Mo1844 Selective Agonists of Somatostatin Receptors Type 1 or 2 Prevent Visceral Hyperalgesia Induced by Activation of Peripheral CRF1 Receptors in Mice

Abstract

G A A b st ra ct s brought a new understanding on the mechanisms of chronic visceral pain. The present study hypothesizes that inflammation of visceral organs cause glial activation, leading to the release of pro-inflammatory cytokines, resulting in hyperalgesia. Therefore, the inhibition of microglial activation can attenuate visceral hyperalgesia. We also hypothesize that glialspecific purinergic P2X7 receptors play a role in glial-neuron cross talk and blocking of these receptors might produce an analgesic effect. Methods: Colonic inflammation was induced inmale Sprague-Dawley rats (n=12) by intracolonic administration of either zymosan (25mg/ml, 0.5ml) or tri-nitrobenzenesulphonic acid (TNBS). Visceral hyperalgesia was determined by measuring the viscero-motor response (VMR) to graded colorectal distension (CRD) prior, 3hr (for zymosan) and 7 days (for TNBS) after induction of colonic inflammation. The effects of minocycline, (a broad-spectrum tetracycline antibiotic and a microglial inhibitor) and brilliant blue G (BBG; a selective P2X7 antagonist) were tested on VMRs to CRD in preand post-inflamed conditions. Electrophysiological studies involving extracellular single-unit recordings were made from CRD-sensitive pelvic nerve afferent (PNA) fibers in naive non-inflamed and TNBS-treated animals and the effect of minocycline (50mg/kg, i.v.) on the responses of PNAs to graded CRD was studied 30 and 60mins following drug administration. Results: Colonic inflammation produced visceral hyperalgesia to CRD. Administration of minocycline (50mg/kg, i.p.) significantly (p<0.05) attenuated the visceral hyperalgesia in both zymosanand TNBS-treated rats, but not in naive non-inflamed rats. Similarly, selective blocking of P2X7 receptors by BBG (50mg/kg i.p.) attenuated VMRs to CRD in TNBS-treated rats, but not in naive rats. In electrophysiology experiments, minocycline significantly (p<0.05) attenuated mechanotransduction of CRD-sensitive PNA (n=6) to CRD, but had no effect on responses of CRD-sensitive PNA (n=4) from naive non-inflamed rats. Conclusions: Activated glial cells plays an important role in initiating and maintaining visceral hyperalgesia in a rat model of post-inflammatory pain. Blocking the function of glial cells by minocycline or by blocking the glial-specific P2X7 receptor can attenuate visceral hyperalgesia. This effect is partly via peripheral actions of these drugs, which might prove to be a vital target for the treatment of visceral hyperalgesia.