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Open Access Research

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

Polina Feldman1, Michael R Due2, Matthew S Ripsch2, Rajesh Khanna3 and Fletcher A White2*

Author Affiliations

1 Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University, School of Medicine, 950 West Walnut Street, Indianapolis, IN, 46202, USA

2 Department of Anesthesia, Paul and Carole Stark Neurosciences Research Institute, Indiana University, School of Medicine, 950 West Walnut St, Indianapolis, IN, 46202, USA

3 Department of Pharmacology and Toxicology, Paul and Carole Stark Neurosciences Research Institute;, Indiana University, School of Medicine, 950 West Walnut St, Indianapolis, IN, 46202, USA

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Journal of Neuroinflammation 2012, 9:180  doi:10.1186/1742-2094-9-180

Published: 23 July 2012

Abstract

Background

High-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.

Results

Redistribution 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.

Conclusions

We 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.