The persistent release of HMGB1 contributes to tactile hyperalgesia in a rodent model of neuropathic pain

Polina Feldman,Matthew S Ripsch,Rajesh Khanna,Fletcher A White,Michael R Due

doi:10.1186/1742-2094-9-180

Polina Feldman, Matthew S Ripsch + Show 3 more

Open Access

https://doi.org/10.1186/1742-2094-9-180

Copy DOI

Abstract

BackgroundHigh-mobility group box-1 protein (HMGB1) is a nuclear protein that regulates gene expression throughout the body. It can also become cytoplasmic and function as a neuromodulatory cytokine after tissue damage or injury. The manner in which HMGB1 influences the peripheral nervous system following nerve injury is unclear. The present study investigated the degree to which HMGB1 signaling contributes to the maintenance of neuropathic pain behavior in the rodent.ResultsRedistribution of HMGB1 from the nucleus to the cytoplasm occurred in both sensory neurons derived from a tibial nerve injured (TNI) rat and in a sensory neuron-like cell line following exposure to a depolarizing stimulus. We also observe that exogenous administration of HMGB1 to acutely dissociated sensory neurons derived from naïve or TNI rodents elicit increased excitability. Furthermore systemic injection of glycyrrhizin (50 mg/kg; i.p.), a known inhibitor of HMGB1, reversed TNI-induced mechanical hyperalgesia at fourteen days and three months following nerve injury.ConclusionsWe have identified that a persistent endogenous release of HMGB1 by sensory neurons may be a potent, physiologically relevant modulator of neuronal excitability. More importantly, the use of the anti-inflammatory compound and known inhibitor of HMGB1, glycyrrhizin, has the ability to diminish persistent pain behavior in a model of peripheral neuropathy, presumably through its ability to neutralize the cyotkine. The identification of HMGB1 as a potential therapeutic target may contribute to a better understanding of mechanisms associated with chronic pain syndromes.

Highlights

High-mobility group box-1 protein (HMGB1) is a nuclear protein that regulates gene expression throughout the body
The percentage of positive cytoplasmic HMGB1-IR sensory neurons is increased after tibial nerve injury (TNI) at post-injury day (PID) 14 compared to sham and naïve (Figure 1C; n = 3, ANOVA, F = 17.36; Bonferroni multiple comparison test, *P < 0.01)
The expression of activating transcription factor 3 (ATF3), a cellular marker of nerve injury was used to reveal the primary afferent fibers that are engaged by TNI [17,18]

Summary

Introduction

High-mobility group box-1 protein (HMGB1) is a nuclear protein that regulates gene expression throughout the body. It can become cytoplasmic and function as a neuromodulatory cytokine after tissue damage or injury. The manner in which HMGB1 influences the peripheral nervous system following nerve injury is unclear. There is the suggestion that HMGB1 may contribute to the development of neuropathic pain states [8]. Perisciatic or intrathecal administration of HMGB1 produces rapid thermal hyperalgesia and mechanical allodynia in the rat [8,9]. Spinal nerve ligation-induced mechanical allodynia, but not thermal hyperalgesia, can be partially reversed if animals are pre-treated with intrathecal anti-HMGB1 antibody therapy [8]. Though HMGB1 may contribute to the development of neuropathic pain, the cellular source of HMGB1 that contributes to ongoing chronic pain behavior and the underlying role of HMGB1 in neuropathic pain are unknown

Methods

Results

Discussion

Conclusion