title: Intracerebroventricular 4-methylcatechol (4-MC) ameliorates chronic pain associated with depression-like behavior via induction of brain-derived neurotrophic factor (BDNF).
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.
authors.affiliation: Division of Neurosciences, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Fukuhara
authors.forename: Kozo
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Seiko
authors.initials: S
authors.lastname: Yasuda
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kishishita
authors.forename: Hae-Kyu
authors.initials: HK
authors.lastname: Kim
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kakeda
authors.forename: Misa
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Takafumi
authors.initials: T
authors.lastname: Norii
authors.forename: Toshizo
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002396:Catechols / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D059350:Chronic Pain / Q000150:complications* / Q000188:drug therapy*; D003863:Depression / Q000150:complications / Q000188:drug therapy*; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D007276:Injections, Intraventricular; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012149:Restraint, Physical
chemical_list: D000700:Analgesics; D000928:Antidepressive Agents; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D002396:Catechols; C018599:4-methylcatechol; C506614:mirdametinib; D004159:Diphenylamine