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Cellular and Molecular Neurobiology

, Volume 32, Issue 6, pp 971–977 | Cite as

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

  • Kayoko Fukuhara
  • Kozo Ishikawa
  • Seiko Yasuda
  • Yusuke Kishishita
  • Hae-Kyu Kim
  • Takahiro Kakeda
  • Misa Yamamoto
  • Takafumi Norii
  • Toshizo IshikawaEmail author
Original Research

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.

Keywords

CCI Neuropathic pain Mood disorder BDNF 4-Methylcatechol ERK1/2 

Notes

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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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Kayoko Fukuhara
    • 1
    • 2
  • Kozo Ishikawa
    • 1
  • Seiko Yasuda
    • 1
  • Yusuke Kishishita
    • 1
  • Hae-Kyu Kim
    • 3
  • Takahiro Kakeda
    • 4
  • Misa Yamamoto
    • 1
  • Takafumi Norii
    • 2
  • Toshizo Ishikawa
    • 1
    • 5
    Email author
  1. 1.Division of NeurosciencesYamaguchi University Graduate School of MedicineUbeJapan
  2. 2.Department of Food and NutritionUbe Frontier CollegeUbeJapan
  3. 3.Department of Anesthesia and Pain MedicinePusan National University School of Medicine 1-10BusanKorea
  4. 4.Department of Nursing, Faculty of Health and WelfareKawasaki University of Medical WelfareKurashikiJapan
  5. 5.Department of Laboratory SciencesYamaguchi University Graduate School of MedicineUbeJapan

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