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Enhanced neuroinflammation and pain hypersensitivity after peripheral nerve injury in rats expressing mutated superoxide dismutase 1.

Berger JV, Deumens R, Goursaud S, Schäfer S, Lavand'homme P, Joosten EA, Hermans E - J Neuroinflammation (2011)

Bottom Line: 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.Taken together, our findings show that exacerbated microglial activation and subsequent inflammatory and nitroxidative processes are associated with the severity of neuropathic pain symptoms.

View Article: PubMed Central - HTML - PubMed

Affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.

ABSTRACT

Background: 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. The present study investigated the severity of neuropathic pain and the degree of glial activation in an inflammatory- and nitroxidative-prone animal model.

Methods: Transgenic rats expressing mutated superoxide dismutase 1 (hSOD1 G93A) 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.

Results: PSNL 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 hSOD1 G93A rats.

Conclusions: Taken together, our findings show that exacerbated microglial activation and subsequent inflammatory and nitroxidative processes are associated with the severity of neuropathic pain symptoms.

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Rats expressing hSOD1G93A show enhanced pain hypersensitivity after PSNL. Rats were tested for thermal and mechanical hypersensitivity for 21 days after surgery. Paw withdrawal latencies (PWL) of the ipsilateral (A) or contralateral (B) hind paws after thermal stimulation, expressed as a percentage of the baseline PWL. PSNL induced a decrease of PWL in both WT and hSOD1G93A rats on the ipsilateral side, compared to their respective sham controls (statistics not shown). The ANOVA repeated measures revealed enhanced pain hypersensitivity for hSOD1G93A rats compared to WT rats after PSNL. (C,D) 50% paw withdrawal threshold (PWT) of the ipsilateral (C) or contralateral (D) hind paws after mechanical stimulation, expressed in grams. PSNL triggered mechanical hypersensitivity in both WT and transgenic rats (statistics not shown), but no statistical difference was evidenced between WT and transgenic rats after ligation. (E-H) Area under the curve (AUC) analysis of the corresponding graph confirmed the enhanced ipsilateral thermal hypersensitivity in transgenic rats compared to WT rats after PSNL (#p < 0.05), while mechanical hypersensitivity only tends to be amplified in transgenic rats after lesion (p = 0.08); ANOVA and Tukey post-hoc test. Each group included 6 to 8 animals.
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Figure 2: Rats expressing hSOD1G93A show enhanced pain hypersensitivity after PSNL. Rats were tested for thermal and mechanical hypersensitivity for 21 days after surgery. Paw withdrawal latencies (PWL) of the ipsilateral (A) or contralateral (B) hind paws after thermal stimulation, expressed as a percentage of the baseline PWL. PSNL induced a decrease of PWL in both WT and hSOD1G93A rats on the ipsilateral side, compared to their respective sham controls (statistics not shown). The ANOVA repeated measures revealed enhanced pain hypersensitivity for hSOD1G93A rats compared to WT rats after PSNL. (C,D) 50% paw withdrawal threshold (PWT) of the ipsilateral (C) or contralateral (D) hind paws after mechanical stimulation, expressed in grams. PSNL triggered mechanical hypersensitivity in both WT and transgenic rats (statistics not shown), but no statistical difference was evidenced between WT and transgenic rats after ligation. (E-H) Area under the curve (AUC) analysis of the corresponding graph confirmed the enhanced ipsilateral thermal hypersensitivity in transgenic rats compared to WT rats after PSNL (#p < 0.05), while mechanical hypersensitivity only tends to be amplified in transgenic rats after lesion (p = 0.08); ANOVA and Tukey post-hoc test. Each group included 6 to 8 animals.

Mentions: Hypersensitivity to thermal and mechanical stimulation of hind paws was monitored during 21 days after sham or PSNL surgery, in both WT and transgenic rats (Figure 2). Noteworthy, uninjured WT and hSOD1G93A rats showed similar baseline paw withdrawal latencies (PWL) and paw withdrawal thresholds (PWT). After PSNL however, a clear and significant decline in the withdrawal latency after thermal stimulation of ipsilateral hind paws was observed in ligated animals in comparison with their respective sham group (Figure 2A). Importantly, no difference in the PWL could be detected between both WT and transgenic sham groups throughout the period of thermal pain hypersensitivity assessment. The response was moreover unilateral as the withdrawal latency of contralateral paws was unaffected for both WT and hSOD1G93A rats (Figure 2B). Interestingly, thermal pain hypersensitivity after PSNL was more pronounced for transgenic compared to WT animals. Area under the curve analysis confirmed the significantly enhanced ipsilateral thermal pain hypersensitivity for transgenic ligated rats as compared to WT ligated rats (Figure 2E), while contralateral values were unchanged (Figure 2F).


