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


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.


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



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


  1. Alkon DL, Epstein H, Kuzirian A, Bennett MC, Nelson TJ (2005) Protein synthesis required for long-term memory is induced by PKC activation on days before associative learning. Proc Natl Acad Sci USA 102:16432–16437PubMedCrossRefGoogle Scholar
  2. Beck T, Lindholm D, Castren E, Wree A (1994) Brain-derived neurotrophic factor protects against ischemic cell damage in rat hippocampus. J Cereb Blood Flow Metab 14:689–692PubMedCrossRefGoogle Scholar
  3. Bennett GJ, Xie YK (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in men. Pain 33:87–107PubMedCrossRefGoogle Scholar
  4. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS (2000) Hippocampal volume reduction in major depression. Am J Psychiatry 157(1):115–118PubMedGoogle Scholar
  5. Cejas PJ, Martinez M, Karmally S, McKillop M, McKillop J, Plunkett JA, Oudega M, Eaton M (2000) Lumber transplant of neurons genetically modified to secrete brain-derived neurotrophic factor attenuates allodynia and hyperalgesia after sciatic nerve constriction. Pain 86:195–210PubMedCrossRefGoogle Scholar
  6. Fukumitsu H, Sometani A, Ohmiya M, Nitta A, Nomoto H, Furukawa Y, Furukawa S (1999) Induction of a physiologically active brain-derived neurotrophic factor in the infant rat brain by peripheral administration of 4-methylcatechol. Neurosci Lett 274:115–118PubMedCrossRefGoogle Scholar
  7. Furukawa Y, Tomioka N, Sato W, Satoyoshi E, Hayashi K, Furukawa S (1989) Catecholamine increase nerve growth factor mRNA content in both mouse astroglial cells and fibroblast cells. FEBS Lett 247:463–467PubMedCrossRefGoogle Scholar
  8. Gao YJ, Ji RR (2009) c-Fos and pERK, which is a better marker for neuronal activation and central sensitization after noxious stimulation and tissue injury? Open Pain J 2:11–17PubMedCrossRefGoogle Scholar
  9. Hanaoka Y, Ohi T, Furukawa S, Furukawa Y, Hayashi K, Matsukura S (1994) The therapeutic effects of 4-methylcatechol, a stimulator of endogenous nerve growth factor synthesis, on experimental diabetic neuropathy in rats. J Neurol Sci 122:28–32PubMedCrossRefGoogle Scholar
  10. Heldt SA, Stanek L, Chhatwal JP, Ressler KJ (2007) Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol Psychiatry 12(7):656–670PubMedCrossRefGoogle Scholar
  11. Henderson CE, Bloch-Gallego E, Camu W, Gouin A, Mettling C (1993) Neurotrophic factors in development and plasticity of spinal neurons. Restor Neurol Neurosci 5(1):15–28PubMedGoogle Scholar
  12. Hohn A, Leibrock J, Bailey K, Barde YA (1990) Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family. Nature 344(6264):339–341PubMedCrossRefGoogle Scholar
  13. Ishikawa K (2011) Possible involvement of brain-derived neurotrophic factor in analgesic effects of 4-methylcatechol on neuropathic pain. Bull Yamaguchi Med Sch 57(3–4):49–55Google Scholar
  14. Ishikawa T, Marsala M, Sakabe T, Yaksh TL (2001) Characterization of spinal amino acid release and touch-evoked allodynia produced by spinal glycine or GABA-A receptor antagonist. Neuroscience 98:781–786Google Scholar
  15. Kaechi K, Ikegami R, Nakamura N, Nakajima M, Furukawa Y, Furukawa S (1995) 4-Methylcatechol, an inducer of nerve growth factor synthesis, enhances peripheral nerve regeneration across nerve gaps. J Pharmacol Exp Ther 272(3):1300–1304PubMedGoogle Scholar
  16. Kafitz KW, Rose CR, Thoenen H, Konnerth A (1999) Neurotrophin-evoked rapid excitation through TrkB receptors. Nature 401(6756):918–921PubMedCrossRefGoogle Scholar
  17. Kourounakis A, Bodor N, Simpkins J (1997) Synthesis and evaluation of brain-targeted chemical delivery systems for the neurotrophomodulator 4-methylcatechol. J Pharm Pharmacol 49:1–9PubMedCrossRefGoogle Scholar
  18. Levivier M, Przedborski S, Bencsics C, Kang UJ (1995) Intrastriatal implantation of fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevents degeneration of dopaminergic neurons in a rat model of Parkinson’s disease. J Neurosci 15(12):7810–7820PubMedGoogle Scholar
