Cellular and Molecular Neurobiology

, Volume 34, Issue 8, pp 1199–1208 | Cite as

Imipramine Ameliorates Pain-related Negative Emotion via Induction of Brain-derived Neurotrophic Factor

  • Seiko Yasuda
  • Mitsuhiro Yoshida
  • Hirotaka Yamagata
  • Yasutake Iwanaga
  • Hiromi Suenaga
  • Kozo Ishikawa
  • Masako Nakano
  • Satoshi Okuyama
  • Yoshiko Furukawa
  • Shoei Furukawa
  • Toshizo IshikawaEmail author
Original Research


Depression-like behavior is often complicated by chronic pain. Antidepressants including imipramine (IMI) are widely used to treat chronic pain, but the mechanisms are not fully understood. Brain-derived neurotrophic factor (BDNF) is a neuromodulator that reduces depression by regulating synaptic transmission. We aimed to characterize the antidepressant effects of IMI without analgesia based on BDNF (trkB)-mediated signaling and gene expression in chronic pain. A chronic constriction injury (CCI) model was constructed in Sprague-Dawley (SD) rats. IMI (5 mg/kg, i.p.) was administered from day 10 after CCI. The pain response was assessed using the paw withdrawal latency (PWL) and depression was judged from the immobility time in a forced swim test. Anti-BDNF antibody, K252a, or 5,7-dihydroxytryptamine (5,7-DHT) were used to examine the antidepressant effects of imipramine. Changes in pERK1/2 (immunohistochemistry), 5-HT and BDNF (ELISA), and BDNF mRNA (RT-PCR) were measured in the anterior cingulate cortex (ACC), rostral ventromedial medulla (RVM), and spinal cord. After CCI, rats showed decreased PWL and increased immobility time. A low dose of IMI reduced the immobility time without having analgesic effects. This antidepressant effect was reversed by anti-BDNF antibody, K252a, and 5,7-DHT. IMI reduced excessive activation of pERK1/2 associated with decreased pCREB and BDNF mRNA, and these changes were reversed by 5,7-DHT. These results show that IMI reduces pain-related negative emotion without influencing pain and that this effect is diminished by denervation of 5-HT neurons and by anti-BDNF treatment. IMI also normalizes derangement of ERK/CREB coupling, which leads to induction of BDNF. This suggests a possible interaction between 5-HT and BDNF.


Chronic pain Pain-related negative emotion 5-HT BDNF pERK1/2 



This study was supported in part by Scientific Research Grant No. 15390475 to TI from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Conflict of interest

The authors confirm that this article content has no conflicts of interest.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Seiko Yasuda
    • 1
  • Mitsuhiro Yoshida
    • 1
    • 2
  • Hirotaka Yamagata
    • 3
  • Yasutake Iwanaga
    • 1
  • Hiromi Suenaga
    • 1
  • Kozo Ishikawa
    • 1
    • 4
  • Masako Nakano
    • 4
  • Satoshi Okuyama
    • 5
  • Yoshiko Furukawa
    • 5
  • Shoei Furukawa
    • 6
  • Toshizo Ishikawa
    • 1
    Email author
  1. 1.Division of NeurosciencesYamaguchi University Graduate School of MedicineUbeJapan
  2. 2.Division of Dental Anesthesiology, Department of Control of Physical FunctionsKyushu Dental UniversityKitakyushuJapan
  3. 3.Department of PsychiatryYamaguchi University Graduate School of MedicineUbeJapan
  4. 4.Department of 2nd AnatomySapporo Medical UniversitySapporoJapan
  5. 5.Department of Pharmaceutical Pharmacology, College of Pharmaceutical SciencesMatsuyama UniversityMatsuyamaJapan
  6. 6.Laboratory of Molecular Biology, Department of Biofunctional AnalysisGifu Pharmaceutical UniversityGifuJapan

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