Analgesic Effect of Intrathecal Administration of Orexin on Neuropathic Pain in Rats

Orexin-A, a hypothalamic peptide found in the neurons of the lateral hypothalamus, has been shown to modulate pain. We examined whether orexin could alleviate heat-evoked hyperalgesia in rats caused by chronic constriction injury (CCI) of the sciatic nerve. Orexin-A, orexin-B, the vehicle, or orexin-A-antiserum was intrathecally administered to CCI rats. Paw withdrawal latency (PWL) was measured from 30 to 300 minutes after injection, which was repeated for 2 days. Orexin-A administration normalized ¢PWL (PWL in the CCI side minus PWL in the control side) and inhibited heat-evoked hyperalgesia in CCI rats, while orexin-A antiserum inhibited the normalization of heat-evoked hyperalgesia caused by orexin-A two-fold. In contrast, orexin-B had no significant effect. These results suggest that orexin-A may be applicable for treatment of neuropathic pain. A hypothalamic peptide known as orexin (hypocretin) is found in the neurons of the lateral hypothalamus (1, 2) and has been reported to be involved with feeding behavior and energy homeostasis (3), sleep/wakefulness (4, 5), the sympathetic nervous system (6) and pain (7-9). Further, some reports have noted that the peptide may be an important anti-nociceptive and anti-hyperalgesic agent (7- 9). Orexin fibers also have a role in sensory processing, while the presence of robust projections from the hypothalamus to lamina 1 of the spinal cord strongly implicates orexin in the modulation of nociceptive pathways (8, 10). In addition, results of behavioral tests using an inflammatory pain model suggested that orexin-A is a potent analgesic (7, 9). Peripheral inflammation induced by intra-plantar injection of carrageenan and formalin are models of inflammatory pain in animals, while chronic constriction injury (CCI) of the sciatic nerve (11), one of the most widely used models for the study of neuropathic pain, has been reported to induce an inflammatory response in the ipsilateral hind paw (12, 13). The aim of the present study was to investigate the alleviation of heat-evoked hyperalgesia by orexin in a rat neuropathic pain model as well as the effect of orexin antiserum.