Role of hypocretin-1,2 (orexin A and B) in pain perception

Hypocretins/orexins are primary excitatory neuropeptides located exclusively in neurons of the lateral hypothalamic area, which send projections to most monoaminergic nuclei. It has been reported that i.c.v. injection of hypocretin 1 (orexin A) enhances wakefulness in rats and mice. The present work was carried out to examine the roles of hypocretins in nociception in mice. The presence of robust projections from the hypothalamus to laminae I and II of the spinal cord strongly suggests the role of hypocretins in the nociceptive pathways. Localization of the fibers of hypocretin-containing neurons in the hypothalamus, locus coeruleus, thalamus and periaqueductal gray is also consistent with their central roles in sensory processing. To investigate the role of these hypothalamic peptides, C57BL/6 mice were administered with hypocretin 1 and 2 (i.c.v.) and intrathecally (I.T.), and examined for pain thresholds using three kinds of nociceptive tasks. These included assays for thermal (hot-plate, tail-flick, paw-withdrawal), mechanical (tail-pressure), chemical (formalin, capsaicin and abdominal stretch) nociceptions and behavioral responses. The I.C.V. and I.T. administration of hypocretins produced morphine-like anti-nociceptive effects in mice. The anti-nociceptive effects of hypocretins 1 (orexin A) were more remarkable than those of hypocretins 2 (orexin B). The effects of hypocretin 1 were completely blocked by 3-dipropyl-8-cyclopentylxanthine (DPCPX), a nonselective adenosine receptor antagonist but not by naloxone. No motor impairments were observed with both of the compounds at the doses studied. The present findings suggested that the hypocretin-containing neurons in the hypothalamus have a potential role in the modulation of nociceptive transmission.