Chronic constriction injury (CCI) to the rat sciatic nerve results in osteopenia in the affected hind limb. One possible mechanism for this osteopenia is neurogenic inflammation, in which neuropeptides, represented by substance P (SP), are involved. We attempted to determine whether capsaicin treatment, which can deplete SP from nerve terminals, is effective in inhibiting osteopenia induced by CCI. Capsaicin (total dose, 125 mg/kg) or the vehicle alone was given intraperitoneally to adult rats 2 days before (Experiment 1) and 7 days after (Experiment 2) CCI surgery. Paw withdrawal latency (PWL) was measured prior to and every week for 5 weeks after surgery. Bone mineral density (BMD) and the number of osteoclasts in tibial bones were determined 5 weeks after surgery. In rats treated with the vehicle, BMD on the CCI side was decreased significantly, while the number of osteoclasts was significantly increased in both experiments. Capsaicin treatment either before or 1 week after surgery inhibited the decreases in BMD as well as the increase in the number of osteoclasts on the CCI side. PWL for the CCI side in the vehicle group was significantly shorter than for the sham side in both experiments. However, capsaicin treatment before surgery resolved heat hyperalgesia in Experiment 1, while in Experiment 2, even though heat hyperalgesia developed on the CCI side, it was resolved by capsaicin treatment. The results of the present study show that capsaicin inhibits the development of osteopenia as well as heat hyperalgesia induced by CCI. They also support our hypothesis that neurogenic SP release is involved in the pathogenesis of bony changes induced by CCI.