Jan. 15, 2002 CHAPEL HILL - A brain protein linked to narcolepsy, the sudden, uncontrollable and inexplicable onset of sleep, helps regulate bodily sensations.
Exactly how that protein, hypocretin-2, is involved in narcolepsy remains unclear. Indications are that people and animals exhibiting narcoleptic symptoms are deficient in this protein or the molecular receptor to which it attaches.
But the new findings by neuroscientists at the University of North Carolina at Chapel Hill and Yale University may open a door to the answer. Their report is the cover story for the January 15 issue of the Journal of Physiology.
According to Dr. Edward R. Perl, professor of cell and molecular physiology at UNC-Chapel Hill School of Medicine and the report's corresponding author, hypocretin peptides are distributed widely throughout the brain. They arise from part of the hypothalamus, a region prominently involved in regulation of the autonomic nervous system, endocrine activity, and mood and motivational states. Recently, these proteins have been implicated in the regulation of behaviors associated with arousal such as feeding and sleep.
Perl and his colleagues were intrigued by the observation that hypocretin nerve fibers terminate in a spinal cord region involved in sensations about pain-causing events.
"We wanted to learn the effects of hypocretin peptide on neurones of the dorsal portion of the spinal cord that processes information from pain and temperature sense organs. The protein the researchers tested was hypocrtin-2, which specifically target the cell receptor associated with narcolepsy. The effects they found were complex. Hypocretin-2 excited a subset of nerve cells in the outermost cell layers in the spinal dorsal horn, and apparently these neurons, in turn, inhibited activity of other neurons, "as if a complex re-setting of the apparatus that was receiving sensory input from the body is modulated by hypocretin," Perl said.
"Our presumption from these observations is that when neurons distributing hypocretin-2 become active, this produces a suppression of activity in certain neurons associated with pain and temperature sensation," he said.
Perl is no stranger to pain research. He was first to document the existence of nociceptors, sensory fibers specially activated by tissue damage and their relation to the pain sensation. "This is the first report on the effects of hypocretin on the spinal cord neurones," Perl stated.
It may be that a decrease of the protein "helps people sleep and minimizes attention to minor inputs. Conversely, an increase helps a person to continue to do an essential function like eating even when there are minor inputs from the peripheral nervous system, such as occurs when one sits on a rough edge," the neurophysiologist explained.
The implications for narcolepsy remain hypothetical, he added. "The link at this stage is circumstantial. But it does suggest there's a mechanism connecting what keeps us behaviorally awake to modulation of sensory input from the body. We've uncovered a piece of that mechanism."
Perl thinks "a much more general role" for hypocretin-2 exists than narcolepsy alone would suggest. "These proteins are obviously important and significant parts of the brain processes regulating essential behaviors."
Co-authors with Perl were Drs. Timothy J. Grudt of UNC and Anthony N. van den Pol of Yale University School of Medicine.
Study funding came from the National Institute of Neurological Disorders and Stroke, National Institutes of Health.
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