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Sigma-1 receptor expression in sensory neurons and the effect of painful peripheral nerve injury.

ABSTRACT: The sigma-1 receptor (?1R), an endoplasmic reticulum chaperone protein, is widely distributed and regulates numerous intracellular processes in neurons. Nerve injury alters the structure and function of axotomized dorsal root ganglion (DRG) neurons, contributing to the development of pain. The ?1R is enriched in the spinal cord and modulates pain after peripheral nerve injury. However, ?1R expression in the DRG has not been studied. We therefore characterized ?1R expression in DRGs at baseline and following spinal nerve ligation (SNL) in rats.Immunohistochemical (IHC) studies in DRG sections show ?1R in both neuronal somata and satellite glial cells. The punctate distribution of ?1R in the neuronal cytoplasm suggests expression in the endoplasmic reticulum. When classified by neuronal size, large neurons (>1300 ?m) showed higher levels of ?1R staining than other groups (700-1300 ?m, <700 ?m). Comparing ?1R expression in neuronal groups characterized by expression of calcitonin gene-related peptide (CGRP), isolectin-B4 (IB4) and neurofilament-200 (NF-200), we found ?1R expression in all three neuronal subpopulations, with highest levels of ?1R expression in the NF-200 group. After SNL, lysates from L5 DRGs that contains axotomized neurons showed decreased ?1R protein but unaffected transcript level, compared with Control DRGs. IHC images also showed decreased ?1R protein expression, in SNL L5 DRGs, and to a lesser extent in the neighboring SNL L4 DRGs. Neurons labeled by CGRP and NF-200 showed decreased ?1R expression in L5 and, to a lesser extent, L4 DRGs. In IB4-labeled neurons, ?1R expression decreased only in axotomized L5 DRGs. Satellite cells also showed decreased ?1R expression in L5 DRGs after SNL.Our data show that ?1R is present in both sensory neurons and satellite cells in rat DRGs. Expression of ?1R is down-regulated in axotomized neurons as well as in their accompanying satellite glial cells, while neighboring uninjured neurons show a lesser down-regulation. Therefore, elevated ?1R expression in neuropathic pain is not an explanation for pain relief after ?1R blockade. This implies that increased levels of endogenous ?1R agonists may play a role, and diminished neuroprotection from loss of glial ?1R may be a contributing factor.

SUBMITTER: Bangaru ML

PROVIDER: S-EPMC3847629 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Sigma-1 receptor expression in sensory neurons and the effect of painful peripheral nerve injury.

Bangaru Madhavi L ML Weihrauch Dorothee D Tang Qing-Bo QB Zoga Vasiliki V Hogan Quinn Q Wu Hsiang-en HE

Molecular pain 20130910

<h4>Background</h4>The sigma-1 receptor (σ1R), an endoplasmic reticulum chaperone protein, is widely distributed and regulates numerous intracellular processes in neurons. Nerve injury alters the structure and function of axotomized dorsal root ganglion (DRG) neurons, contributing to the development of pain. The σ1R is enriched in the spinal cord and modulates pain after peripheral nerve injury. However, σ1R expression in the DRG has not been studied. We therefore characterized σ1R expression in ...[more]

PMID: 24015960

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Project description:Sigma-1 Receptor has been shown to localize to sites of peripheral nerve injury and back pain. Radioligand probes have been developed to localize Sigma-1 Receptor and thus image pain source. However, in non-pain conditions, Sigma-1 Receptor expression has also been demonstrated in the central nervous system and dorsal root ganglion. This work aimed to study Sigma-1 Receptor expression in a microglial cell population in the lumbar spine following peripheral nerve injury. A publicly available transcriptomic dataset of 102,691 L4/5 mouse microglial cells from a sciatic-sural nerve spared nerve injury model and 93,027 age and sex matched cells from a sham model was used. At each of three time points-postoperative day 3, postoperative day 14, and postoperative month 5-gene expression data was recorded for both spared nerve injury and Sham cell groups. For all cells, 27,998 genes were sequenced. All cells were clustered into 12 distinct subclusters and gene set enrichment pathway analysis was performed. For both the spared nerve injury and Sham groups, Sigma-1 Receptor expression significantly decreased at each time point following surgery. At the 5-month postoperative time point, only one of twelve subclusters showed significantly increased Sigma-1 Receptor expression in spared nerve injury cells as compared to Sham cells (p = 0.0064). Pathway analysis of this cluster showed a significantly increased expression of the inflammatory response pathway in the spared nerve injury cells relative to Sham cells at the 5-month time point (p = 6.74e-05). A distinct subcluster of L4/5 microglia was identified which overexpress Sigma-1 Receptor following peripheral nerve injury consistent with neuropathic pain inflammatory response functioning. This indicates that upregulated Sigma-1 Receptor in the central nervous system characterizes post-acute peripheral nerve injury and may be further developed for clinical use in the differentiation between low back pain secondary to peripheral nerve injury and low back pain not associated with peripheral nerve injury in cases where the pain cannot be localized.

Project description:ObjectiveThis study aims to evaluate the effectiveness of neural mobilization (NM) in the management of sensory dysfunction and nerve degeneration related to experimental painful diabetic neuropathy (PDN).MethodsThis is a pre-clinical animal study performed in the streptozocin-induced diabetic rat model. Three groups were included: a treatment group of rats with PDN receiving NM under anesthesia (PDN-NM, n = 10), a sham treatment group of rats with PDN that received only anesthesia (PDN-Sham, n = 9), and a vehicle control group with nondiabetic animals (Vehicle, n = 10). Rats in the PDN-NM and PDN-Sham groups received 1 treatment session on days 10, 12, and 14 after streptozocin injection, with a 48-hour rest period between sessions. Behavioral tests were performed using von Frey and Plantar tests. Evaluation for peripheral nerve degeneration was performed through measuring protein gene product 9.5-positive intra-epidermal nerve fiber density in hind-paw skin biopsies. All measurements were performed by a blinded investigator.ResultsThe behavioral tests showed that a single NM session could reduce hyperalgesia, which was maintained for 48 hours. The second treatment session further improved this treatment effect, and the third session maintained it. These results suggest that it requires multiple treatment sessions to produce and maintain hypoalgesic effects. Skin biopsy analysis showed that the protein gene product 9.5-positive intra-epidermal nerve fiber density was higher on the experimental side of the PDN-NM group compared with the PDN-Sham group, suggesting NM may mitigate the degeneration of peripheral nerves.ConclusionThis study demonstrated that NM may be an effective method to manage experimentally induced PDN, potentially through mitigation of nerve degeneration. Further studies are needed to develop standardized protocols for clinical use.ImpactThese findings provide neurophysiological evidence for the use of NM in PDN and can form the basis for the development of physical therapy-based programs in clinics.

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Sigma-1 receptor expression in sensory neurons and the effect of painful peripheral nerve injury.

Publications

Sigma-1 receptor expression in sensory neurons and the effect of painful peripheral nerve injury.

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