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

Background: Transforming growth factor beta (TGF beta) 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 TGF beta on nociception. Methods: We tested the in vitro effects of TGF beta 1 on the excitability of dorsal root ganglia (DRG) neurons and the function of potassium (K) channels. We also studied the effects of TGF beta 1 infusion on pain responses to noxious electrical stimulation in healthy rats as well as the effects of neutralization of TGF beta 1 on evoked pain behaviors in a rat model of chronic pancreatitis. Results: Exposure to TGF beta 1 in vitro increased sensory neuronal excitability, decreased voltage-gated A-type K+ currents (IA) and downregulated expression of the Kv1.4 (KCNA4) gene. Further TGF beta 1 infusion into the naive rat pancreas in vivo induces hyperalgesia and conversely, neutralization of TGF beta 1 attenuates hyperalgesia only in rats with experimental chronic pancreatitis. Paradoxically, TGF beta 1 neutralization in naive rats results in pancreatic hyperalgesia. Conclusions: TGF beta 1 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.