Previous reports show that central glutamate release and activation of glutamate receptors are critical for development and maintenance of mechanical hyperalgesia resulting from repeated acid injection. Peripherally, glutamate increases are observed in models of joint inflammation, infusion of glutamate produces mechanical hyperalgesia, and blockade of glutamate receptors intraarticularly reduces hyperalgesia. Therefore, we tested the hypothesis that infusion of acidic saline into muscle or skin will increase release of glutamate. Rats were anesthetized with isofluorane and a microdialysis fiber was inserted into either the gastrocnemius muscle or the overlying skin. We then infused pH 7.2 or pH 4.0 saline through the microdialysis fiber and analyzed the dialysate for glutamate using HPLC. Surprisingly, there was a decrease in the concentrations of glutamate in response to acidic saline infusion into the muscle or skin that persisted through infusion and for 1 h after infusion. Thus, these data suggest that glutamate in muscle or skin is negatively modulated by acidic saline and may be unrelated to the hyperalgesia observed after acidic saline injections. Supported by NIH grant AR052316.