Elsevier

Brain Research

Volume 1026, Issue 2, 12 November 2004, Pages 185-193
Brain Research

Research report
Sialic acid contributes to hyperexcitability of dorsal root ganglion neurons in rats with peripheral nerve injury

https://doi.org/10.1016/j.brainres.2004.07.075Get rights and content

Abstract

Axonal injury of the dorsal root ganglion (DRG) neurons may alter the synthesis of certain membrane proteins that are responsible for the development of abnormal hyperexcitability. The external domains of most of these membrane proteins are sialylated. Because sialic acid carries heavy negative charges, the increase of sialylated proteins may increase neurons' negative surface charges, which will have predictable effects on the voltage-gated channels, and affect the excitability of injured neurons. Using intracellular electrophysiological recording, we demonstrated that following chronic constriction injury (CCI) of the sciatic nerve, Aα/β DRG neurons become hyperexcitable, as indicated by a more depolarized resting membrane potential (Vm) and a lowered threshold current (TIC). More interestingly, the excitability of injured DRG neurons was reduced substantially when the extracellular sialic acid was removed by pretreatment with neuraminidase. The Vm was less depolarized and the TIC increased robustly as compared to the CCI neurons without neuraminidase treatment. However, desialylation of normal, intact neurons had no significant effect on the Vm and less effect on the TIC. Our results suggest that the hyperexcitability of injured sensory neurons may be associated with increased negatively charged sialic acid residues on the surface of the neuronal somata.

Introduction

Injury of the peripheral nerve can lead to comprehensive changes in the electrical properties of dorsal root ganglion (DRG) neurons. The hyperexcitability of axotomized DRG neurons, characterized by low threshold currents (rheobase), the presence of ectopic spontaneous discharge (ESD), and subthreshold oscillations of membrane potential, is associated closely with abnormal pain states, such as hyperalgesia, allodynia, spontaneous pain, and paresthesia [19], [23], [37], [42], [45], [48].

It is generally believed that the enhancement of neuronal excitability following nerve injury can be attributed to altered expression of selective sodium channels [8], [13] or sodium channel subunits, such as Nav1.3, and Nav1.6 [5], [7], [44]. In addition, an increase in calcium channel subunit [26], [31] and some receptor proteins [6], [16], [21] and a decrease in certain potassium channels [9] in the cell membrane of primary sensory neurons are factors proven to relate to enhanced excitability of DRG neurons.

In seeking the causes of nerve injury-induced membrane property changes, what may have been overlooked is the role of heavy glycosylation of most transmembrane proteins on the extracytoplasmic side of the neuron, on which a large portion of carbohydrates take the form of sialic acid residues that carry negative charges at a physiological pH [2], [14], [25], [28], [34]. The strong negative surface charges carried by sialic acid over the external domains of the transmembrane proteins could affect the excitability of the injured neurons. Results from our earlier study demonstrated that increased sialic acid at the injury site of the sciatic nerve plays an important role in the generation of ESD recorded from teased myelinated fibers [49]. In this study, using chronic constriction injury (CCI) rats, we examined the relationship between glycosylation, particularly terminal sialylation, and the hyperexcitability of large Aα/β DRG neurons.

Section snippets

Preparation of CCI rats

Experiments were performed on adult Sprague–Dawley rats weighing 180–200 g. All experimental procedures were done in concordance with the recommendations of the International Association for the Study of Pain (IASP). The operative procedures for producing a CCI of the sciatic nerve have been described previously [3]. Thermal hyperalgesia was present on the ipsilateral hind paw of all rats used. Behavioral changes peaked at 7–14 postoperative (PO) days and remained at this level for up to 21

Results

A total of 71 control and 66 CCI neurons were studied. The CVs of the dorsal roots ranged from 12.33 to 31.49 m/s (20.79±0.60 m/s) for control DRG, and from 12.58 to 39.07 m/s (22.58±0.64) for CCI DRG neurons.

Changes in electrical properties of Aα/β neurons following CCI

In this study, comprehensive changes in the electrophysiological properties of Aα/β neurons were observed following CCI. In general, the results are consistent with previous reports on axotomized [1], [20], [27], [36] and compressed DRGs [48]. However, changes in the passive properties induced by nerve injury may vary under different circumstances; for example, Kim et al. [20] reported that axotomy increased the excitability of DRG neurons by decreasing the Vm in C-neurons but not in A-neurons.

Acknowledgments

We would like to thank Drs. Robert H. LaMotte at Yale University and Jun-Ming Zhang at the University of Arkansas for Medical Sciences for their comments on this manuscript. This study was supported by the National Natural Science Foundation of China (Grant Nos. 39770247 and 39830150).

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    1

    Present Address: Neuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.

    2

    Present Address: Department of Anesthesiology, University of Arkansas Medical Sciences, Little Rock, AR 72205, USA.

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