Behavioural NeuroscienceUltra-low dose naloxone restores the antinociceptive effect of morphine in pertussis toxin–treated rats and prevents glutamate transporter downregulation by suppressing the p38 mitogen-activated protein kinase signaling pathway
Section snippets
Animal preparation and intrathecal drug delivery
One hundred twenty-three 8-week-old male Wistar rats (320–370 g) were anaesthetized with phenobarbital (65 mg/kg, intraperitoneally; Sigma, MO, USA) and implanted with an intrathecal catheter; in 33, a microdialysis probe was also inserted via the atlanto-occipital membrane down to spinal cord segments L5–S3 for CSF dialysate collection. After catheterization, the rats were housed individually in their home cages for recovery and maintained on a 12-h light/dark cycle, with food and water freely
Ultra-low dose naloxone reverses PTX-induced mechanical allodynia
Fig. 1 shows the time course of the mechanical PWT test (A) and the area under the curve (AUC) for the results in A (B). The baseline value for the PWT in naïve rats was 49.32±0.23 g (n=5). Intrathecal morphine injection had no effect on the normal baseline. Four days after intrathecal PTX injection, the rats displayed a significant reduction in the mechanical PWT, with an average PWT of 27.73±3.96 g. Intrathecal injection of morphine (10 μg) resulted in a significant reversal of the reduction
Discussion
In the present study, PTX was found to induce p38 MAPK phosphorylation in the rat spinal cord dorsal horn, and this was attenuated by ultra-low dose naloxone. In addition, the p38 MAPK inhibitor SB203580 partially reversed the reduction of the antinociceptive effect of morphine, increase in CSF EAA levels, and the activation of microglia seen in PTX-treated rats. These results show that the suppressive effect of ultra-low dose naloxone on neuroinflammation and the increase in CSF EAAs in
Conclusion
Taking together our previous study (Tsai et al., 2008) and the present results, the possible cellular mechanisms of ultra-low dose of naloxone in treating neuropathic pain of PTX-treated rats are described in Fig. 11. PTX-treatment (1) inhibited glutamate metabolism enzyme glutamate dehydrogenase (GDH) and glutamine synthase (GS), which results in an increasing of EAAs accumulation in the synaptic junction, (2) increased P-p38 MAPK and pro-inflammatory cytokines expression, (3) subsequently
Acknowledgments
This study was supported by grants from the National Health Research Institutes, Taiwan (NHRI-EX97-9401NP), Tri-Service General Hospital (TSGH-C97-71), and the Chi-Mei Medical Center (CMNDMC9719). It was performed at the Nociception Signal Transduction Laboratory, Department of Anesthesiology, Tri-service General Hospital and the National Defense Medical Center.
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