NR2B Expression in Rat DRG Is Differentially Regulated Following Peripheral Nerve Injuries That Lead to Transient or Sustained Stimuli-Evoked Hypersensitivity.

Monica Norcini,Esperanza Recio-Pinto,Alexandra Sideris,Jin Zhang,Samantha M Adler,Lourdes A M Hernandez,Thomas J J Blanck

doi:10.3389/fnmol.2016.00100

Monica Norcini, Esperanza Recio-Pinto + Show 5 more

Open Access

https://doi.org/10.3389/fnmol.2016.00100

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Abstract

Following injury, primary sensory neurons undergo changes that drive central sensitization and contribute to the maintenance of persistent hypersensitivity. NR2B expression in the dorsal root ganglia (DRG) has not been previously examined in neuropathic pain models. Here, we investigated if changes in NR2B expression within the DRG are associated with hypersensitivities that result from peripheral nerve injuries. This was done by comparing the NR2B expression in the DRG derived from two modalities of the spared nerve injury (SNI) model, since each variant produces different neuropathic pain phenotypes. Using the electronic von Frey to stimulate the spared and non-spared regions of the hindpaws, we demonstrated that sural-SNI animals develop sustained neuropathic pain in both regions while the tibial-SNI animals recover. NR2B expression was measured at Day 23 and Day 86 post-injury. At Day 23 and 86 post-injury, sural-SNI animals display strong hypersensitivity, whereas tibial-SNI animals display 50 and 100% recovery from post-injury-induced hypersensitivity, respectively. In tibial-SNI at Day 86, but not at Day 23 the perinuclear region of the neuronal somata displayed an increase in NR2B protein. This retention of NR2B protein within the perinuclear region, which will render them non-functional, correlates with the recovery observed in tibial-SNI. In sural-SNI at Day 86, DRG displayed an increase in NR2B mRNA which correlates with the development of sustained hypersensitivity in this model. The increase in NR2B mRNA was not associated with an increase in NR2B protein within the neuronal somata. The latter may result from a decrease in kinesin Kif17, since Kif17 mediates NR2B transport to the soma’s plasma membrane. In both SNIs, microglia/macrophages showed a transient increase in NR2B protein detected at Day 23 but not at Day 86, which correlates with the initial post-injury induced hypersensitivity in both SNIs. In tibial-SNI at Day 86, but not at Day 23, satellite glia cells (SGCs) displayed an increase in NR2B protein. This study is the first to characterize of cell-specific changes in NR2B expression within the DRG following peripheral nerve injury. We discuss how the observed NR2B changes in DRG can contribute to the different neuropathic pain phenotypes displayed by each SNI variant.

Highlights

In humans with chronic allodynia associated with previous surgical fields and neuromas, altered central processing is not autonomous, and appears to depend on continued peripheral nerve input (Hoffert et al, 1984; Gracely et al, 1992; Gold and Gebhart, 2010)
We found that the level of NR2B intensity labeling in the neuronal soma was not changed in Sham operated animals, as compared to that observed in naïve animals (Figure 2F)
We found that KIF17 transcripts were down-regulated only in the ipsilateral L4-dorsal root ganglia (DRG) of sural-spared nerve injury (SNI) (Figure 9A), but no change was found in the level of kinesin family member 5b (Kif5b) transcripts (Figure 9B)

Summary

Introduction

In humans with chronic allodynia associated with previous surgical fields and neuromas, altered central processing is not autonomous, and appears to depend on continued peripheral nerve input (Hoffert et al, 1984; Gracely et al, 1992; Gold and Gebhart, 2010). Compared to general NMDAr blockers, specific NR2B antagonists display lower central toxicity both in animal models (sural-SNI, sciatic nerve ligation, spinal nerve ligation, inflammatory pain; Boyce et al, 1999; Swartjes et al, 2011) and in clinical trials (Mony et al, 2009), which reflects the more restricted expression of NR2B in the brain (Watanabe et al, 1993; Farrant et al, 1994). In suralSNI, oral immunization with anti-NR2B decreases mechanical hypersensitivity and NR2B expression in the spinal cord (but not in the brain; Wang et al, 2007). Since NR2B is the predominant NR2 subunit within the DRG, in this study we investigated how NR2B changes in the peripheral DRG are related to stimuli-evoked hypersensitivities in rats by using two variants of the spared nerve injury (SNI) model. We investigated whether sustained mechanical and cold hypersensitivity resulting from the sural-SNI variant is accompanied by an increase in NR2B expression within the DRG

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