Sleep deprivation makes rats more vulnerable to nerve injury-induced neuropathic pain, probably because of associated lower melatonin levels. Melatonin supplements to restore a circadian variation in melatonin concentrations during the sleep deprived period could alleviate nerve injury-induced behavioral hypersensitivity.

In this study, we examined the relationship between astrocyte activation in the cuneate nucleus (CN) and behavioral hypersensitivity after chronic constriction injury (CCI) of the median nerve. In addition, we also examined the effects of pre-emptive treatment with a number of drugs on astrocyte activation and hypersensitivity development in this model. Using immunohistochemistry and immunoblotting, little glial fibrillary acidic protein (GFAP; an astrocyte marker) immunoreactivity was detected in the CN of the normal rats. As early as 3 days after CCI, there was a significant increase in GFAP immunoreactivity in the lesion side of CN, and this reached a maximum at 7 days, and was followed by a decline. Counting of GFAP-immunoreactive astrocytes revealed that astrocytic hypertrophy, but not proliferation, contributes to increased GFAP immunoreactivity. Furthermore, microinjection of the glial activation inhibitor, fluorocitrate, into the CN at 3 days after CCI attenuated injury-induced behavioral hypersensitivity in a dose-dependent manner. These results suggest that median nerve injury-induced astrocytic activation in the CN modulated the development of behavioral hypersensitivity. Animals received MK-801 (glutamate N-methyl-d-aspartate (NMDA) receptor antagonist), clonidine (alpha(2)-adrenoreceptor agonist), tetrodotoxin (TTX, sodium channel blocker) or lidocaine (local anesthetic) 30 min prior to median nerve CCI. Pre-treatment with MK-801, TTX, and 2% lidocaine, but not clonidine, attenuated GFAP immunoreactivity and behavioral hypersensitivity following median nerve injury. In conclusion, suppressing reactions to injury, such as the generation of ectopic discharges and activation of NMDA receptors, can decrease astrocyte activation in the CN and attenuate neuropathic pain sensations.

In this study, we examined the relationships between p38 mitogen-activated protein kinase (MAPK) activation in the cuneate nucleus (CN) and behavioral hypersensitivity after chronic constriction injury (CCI) of the median nerve. We further investigated effects of melatonin administration and pinealectomy on p38 MAPK activation and development of hypersensitivity. Using immunohistochemistry and immunoblotting, low levels of phosphorylated p38 (p-p38) MAPK were detected in CN of normal rats. As early as 1 day after CCI, p-p38 MAPK levels in the ipsilateral CN were significantly increased (1.4 ± 0.2-fold, P < 0.05), which reached a maximum at 7 days (5.1 ± 0.4-fold, P < 0.001). Double immunofluorescence labeling with cell-specific markers showed that p-p38 MAPK immunoreactive cells co-expressed OX-42, a microglia activation maker, suggesting the expression of p-p38 MAPK in microglia. Microinjection of SB203580, a p38 MAPK inhibitor, into the CN 1 day after CCI attenuated injury-induced behavioral hypersensitivity in a dose-dependent manner. Furthermore, animals received melatonin treatment at daily doses of 37.5, 75, 150, or 300 mg/kg from 30 min before until 3 days after CCI. Melatonin treatment dose-dependently attenuated p-p38 MAPK levels, release of pro-inflammatory cytokines, and behavioral hypersensitivity following CCI; conversely, pinealectomy that resulted in a reduction in endogenous melatonin levels exacerbated these effects. In conclusion, median nerve injury-induced microglial p38 MAPK activation in the CN modulated development of behavioral hypersensitivity. Melatonin supplementation eased neuropathic pain via inhibition of p38 MAPK signaling pathway; contrarily, reducing endogenous blood melatonin levels by pinealectomy promoted phosphorylation of p38 MAPK and made rats more vulnerable to nerve injury-induced neuropathic pain.

Lemierre syndrome is an extremely rare disease characterized by oropharyngeal infection, septicemia, internal jugular vein thrombosis, and skip lesions. The most common causative pathogen is Fusobacterium necrophorum. We reported a 45-year-old woman who presented with left neck painful swelling and septicemia. Magnetic resonance imaging of the head and neck demonstrated venous thrombosis extending from the left internal jugular vein to the sigmoid sinus. During admission we discovered that the patient had uncontrolled diabetes mellitus. We also found a metastatic lesion through chest radiography. Klebsiella pneumoniae was cultivated from both blood samples and pus from deep neck spaces. Surgical drainage, early and adequate antibiotic treatment, anticoagulation, and strict control of blood glucose led to the patient's complete recovery. Because Lemierre syndrome is a forgotten disease in the era of antibiotics, awareness of the signs and symptoms of this disease is important because of its associated high mortality rate. This case illustrated that the presence of K pneumoniae can lead to Lemierre syndrome.