A preconditioning nerve lesion inhibits mechanical pain hypersensitivity following subsequent neuropathic injury

Gila Moalem-Taylor, Man Li, Haydn N Allbutt, Ann Wu, David J Tracey, Gila Moalem-Taylor, Man Li, Haydn N Allbutt, Ann Wu, David J Tracey

Abstract

Background: A preconditioning stimulus can trigger a neuroprotective phenotype in the nervous system - a preconditioning nerve lesion causes a significant increase in axonal regeneration, and cerebral preconditioning protects against subsequent ischemia. We hypothesized that a preconditioning nerve lesion induces gene/protein modifications, neuronal changes, and immune activation that may affect pain sensation following subsequent nerve injury. We examined whether a preconditioning lesion affects neuropathic pain and neuroinflammation after peripheral nerve injury.

Results: We found that a preconditioning crush injury to a terminal branch of the sciatic nerve seven days before partial ligation of the sciatic nerve (PSNL; a model of neuropathic pain) induced a significant attenuation of pain hypersensitivity, particularly mechanical allodynia. A preconditioning lesion of the tibial nerve induced a long-term significant increase in paw-withdrawal threshold to mechanical stimuli and paw-withdrawal latency to thermal stimuli, after PSNL. A preconditioning lesion of the common peroneal induced a smaller but significant short-term increase in paw-withdrawal threshold to mechanical stimuli, after PSNL. There was no difference between preconditioned and unconditioned animals in neuronal damage and macrophage and T-cell infiltration into the dorsal root ganglia (DRGs) or in astrocyte and microglia activation in the spinal dorsal and ventral horns.

Conclusions: These results suggest that prior exposure to a mild nerve lesion protects against adverse effects of subsequent neuropathic injury, and that this conditioning-induced inhibition of pain hypersensitivity is not dependent on neuroinflammation in DRGs and spinal cord. Identifying the underlying mechanisms may have important implications for the understanding of neuropathic pain due to nerve injury.

Figures

Figure 1
Figure 1
Effects of preconditioning nerve lesion on neuropathic pain behaviors due to partial ligation of the left sciatic nerve. (A-B) Tibial nerve crush injury (left) inhibits PSNL-induced mechanical and thermal pain hypersensitivity. Withdrawal thresholds to mechanical stimuli (d9-d26) (A) and withdrawal latencies to thermal stimuli (d9-d16) (B) were significantly greater in the ipsilateral left hindpaws of rats that underwent left tibial crush injury 1 week before PSNL than in rats that underwent only PSNL. No significant differences in paw withdrawal thresholds (A) and in paw withdrawal latencies (B) were observed in the contralateral right side. (C-D) Peroneal nerve crush injury (left) inhibits PSNL-induced mechanical, but not thermal, pain hypersensitivity. Withdrawal thresholds to mechanical stimuli (d14-d19) (C) were significantly greater in ipsilateral left hindpaws of rats that underwent left peroneal crush injury 1 week before PSNL than in rats that underwent only PSNL. No significant differences in paw withdrawal thresholds were observed in the contralateral right side. (D) No significant differences were observed in paw withdrawal latencies to thermal stimuli in both the ipsilateral and contralateral sides. (E) Tibial nerve crush injury (right; on the other side of the PSNL) transiently inhibits PSNL-induced mechanical pain hypersensitivity. Withdrawal thresholds to mechanical stimuli (d11) were significantly greater in ipsilateral left hindpaws of rats that underwent right tibial crush injury 1 week before PSNL than in rats that underwent only PSNL. No significant differences were observed in the right side, contralateral to PSNL. (n = 6 rats per group, *P < 0.05, ** P < 0.01, *** P < 0.001, two-way RM ANOVA followed by Bonferroni post-tests). Data are expressed as mean ± s.e.m. Arrowheads indicate day of surgery for crush injury and PSNL.
Figure 2
Figure 2
Effects of preconditioning nerve lesion on PSNL-induced neuronal damage and inflammation in L4/5 DRGs. (A-B) Percentage of ATF3+ DRG neurons in populations of large NF-200-expressing neurons, and small peripherin-expressing neurons. Compared to the contralateral uninjured side, a large increase in NF-200 neurons (green) containing ATF3+ nuclei (red) (A) and in peripherin positive neurons (green) containing ATF3+ nuclei (red) (B) was observed on the side ipsilateral to PSNL in all groups. On the ipsilateral side, there was no significant difference between preconditioned (crush-injured) and unconditioned (no crush) groups. On the contralateral side, the percentage of NF-200 neurons containing ATF3+ nuclei (A) and peripherin neurons containing ATF3+ nuclei (B) was significantly higher in the rats that underwent right tibial nerve crush injury as compared to all other groups. (C-D) Macrophage and T-cell presence in DRGs. Compared to the contralateral uninjured side, ED1 immunoreactivity (in green) (C) and the number of T cells (in green) (D) were markedly increased after PSNL on the ipsilateral side, but with no significant difference between preconditioned and unconditioned groups. On the contralateral side, ED1 immunoreactivity (C) and T-cell numbers (D) were significantly higher in the rats that underwent right tibial nerve crush injury as compared to all other groups. Micrographs on the right of each histogram show representative examples of immunoreactivity in DRGs from injured (ipsilateral) and uninjured (contralateral) sides. (n = 3 rats per group, *P < 0.05, ** P < 0.01, *** P < 0.001, two-way ANOVA followed by Bonferroni post-tests). Data are expressed as mean ± s.e.m. Scale bars represent 50 μm.
Figure 3
Figure 3
Effects of preconditioning nerve lesion on glial activation in lumbar spinal cord (L4-6), 1 week after partial ligation of the left sciatic nerve. (A) Activation of microglia in the ipsilateral dorsal and ventral horn of the spinal cord was significantly increased 7 days after PSNL in both preconditioned (crush-injured) and unconditioned (no crush) rats as compared to normal rats and to the contralateral uninjured side. Activation of microglia in the contralateral dorsal and ventral horn of the spinal cord was significantly increased only in the rats that underwent (2 weeks before) right tibial nerve crush injury. (B) Activation of astrocytes in the ipsilateral dorsal horn of the spinal cord was significantly increased 7 days after PSNL in both preconditioned (crush-injured) and unconditioned (no crush) groups as compared to normal rats. Astrocyte activation was significantly increased in the ventral horn of preconditioned rats (left tibial and left peroneal crush) as compared to normal rats. In the contralateral spinal cord, no significant differences were observed between the groups, except for the dorsal horn of preconditioned rats (left tibial crush) as compared to normal rats. Micrographs (right panel) show examples of immunoreactivity to IBA1 (microglia, in red) and GFAP (astrocytes, in green) in sides ipsilateral (left) and contralateral (right) to PSNL in both dorsal and ventral spinal cords of unconditioned rats. (n = 3 rats per group, *P < 0.05, ** P < 0.01, *** P < 0.001, two-way ANOVA followed by Bonferroni post-tests). Data are expressed as mean ± s.e.m. Scale bars represent 50 μm.

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