLU.

Fig. 5

Effects of physical exercise (15 RPM), gabapentin (GBP, 50 mg/kg), and fluoxetine (FLU, 10 mg/kg) on the reserpine (RSP, 1 mg/kg)-induced depression-like behaviors in mice. (A) Administration of GBP or FLU inhibited the RSP-induced increased immobility time (sec) during the forced swimming test, but less effectively than physical exercise. (B~D) Representative images for visualization of the path of movement during the open field test (B). Administration of GBP or FLU restored the RSP-induced decrease in the total moved distance (C) and the number of crossings in the box during the open field test, but less effectively than physical exercise (D). n=10~14 mice/group. ^##p<0.01, ^###p<0.001 vs RSP; ^†p<0.05, ^††p<0.01, ^†††p<0.001 vs RSP+GBP; ^‡p<0.05, ^‡‡p<0.01 vs RSP+FLU.