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Open Access Research

Transforming growth factor beta induces sensory neuronal hyperexcitability, and contributes to pancreatic pain and hyperalgesia in rats with chronic pancreatitis

Yaohui Zhu1, Tugba Colak2, Mohan Shenoy2, Liansheng Liu1, Kshama Mehta2, Reetesh Pai4, Bende Zou3, Xinmin Simon Xie23 and Pankaj J Pasricha1*

Author Affiliations

1 Johns Hopkins Center for Neurogastroenterology, Department of Medicine, Division of Gastroenterology and Hepatology, Baltimore, MD, 21205, USA

2 Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

3 Afasci Inc, Redwood City, CA, USA

4 Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA

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Molecular Pain 2012, 8:65  doi:10.1186/1744-8069-8-65

Published: 11 September 2012

Abstract

Background

Transforming growth factor beta (TGFβ) is upregulated in chronic inflammation, where it plays a key role in wound healing and promoting fibrosis. However, little is known about the peripheral effects of TGFβ on nociception.

Methods

We tested the in vitro effects of TGFβ1 on the excitability of dorsal root ganglia (DRG) neurons and the function of potassium (K) channels. We also studied the effects of TGFβ1 infusion on pain responses to noxious electrical stimulation in healthy rats as well as the effects of neutralization of TGFβ1 on evoked pain behaviors in a rat model of chronic pancreatitis.

Results

Exposure to TGFβ1 in vitro increased sensory neuronal excitability, decreased voltage-gated A-type K+ currents (IA) and downregulated expression of the Kv1.4 (KCNA4) gene. Further TGFβ1 infusion into the naïve rat pancreas in vivo induces hyperalgesia and conversely, neutralization of TGFβ1 attenuates hyperalgesia only in rats with experimental chronic pancreatitis. Paradoxically, TGFβ1 neutralization in naïve rats results in pancreatic hyperalgesia.

Conclusions

TGFβ1 is an important and complex modulator of sensory neuronal function in chronic inflammation, providing a link between fibrosis and nociception and is a potentially novel target for the treatment of persistent pain associated with chronic pancreatitis.

Keywords:
Transforming growth factor beta; Chronic pain; Neuronal sensitization; Kv channels; Sensory neurons; Chronic pancreatitis