Abstract: Phosphoinositide 3-Kinase (PI3K) is a lipid kinase that phophorylates the D-3 position of phosphatidylinositol lipids to produce PI (3,4,5) P3, which acts as a membrane-embedded secondary messenger to recruit and activate Ptotein Kinase B (PKB/Akt). Current studies indicate that PI3K in the periphery mediates the primary heat hyperalgesia induced by capsaicin or by NGF and there is an activity-dependent phosphorylation of PKB/Akt in adult DRG neurons. In our previous study, we found that PKB/Akt contributes to central sensitization. In this study, we investigated whether the PKB/Akt in the periphery is involved in pain behavior induced by capsaicin . We used a computerized photobeam activity system to measure changes in exploratory behavior in rats. 1%DMSO, a PKB/Akt inhibitor, Akt inhibitor IV, or a PI3K (upstream of PKB/Akt) inhibitor, wortmannin, was injected intradermally with capsaicin respectively, in different groups of rats. Intradermal injection of 1%DMSO plus capsaicin causes a decrease in the total activity, distance traveled, rearing events, rearing time, active time, resting time respectively. However, Akt inhibitor IV significantly prevented the reduction of exploratory behavior induced by capsaicin. Wortmannin had the same effect. The results suggest that PKB/Akt and PI3K contribute to the changes in exploratory behavior induced by capsaicin injection. Intradermal injection of capsaicin induces mechanical hypersensitivity, a sign of central sensitization. Inhibiting PKB/Akt activity effectively prevents behavioral changes that we believe reflect the presence of pain, especially mechanical hypersensitivity. This implies that peripheral application of PKB/Akt inhibitors has potential for therapies to reduce pain hypersensitivity. Supported by NIH grants NS09743 and NS11255.