Recently, we demonstrated that the administration of GAD65-expressing rAAV2 to DRG attenuates peripheral neuropathy by inducing GABA release in the spinal cord. However, the direct injection to DRG is invasive and may therefore cause nerve injury and other side effects. To circumvent this surgical intervention, we explored the potential of a much simpler and less invasive route of sciatic nerve administration. Using a neuropathic pain model, we introduced rAAV2-GAD65 through sciatic nerve and examined its therapeutic potency in pain-related behavior tests. Both GFP and GAD65 expression indicated that effective transgene delivery to the DRG can be accomplished via sciatic nerve administration. Equally importantly, the GABA concentration in the spinal cord increased significantly after GAD65 introduction, and pain symptoms were dramatically reduced and persistently controlled. The implication is that the sciatic nerve is a highly promising route for delivering rAAV2 to the DRG, and thus represents a much less invasive, clinically viable gene therapy option. (C) 2009 Elsevier Inc. All rights reserved.