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The present study reports the beneficial effects of an anti-mouse interleukin-6 (IL-6) receptor antibody (MR16-1) on neuropathic pain in mice with spinal cord injury (SCI). Following laminectomy, contusion SCI models were produced using an Infinite Horizon (IH)-impactor. MR16-1 was continuously injected for 14 days using Alzet osmotic pumps. A mouse IL-6 ELISA kit was then used to analyze IL-6 levels in the spinal cord tissue between 12 and 72 h after injury. Motor and sensory functions were evaluated each week using the Basso Mouse Scale (BMS), plantar von Frey and thermal threshold tests. Histological examinations were performed 42 days after SCI. Between 24 and 72 h after SCI, the expression levels of IL-6 were significantly decreased in the MR16-1 treated group. Six weeks after surgery, the BMS score of the MR16-1-treated group indicated significant recovery of neurological functions. MR16-1-treated mice in the SCI group exhibited lower paw withdrawal thresholds in the plantar von Frey and thermal tests, which were used to evaluate allodynia. MR16-1 treatment significantly increased the area of Luxol fast blue-stained tissue, representing spared myelin sheaths. These results indicate that the continuous inhibition of IL-6 signaling by MR16-1 between the early and sub-acute phases following SCI leads to neurological recovery and the suppression of hyperalgesia and allodynia. Overall, our data suggest that the inhibition of severe inflammation may be a promising neuroprotective approach to limit secondary injury following SCI and that an anti-IL-6 receptor antibody may have clinical potential for the treatment of SCI.

The purpose of this study was to examine the effects of mild hypothermia and hyperthermia on glutamate excitotoxicity. Glutamate-induced cortical lesions were produced in hypothermic (32 degrees C), normothermic (37 degrees C), and hyperthermic (40 degrees C) rats by perfusion of a 0.5 M glutamate solution via a microdialysis probe. The volume of the lesion 7 days after glutamate perfusion was quantified histologically by image analysis. This histological assessment was performed in two experiments; in one, each of the target temperatures was induced before glutamate perfusion, and in the other, each of the target temperatures was induced after stopping the glutamate perfusion. We also examined the effect of temperature on the diffusion of exogenously delivered material in the extracellular space using autoradiography of the perfused glutamate solution containing 14C-labeled sucrose. In the two experiments in which each of the target temperatures was induced before or after glutamate perfusion, the volume of damage was reduced by mild hypothermia and enlarged by mild hyperthermia. The volume of 14C diffusion also increased as brain temperature increased. These results provide evidence that small variations of brain temperature modify glutamate excitotoxicity. The results also suggest that the change in glutamate diffusion in the extracellular space is one mechanism by which mild hypothermia and hyperthermia exert their protective and harmful effects respectively.

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.