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Abstract
BackgroundNeuroinflammation and nitroxidative stress are implicated in the pathophysiology of neuropathic pain. In view of both processes, microglial and astroglial activation in the spinal dorsal horn play a predominant role. The present study investigated the severity of neuropathic pain and the degree of glial activation in an inflammatory- and nitroxidative-prone animal model.MethodsTransgenic rats expressing mutated superoxide dismutase 1 (hSOD1G93A) are classically used as a model for amyotrophic lateral sclerosis (ALS). Because of the associated inflammatory- and nitroxidative-prone properties, this model was used to study thermal and mechanical hypersensitivity following partial sciatic nerve ligation (PSNL). Next to pain hypersensitivity assessment, microglial and astroglial activation states were moreover characterized, as well as inflammatory marker gene expression and the glutamate clearance system.ResultsPSNL induced thermal and mechanical hypersensitivity in both wild-type (WT) and transgenic rats. However, the degree of thermal hypersensitivity was found to be exacerbated in transgenic rats while mechanical hypersensitivity was only slightly and not significantly increased. Microglial Iba1 expression was found to be increased in the ipsilateral dorsal horn of the lumbar spinal cord after PSNL but such Iba1 up-regulation was enhanced in transgenic rats as compared WT rats, both at 3 days and at 21 days after injury. Moreover, mRNA levels of Nox2, a key enzyme in microglial activation, but also of pro-inflammatory markers (IL-1β and TLR4) were not modified in WT ligated rats at 21 days after PSNL as compared to WT sham group while transgenic ligated rats showed up-regulated gene expression of these 3 targets. On the other hand, the PSNL-induced increase in GFAP immunoreactivity spreading that was evidenced in WT rats was unexpectedly found to be attenuated in transgenic ligated rats. Finally, GLT-1 gene expression and uptake activity were shown to be similar between WT sham and WT ligated rats at 21 days after injury, while both parameters were significantly increased in the ipsilateral dorsal region of the lumbar spinal cord of hSOD1G93A rats.ConclusionsTaken together, our findings show that exacerbated microglial activation and subsequent inflammatory and nitroxidative processes are associated with the severity of neuropathic pain symptoms.
Highlights
Neuroinflammation and nitroxidative stress are implicated in the pathophysiology of neuropathic pain
The increase in ionized-calcium binding adaptor molecule 1 (Iba1) gene expression induced by partial sciatic nerve ligation (PSNL) was significantly higher in transgenic rats as compared to WT animals
At 21 days post surgery (Figure 1B), Iba1 gene expression appeared significantly increased in both ligated groups, but mRNA levels were clearly and significantly higher in samples from transgenic ligated rats when compared with WT ligated rats
Summary
Neuroinflammation and nitroxidative stress are implicated in the pathophysiology of neuropathic pain In view of both processes, microglial and astroglial activation in the spinal dorsal horn play a predominant role. To pain hypersensitivity assessment, microglial and astroglial activation states were characterized, as well as inflammatory marker gene expression and the glutamate clearance system. Glial cells become activated, as classically characterized by hypertrophied morphology, increased proliferation and up-regulation of specific markers, like ionized-calcium binding adaptor molecule 1 (Iba1) for microglia, or glial fibrillary acidic protein (GFAP) for astroglia [6,7]. Among many different glial activation states, some have been related to neuropathic pain [8], characterized notably by up-regulation of pro-inflammatory proteins such as Toll-like receptor 4 (TLR4) [9] or NADPH oxidase 2 (Nox2) [10]. Activation of astrocytes may interfere with the capacity of these cells to buffer the excitatory transmitter glutamate, through altered expression and/ or function of astroglial glutamate transporters, GLAST and GLT-1, thereby affecting the pain synapse [12,13,14]
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