Hypothalamic hypocretin (orexin): Robust innervation of the spinal cord

Hypocretin (orexin) is synthesized by neurons in the lateral hypothalamus a nd has been reported to increase food intake and regulate the neuroendocrin e system. In the present paper, long descending axonal projections that con tain hypocretin were found that innervate all levels of the spinal cord fro m cervical to sacral segments, as studied in mouse, rat, and human spinal c ord and not previously described. High densities of axonal innervation are found in regions of the spinal cord related to modulation of sensation and pain, notably in the marginal zone (lamina 1). Innervation of the intermedi olateral column and lamina 10 as well as strong innervation of the caudal r egion of the sacral cord suggest that hypocretin may participate in the reg ulation of both the sympathetic and parasympathetic parts of the autonomic nervous system. Double-labeling experiments in mice combining retrograde tr ansport of diamidino yellow after spinal cord injections and immunocytochem istry support the concept that hypocretin-immunoreactive fibers in the cord originate from the neurons in the lateral hypothalamus. Digital-imaging ph ysiological studies with fura-e detected a rise in intracellular calcium in response to hypocretin in cultured rat spinal cord neurons, indicating tha t spinal cord neurons express hypocretin-responsive receptors. A greater nu mber of cervical cord neurons responded to hypocretin than another hypothal amo-spinal neuropeptide, oxytocin. These data suggest that in addition to p ossible roles in feeding and endocrine regulation, the descending hypocreti n fiber system may play a role in modulation of sensory input, particularly in regions of the cord related to pain perception and autonomic tone.