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.

Sex differences in depression-like behavior after nerve injury are associated with differential changes in brain-derived neurotrophic factor levels in mice subjected to early life stress

“…On the other hand, neuropathic pain decreased the levels of BDNF in the hippocampus [36]. The intracerebroventricular administration of 4-methylcatechol, a potent stimulator of BDNF synthesis, decreased the depression-like behavior induced by neuropathic pain [37]. Therefore, sex-specific changes in BNDF levels after stress in early life may contribute to differential susceptibility to the effects of neuropathic pain on emotional function.…”

m-Trifluoromethyl-diphenyl diselenide, a multi-target selenium compound, prevented mechanical allodynia and depressive-like behavior in a mouse comorbid pain and depression model

“…We also found a reduction of brain-derived neurotrophic factor (BDNF) levels in the contralateral cortices and hippocampi of mice after 4 weeks of PSNL that may be an effect of increased levels of cytokines and corticosterone (Koo and Duman, 2008;Liu et al, 2003) and acute and subchronic treatments with (m-CF 3 -PhSe) 2 were effective in restoring the BDNF levels in both regions. The lack of BDNF in the limbic system has been related to pathophysiology of depression and also to neuropathic pain concurrent with mood disorders (Duman and Monteggia, 2006;Fukuhara et al, 2012).…”

The hippocampus and TNF: Common links between chronic pain and depression

“…Thus, the administration of 4-methylcatechol, a potent stimulator of BDNF synthesis (Furukawa et al, 1989;Kourounakis et al, 1997), may exert antidepressant and analgesic effects on chronic pain via induction of BDNF in the brain (Fukuhara et al, 2012). Therefore, specifically increasing BDNF may be a novel treatment strategy for chronic pain associated with depression.…”