Mo1845 P2×7 Receptors Facilitate Visceral Hypersensitivity Through Activation of Spinal Cord Microglia

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 in male 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 pre-and post-inflamed conditions.Electrophysiological studies involving extracellular single-unit recordings were made from CRD-sensitive pelvic nerve afferent (PNA) fibers in naïve 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 zymosan-and TNBS-treated rats, but not in naïve 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 naïve 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 naïve 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.