Role of vanilloid receptor 1 (VR1) in increased nociceptive signaling in experimental pancreatitis

Abstract

Background/Aims: Vanilloid receptor 1 (VR1) plays a fundamental role in the transduction of pain due to peripheral tissue injury/inflammation. The aim of our study was to determine its role in visceral pain in a rat model of pancreetitis by measuring spinal cord c-fos as a functional marker. Methods: Pancreatitis was induced with two i.p. injections of L-arginine; control animals received saline and experiments were performed 5 days post-injection. Afferent responses were quantified by counting the number of c-fos immunoreactive neurons in spinal cord segments T8-TlO two hours after intraductal (i.d.) infusion of capsaicin (0.5 mg/kg), acid(pH 6) or vehicle with or without pre-treatment with the VR1 antagonist capsazepine (i.d.,O.5 mg/kg). To determine whether the number of pancreatic afferents expressing VR1 was increased in pancreatitis, the number of neurons in dorsal root ganglia T9-T11 positive for the retrograde label Dil and VR1 in pancreatitis and control rats was compared. Results: C-fos IR was significantly increased after acid or capsaicin stimulation compared to the vehicle injected group(40.9+-10.2/52.6+-11.8 vs 19.6+_6.6; p O.O5),capsazepine effectively blocked c-fos expression induced by acid and capsaicin(28.4+_8.6,p O.O5).Conciusions: The increased expression of c-los in response to capsaicin or acid stimulation in pancreatitis rats indicates that pancreatic afferents are sensitized in this model. Inhibition of the responses to acid and capsaicin by pre-treatment with a VR1 antagonist suggests that these responses require VR1 activation and that sensitization of afferent neurons in pancreatitis involves an increase in VR1 activity. These results imply that VR1 plays a critical role in pain transmission in pancreatitis. Our results also suggest that capsazepine may be an effective therapeutic agent in treating pain in pancreetitis.