Opioid receptor like 1 (ORL) receptor activation displayed an anti-nociceptive effect at spinal level for acute and neuropathic pain. SCH221510， an orally active non-peptide ORL agonist， was reported to be effective in treating neuropathic pain. The present study used ORL antagonist and siRNA to investigate that ORL activation mediates intrathecal SCH221510 analgesia in neuropathic pain induced by chronic constrictive injury (CCI) to rat sciatic nerve. Paw withdrawal latency and 50% mechanical threshold were measured for thermal and mechanical hypersensitivity in rats. CCI significantly decreased paw withdrawal latency and mechanical threshold. SCH221510 (3， 10， 30 μg) or ORL antagonist ([Nphe]nociceptin(1-13)NH， 10 μg) was intrathecally injected to test the behavioral effects on neuropathic pain. Intrathecal siRNA was started on 1 day before CCI surgery and maintained for 7 days. L4-L5 spinal cord ORL mRNA and protein were measured by real-time PCR and Western blot. The effect of intrathecal siRNA on SCH2210510 was tested in CCI rats on day 7. Intrathecal SCH221510 dose-dependently reduced thermal and mechanical hypersensitivity induced by CCI. [Nphe]nociceptin(1-13)NH blocked SCH221510 analgesia in CCI rats. Intrathecal siRNA blocked ORL mRNA and protein increase induced by CCI. Intrathecal ORL siRNA did not change thermal and mechanical hypersensitivity induced by nerve injury. Intrathecal siRNA blocked SCH221510 analgesia in neuropathic pain at spinal level. Conclusively， ORL activation mediates SCH221510 analgesia in neuropathic pain at spinal level. The results warrant a potential clinically applicable drug in treating neuropathic pain.