Spinal orexin-1 receptors mediate anti-hyperalgesic effects of intrathecally-administered orexins in diabetic neuropathic pain model rats

Orexin-A and orexin-B are endogenous ligands of orexin receptors that contain orexin-1 and orexin-2. Activation of the orexinergic system can produce antinociceptive effects in acute inflammatory, mono-neuropathic, and postoperative pain animal models, though the effects of orexins on diabetic neuropathic pain have not been previously investigated. In this study, we studied the anti-hyperalgesic effects of intrathecally administered orexins in a streptozotocin-induced diabetic rat. First, dose-dependent effects were investigated by measuring hind paw withdrawal thresholds in response to noxious-heat and punctate stimuli, after which orexin levels in the cerebrospinal fluid of diabetic rats were measured and compared with those of normal rats using a radioimmunoassay method. The functional role of spinal orexin-1 receptors with the anti-hyperalgesic effects of orexins was also investigated using intrathecal pretreatment with SB-334867, a selective orexin-1 receptor antagonist. Intrathecally administered orexins produced an antinociceptive effect in diabetic rats, however, not in normal rats, though the orexin levels in the cerebrospinal fluid of diabetic rats were similar to those in normal rats. In addition, the anti-hyperalgesic effects of orexins were significantly inhibited by pretreatment with SB-334867. These findings demonstrate that the anti-hyperalgesic effects of orexins in diabetic rats are unlikely due to any direct effect by the supplement on decreased endogenous orexins in the cerebrospinal fluid and that orexin-1 receptors in the spinal cord may be involved in the modulation of nociceptive transmission in diabetic neuropathy. We conclude that the spinal orexinergic system may be a possible target for elucidating the mechanisms of diabetes-induced hyperalgesia.