Hypothalamic Hypocretin (Orexin): Robust Innervation of the Spinal Cord

Abstract

Hypocretin (orexin) is synthesized by neurons in the lateral hypothalamus and has been reported to increase food intake and regulate the neuroendocrine system. In the present paper, long descending axonal projections that contain hypocretin were found that innervate all levels of the spinal cord from cervical to sacral segments, as studied in mouse, rat, and human spinal cord 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 intermediolateral column and lamina 10 as well as strong innervation of the caudal region of the sacral cord suggest that hypocretin may participate in the regulation of both the sympathetic and parasympathetic parts of the autonomic nervous system. Doublelabeling experiments in mice combining retrograde transport of diamidino yellow after spinal cord injections and immunocytochemistry support the concept that hypocretin-immunoreactive fibers in the cord originate from the neurons in the lateral hypothalamus. Digital-imaging physiological studies with fura-2 detected a rise in intracellular calcium in response to hypocretin in cultured rat spinal cord neurons, indicating that spinal cord neurons express hypocretin-responsive receptors. A greater number of cervical cord neurons responded to hypocretin than another hypothalamo-spinal neuropeptide, oxytocin. These data suggest that in addition to possible roles in feeding and endocrine regulation, the descending hypocretin fiber system may play a role in modulation of sensory input, particularly in regions of the cord related to pain perception and autonomic tone.

Neuropeptide Y Inhibits Hypocretin/Orexin Neurons by Multiple Presynaptic and Postsynaptic Mechanisms: Tonic Depression of the Hypothalamic Arousal System

“…In one model of a simple hypothalamic circuit mediating feeding, NPY neurons have been suggested to increase food intake by exciting the orexigenic melanin concentrating hormone (MCH) and hypocretin neurons (Elias et al, 1999;Schwartz et al, 2000;Saper et al, 2002;van den Pol, 2003). This would be consistent with the finding that CNS application of both NPY and hypocretin may increase food intake (Stanley et al, 1993;Sakurai et al, 1998) and the NPY innervation of hypocretin neurons (Broberger et al, 1998;Elias et al, 1998).…”

“…The hypocretin/orexin neurons of the brain are found scattered in the perifornical area/lateral hypothalamus (LH), and their axons project throughout the brain and spinal cord (Peyron et al, 1998;van den Pol, 1999). These neurons have been postulated to play a key role in arousal.…”

Changes in Biochemical Markers of Pain Perception and Stress Response After Spinal Manipulation

“…71 Orexinergic projections were identified in periaqueductal gray matter, the rostral ventral medulla, the dorsal horn, and the dorsal root ganglion. 21,33,67 Emerging evidence shows that the central nervous system administration (intracranial ventricle or intrathecal injection) of orexin A can suppress mechanical allodynia and thermal hypersensitivity in multiple pain models, suggesting the regulation of nociceptive processing via spinal and supraspinal mechanisms. 8,70 In addition, orexins showed antinociceptive effects on models of pain, such as neuropathic pain, carrageenan test, and postoperative pain.…”

Orexinergic bouton density is lower in the cerebral cortex of cetaceans compared to artiodactyls

“…In most mammals the majority of these orexinergic neurons are found within the lateral hypothalamus and perifornical area, but have also been observed in the zona incerta region and the ventrolateral hypothalamus near the optic tract (Peyron et al, 1998;van den Pol, 1999;Wagner et al, 2000;Iqbal et al, 2001;Moore et al, 2001;Yoshida et al, 2006;Nixon and Smale, 2007;Datta and MacLean, 2007;Ettrup et al, 2010;Kruger et al, 2010;Bhagwandin et al, 2011a,b;Gravett et al, 2011;Calvey et al, 2013;Dell et al, 2013;Maseko et al, 2013). A study by Dell et al (2012) comparing the distribution and number of orexinergic neurons in the brain of the giraffe and harbour porpoise showed an additional novel medially located parvocellular cluster of orexinergic neurons in the hypothalamus of these two species, which has since also been reported in the African elephant (Maseko et al, 2013).…”