Modulation Of GW7647 On Acid-sensitive Ion Channels

Objective: Peroxisome proliferator-activated receptor-?(PPAR-?),a lipid activated transcription factor,belongs to nuclear hormone receptor super-family,can relieve pain through a rapid-response mechanism.Asid-sensing icon channels(ASICs),key sensors for extracellular protons,also play an important role in pain sensation.Both PPAR-? and ASIC are expressed in DRG,so it is considered whether there is a functional connection between them.The objective of this subject is to find whether PPAR-? agonist GW7647 modulates the activity of ASICs in rat DRG neurons.Methods: Electrophisological experiments and behavioral experiments are performed in order to explore the mechanism of PPAR-? agonist GW7647 inhibits the activity of the acid sensoring iron channels in primary sensory neurons in the subject.Results: PPAR-? activation acutely inhibited the activity of the acid sensoring iron channels.Pre-application of GW7647 for 2min,the amplitude of the protongated currents decreased in a concentration-dependent manner.GW7647 shifted the concentration-response curve for proton downwards,with a decrease of 36.9±2.3% in the maximal current response to proton,and this effect of inhibiting proton-gated currents can be blocked by GW6471,a selective PPAR-? antagonist.Moreover,PPAR-? activation decreased the number of acidosis-evoked action potentials in rat DRG neurons.Finally,peripheral pre-application of GW7647 relieved acidosis-evoked nociceptive responses in a dose-dependent manner and suppressed CFA-induced mechanical hypersensitivity in rats.Conclusion: Activatiral PPAR-? acutely inhibited functional activity of ASICs in a non-genomic manner,which revealed a novel mechanism underlying rapid analgesia through peripheral PPAR-?.