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Intracerebroventricular 4-Methylcatechol (4-MC) Ameliorates Chronic Pain Associated with Depression-Like Behavior via Induction of Brain-Derived Neurotrophic Factor (BDNF)

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Abstract

Neuropathic pain concurrent with mood disorder from peripheral nerve injury is a serious clinical problem that significantly affects quality of life. Recent studies have suggested that a lack of brain-derived neurotrophic factor (BDNF) in the limbic system may cause this pain–emotion. BDNF is induced in cultured neurons by 4-methylcatechol (4-MC), but the role of 4-MC-induced BDNF in pain–emotion is poorly understood. Thus, we assessed the possible involvement of BDNF in brain in depression-like behavior during chronic pain following peripheral nerve injury. In addition, we examined whether intracerebroventricular (i.c.v.) 4-MC prevents chronic pain in rats and produces an antidepressant effect. Sprague–Dawley rats implanted intracerebroventricularly with a PE-10 tube were subjected to chronic constriction injury (CCI). Pain was assessed by a reduction in paw withdrawal latency (PWL) to heat stimuli after CCI. We also used a forced swimming testing (FST; time of immobility, in seconds) from day 14 to day 21 after CCI. Modulation of pain and emotional behavior was performed by injection of PD0325901 (a MEK1/2 inhibitor). 4-MC (100 nM) was continuously administered i.c.v. for 3 days during the period from day 14 to day 21 after CCI. To block analgesic and antidepressant effects, anti-BDNF antibody or K252a (a TrkB receptor inhibitor) was injected in combination with 4-MC. Naloxone was also coadministered to confirm the analgesic effect of 4-MC. During the chronic stage after CCI, the rats showed a sustained decrease in PWL (thermal hyperalgesia) associated with extension of the time of immobility (depression-like behavior). PD0325901 significantly reduced the decrease in PWL and the increased time of immobility after CCI. The decreased PWL and increased time of immobility were also reduced by 4-MC and by treatment with an ERK1/2 inhibitor. These effects of 4-MC i.c.v. were reversed by anti-BDNF and K252a. The analgesic effect of 4-MC i.c.v. was also antagonized by naloxone. Based on these results, we suggest that a lack of BDNF and activation of ERK1/2 in the pain–emotion network in the CNS may be involved in depression-like behavior during chronic pain. 4-MC i.c.v. ameliorates chronic pain and depression-like behavior by producing of BDNF and normalization of ERK1/2 activation. Therefore, enhancement of BDNF may be a new treatment strategy for chronic pain associated with depression.

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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. We are grateful to Prof. S. Furukawa (Gifu Pharmacological College) for advice on 4-methylcatechol.

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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

    Kayoko Fukuhara, Kozo Ishikawa, Seiko Yasuda, Yusuke Kishishita, Misa Yamamoto & Toshizo Ishikawa

  2. Department of Food and Nutrition, Ube Frontier College, 5-40 Bunkyo, Ube, Yamaguchi, 755-8550, Japan

    Kayoko Fukuhara & Takafumi Norii

  3. Department of Anesthesia and Pain Medicine, Pusan National University School of Medicine 1-10, Ami-dong, Seo-gu, Busan, 602-739, Korea

    Hae-Kyu Kim

  4. Department of Nursing, Faculty of Health and Welfare, Kawasaki University of Medical Welfare, 288 Matsushima, Kurashiki, Okayama, 701-0193, Japan

    Takahiro Kakeda

  5. Department of Laboratory Sciences, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan

    Toshizo Ishikawa

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  1. Kayoko Fukuhara
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  8. Takafumi Norii
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  9. Toshizo Ishikawa
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Correspondence to Toshizo Ishikawa.

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Fukuhara, K., Ishikawa, K., Yasuda, S. et al. Intracerebroventricular 4-Methylcatechol (4-MC) Ameliorates Chronic Pain Associated with Depression-Like Behavior via Induction of Brain-Derived Neurotrophic Factor (BDNF). Cell Mol Neurobiol 32, 971–977 (2012). https://doi.org/10.1007/s10571-011-9782-2

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