  19. Merighi A, Salio C, Ghirri A, Lossi L, Ferrini F, Betelli C, Bardoni R (2008) BDNF as a pain modulator. Prog Neurobiol 85:297–317PubMedCrossRefGoogle Scholar
  20. Moore KA, Kohno T, Karchewski LA, Scholz J, Baba H, Woolf CJ (2002) Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J Neurosci 22:6724–6731PubMedGoogle Scholar
  21. Nitta A, Itoh M, Fukumitsu H, Ohmiya M, Sometani A, Nomoto H, Furukawa Y, Furukawa S (1999) 4-Methylcatechol increases brain-derived neurotrophic factor content and mRNA expression in cultured brain cells or in vivo brain of rats. J Pharmacol Exp Ther 291:1276–1283PubMedGoogle Scholar
  22. Pardridge WM, Kang WS, Buciak JL (1994) Transport of human recombinant brain-derived neurotrophic factor (BDNF) through the rat blood–brain barrier in vivo using vector-mediated peptide drug delivery. Pharm Res 11:738–746PubMedCrossRefGoogle Scholar
  23. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, New YorkGoogle Scholar
  24. Phillips HS, Hains JM, Laramee GR, Rosenthal A, Winslow JW (1990) Wide-spread expression of BDNF but not NT-3 by target areas of basal forebrain cholinergic neuron. Science (Wash DC) 250:290–294CrossRefGoogle Scholar
  25. Porsolt RD, Anton G, Blavet N, Jalfre M (1978) Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 47(4):379–391PubMedCrossRefGoogle Scholar
  26. Saita K, Ohi T, Hanaoka Y, Furukawa S, Furukawa Y, Hayashi K, Matsukura S (1996) A catechol derivative (4-methylcatechol) accelerates the recovery from experimental acrylamide-induced neuropathy. J Pharmacol Exp Ther 276:231–237PubMedGoogle Scholar
  27. Schmidt HD, Duman RS (2007) The role of neurotrophic factors in adult hippocampal neurogenesis, anti-depressant treatments and animal models of depressive-like behavior. Behav Pharmacol 18:391–418PubMedCrossRefGoogle Scholar
  28. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW (1996) Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA 93(9):3908–3913PubMedCrossRefGoogle Scholar
  29. Sun MK, Alkon DL (2002) Depressed or demented: common CNS drug targets? Curr Drug Targets—CNS Neurol Disord 1:575–592PubMedCrossRefGoogle Scholar
  30. Sun M-K, Alkon DL (2005) Protein kinase C isozymes: memory therapeutic potential. Curr Drug Targets CNS Neurol Disord 4(5):541–552PubMedCrossRefGoogle Scholar
  31. Sun M-K, Alkon DL (2008) Effects of 4-methylcatechol on spatial memory and depression. Neuroreport 19(3):355–359PubMedCrossRefGoogle Scholar
  32. Svensson CI, Marsala M, Westerlund A, Calcutt NA, Campana WM, Freshwater JD, Catalano R, Feng Y, Protter AA, Scott B, Yaksh TL (2003) Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem 86:1534–1544PubMedCrossRefGoogle Scholar
  33. Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME (1998) Ca21 influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20:709–726PubMedCrossRefGoogle Scholar
  34. Tsukahara T, Takeda M, Shimohama S, Ohara O, Hashimoto N (1995) Effects of brain-derived neurotrophic factor on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced pakinsonism in monkeys. Neurosurgery 37:733–739PubMedCrossRefGoogle Scholar
  35. Woolf CJ, Salter MW (2000) Neuronal plasticity: increasing the gain in pain. Science 288:1765–1769PubMedCrossRefGoogle Scholar
  36. Zafra F, Lindholm D, Castren E, Hartikka J, Thoenen H (1992) Regulation of brain-derived neurotrophic factor and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes. J Neurosci 12:4793–4799PubMedGoogle Scholar
  37. Zhou J, Pliego-Rivero B, Bradford HF, Stern GM (1996) The BDNF content of postnatal and adult rat brain: the effects of 6-hydroxydopamine lesions in adult brain. Brain Res Dev 97:297–303CrossRefGoogle Scholar
  38. Zhuang ZY, Gerne P, Woolf CJ, Ji RR (2005) ERK is sequentially activated in neuron, microglia, and, astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 114:149–159PubMedCrossRefGoogle Scholar
  39. Zhuo M (2007) Neuronal mechanism for neuropathic pain. Mol Pain 3:14PubMedCrossRefGoogle Scholar

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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