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

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Abstract

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.

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Acknowledgments

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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Authors and Affiliations

  1. Division of Neurosciences, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan

    Seiko Yasuda, Mitsuhiro Yoshida, Yasutake Iwanaga, Hiromi Suenaga, Kozo Ishikawa & Toshizo Ishikawa

  2. Division of Dental Anesthesiology, Department of Control of Physical Functions, Kyushu Dental University, 2-1-6, Manazuru, Kokurakita, Kitakyushu, 803-8580, Japan

    Mitsuhiro Yoshida

  3. Department of Psychiatry, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan

    Hirotaka Yamagata

  4. Department of 2nd Anatomy, Sapporo Medical University, 17-Minami 1 Jou-Nishi, Chuou-ku, Sapporo, 060-8556, Japan

    Kozo Ishikawa & Masako Nakano

  5. Department of Pharmaceutical Pharmacology, College of Pharmaceutical Sciences, Matsuyama University, 4-2, Bunkyo-cho, Matsuyama, Ehim, 790-8578, Japan

    Satoshi Okuyama & Yoshiko Furukawa

  6. Laboratory of Molecular Biology, Department of Biofunctional Analysis, Gifu Pharmaceutical University, Daigaku-nishi 1-25-4, Gifu, 501-1196, Japan

    Shoei Furukawa

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  1. Seiko Yasuda
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  2. Mitsuhiro Yoshida
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  10. Shoei Furukawa
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  11. Toshizo Ishikawa
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Correspondence to Toshizo Ishikawa.

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Yasuda, S., Yoshida, M., Yamagata, H. et al. Imipramine Ameliorates Pain-related Negative Emotion via Induction of Brain-derived Neurotrophic Factor. Cell Mol Neurobiol 34, 1199–1208 (2014). https://doi.org/10.1007/s10571-014-0097-y

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  • DOI: https://doi.org/10.1007/s10571-014-0097-y

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