The finding that sensory neuron-specific G-protein-coupled receptor mRNA is solely expressed in small primary sensory neurons suggests involvement of the receptor in nociceptive modulation. The present study was designed to assess effects of intrathecal administration of bovine adrenal medulla 8-22 and (Tyr6)-gamma2-MSH-6-12, selective sensory neuron-specific receptor agonists, on nocifensive behaviors and expression of spinal c-Fos-like immunoreactivity evoked by intraplantar injection of 2.5% formalin in rats. The agonists were administered 10 min before (pretreatment) and/or after (post-treatment) injection of formalin. Pretreatment with bovine adrenal medulla 8-22 dose-dependently (3, 10 and 30 nmol) decreased time lifting and licking the paw mainly in the second phase. Intrathecal bovine adrenal medulla 8-22 (30 nmol) remarkably suppressed nocifensive behaviors in the first and second phases and the expression of formalin-evoked c-Fos-like immunoreactivity in laminae I-II and V-VI of the spinal dorsal horn at L4-5. Moreover, naloxone (20 microg, intrathecal) failed to antagonize the inhibitory effects of bovine adrenal medulla 8-22. Post-treatment with bovine adrenal medulla 8-22 also exerted inhibition on the second phase behaviors in a dose-dependent manner with a similar efficacy observed in pretreatment groups. Furthermore, post-treatment with (Tyr6)-gamma2-MSH-6-12 (0.5, 1.5 and 5 nmol) also suppressed formalin-evoked nocifensive behaviors in the second phase and c-Fos-like immunoreactivity in the spinal dorsal horn similar with bovine adrenal medulla 8-22. Our results suggest that sensory neuron-specific receptor may play an important role in modulation of spinal nociceptive transmission. This is the first to demonstrate that activation of sensory neuron-specific receptor produces analgesia in the persistent pain model.