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Above results indicated that activity of ASICs was inhibited by GW7647 in vitro . We finally determined whether GW7647 inhibition of ASICs was involved in pain-related behaviors in vivo . Rats displayed an reebok shoes intense flinch/shaking responses after acetic acid (0.6%) was injected into hindpaws. The nociceptive responses mainly occurred during 0-5 min after intraplantar injection of acetic acid [ 16 , 34 ]. We measured the number of flinches that rats spent licking and/or lifting the injected hindpaws. Figure 5A shows that nociceptive responses induced by acetic acid was potently blocked by pre-applied APETx2 (20 ¼M, 50 ¼l), a specific ASIC3 blocker, indicating the involvement of ASIC3 in the acidosis-induced nociception.

We found that GW7647 exerted a rapid inhibiting effect on peak ASIC currents in rat isolated DRG neurons. The inhibiting effect of GW7647 on ASIC currents was blocked by PPAR-± antagonist, indicating involvement of PPAR-±. It has been shown that DRGs contain both PPAR-± mRNA and PPAR-± immunoreactivity in both small and large neuron [ 2 ]. In twenty neurons that are insensitive to GW7647, PPAR-± may be not expressed in these neurons recorded by ASIC currents. GW7647 has been found to attenuate the depolarization-evoked [Ca 2 ] i in small DRG neurons through PPAR-± [ 36 ].

GW7647 shifted the proton concentration response curve downward and reebok cross trainers decreased the maximum response without changing the IC 50 values, indicating that PPAR-± activation resulted in a decrease in the efficiency of ASICs and had no effect on the affinity of ASICs for protons. ASICs are mostly permeable to Na , activation of these channels can thus depolarize membrane potentials to the threshold of excitability and result in bursts of action potentials [ 37 ]. Data from current clamp experiments revealed that acidosis-triggered action potentials were also inhibited by GW7647. This decreased neuronal excitability may correlate with results that ASIC currents were attenuated by GW7647 in voltage clamp experiments.