Enhanced neuroinflammation and pain hypersensitivity after peripheral nerve injury in rats expressing mutated superoxide dismutase 1.

Berger JV, Deumens R, Goursaud S, Schäfer S, Lavand'homme P, Joosten EA, Hermans E - J Neuroinflammation (2011)

Rats expressing hSOD1G93A show enhanced pain hypersensitivity after PSNL. Rats were tested for thermal and mechanical hypersensitivity for 21 days after surgery. Paw withdrawal latencies (PWL) of the ipsilateral (A) or contralateral (B) hind paws after thermal stimulation, expressed as a percentage of the baseline PWL. PSNL induced a decrease of PWL in both WT and hSOD1G93A rats on the ipsilateral side, compared to their respective sham controls (statistics not shown). The ANOVA repeated measures revealed enhanced pain hypersensitivity for hSOD1G93A rats compared to WT rats after PSNL. (C,D) 50% paw withdrawal threshold (PWT) of the ipsilateral (C) or contralateral (D) hind paws after mechanical stimulation, expressed in grams. PSNL triggered mechanical hypersensitivity in both WT and transgenic rats (statistics not shown), but no statistical difference was evidenced between WT and transgenic rats after ligation. (E-H) Area under the curve (AUC) analysis of the corresponding graph confirmed the enhanced ipsilateral thermal hypersensitivity in transgenic rats compared to WT rats after PSNL (#p < 0.05), while mechanical hypersensitivity only tends to be amplified in transgenic rats after lesion (p = 0.08); ANOVA and Tukey post-hoc test. Each group included 6 to 8 animals.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3090736&req=5

Figure 2: Rats expressing hSOD1G93A show enhanced pain hypersensitivity after PSNL. Rats were tested for thermal and mechanical hypersensitivity for 21 days after surgery. Paw withdrawal latencies (PWL) of the ipsilateral (A) or contralateral (B) hind paws after thermal stimulation, expressed as a percentage of the baseline PWL. PSNL induced a decrease of PWL in both WT and hSOD1G93A rats on the ipsilateral side, compared to their respective sham controls (statistics not shown). The ANOVA repeated measures revealed enhanced pain hypersensitivity for hSOD1G93A rats compared to WT rats after PSNL. (C,D) 50% paw withdrawal threshold (PWT) of the ipsilateral (C) or contralateral (D) hind paws after mechanical stimulation, expressed in grams. PSNL triggered mechanical hypersensitivity in both WT and transgenic rats (statistics not shown), but no statistical difference was evidenced between WT and transgenic rats after ligation. (E-H) Area under the curve (AUC) analysis of the corresponding graph confirmed the enhanced ipsilateral thermal hypersensitivity in transgenic rats compared to WT rats after PSNL (#p < 0.05), while mechanical hypersensitivity only tends to be amplified in transgenic rats after lesion (p = 0.08); ANOVA and Tukey post-hoc test. Each group included 6 to 8 animals.
Mentions: Hypersensitivity to thermal and mechanical stimulation of hind paws was monitored during 21 days after sham or PSNL surgery, in both WT and transgenic rats (Figure 2). Noteworthy, uninjured WT and hSOD1G93A rats showed similar baseline paw withdrawal latencies (PWL) and paw withdrawal thresholds (PWT). After PSNL however, a clear and significant decline in the withdrawal latency after thermal stimulation of ipsilateral hind paws was observed in ligated animals in comparison with their respective sham group (Figure 2A). Importantly, no difference in the PWL could be detected between both WT and transgenic sham groups throughout the period of thermal pain hypersensitivity assessment. The response was moreover unilateral as the withdrawal latency of contralateral paws was unaffected for both WT and hSOD1G93A rats (Figure 2B). Interestingly, thermal pain hypersensitivity after PSNL was more pronounced for transgenic compared to WT animals. Area under the curve analysis confirmed the significantly enhanced ipsilateral thermal pain hypersensitivity for transgenic ligated rats as compared to WT ligated rats (Figure 2E), while contralateral values were unchanged (Figure 2F).

Bottom Line: 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.Taken together, our findings show that exacerbated microglial activation and subsequent inflammatory and nitroxidative processes are associated with the severity of neuropathic pain symptoms.

View Article: PubMed Central - HTML - PubMed

Affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.

ABSTRACT

Background: 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. The present study investigated the severity of neuropathic pain and the degree of glial activation in an inflammatory- and nitroxidative-prone animal model.

Methods: Transgenic rats expressing mutated superoxide dismutase 1 (hSOD1 G93A) 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.

Results: PSNL 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 hSOD1 G93A rats.

Conclusions: Taken together, our findings show that exacerbated microglial activation and subsequent inflammatory and nitroxidative processes are associated with the severity of neuropathic pain symptoms.

Show MeSH
Related in: MedlinePlus