Abstract
The hypothalamic peptide orexin-A and the orexin-1 receptor are localized in areas of the brain and spinal cord associated with nociceptive processing. In the present study, localization was confirmed in the spinal cord and demonstrated in the dorsal root ganglion for both orexin-A and the orexin-1 receptor. The link with nociception was extended when orexin-A was shown to be analgesic when given i.v. but not s.c. in mouse and rat models of nociception and hyperalgesia. The efficacy of orexin-A was similar to that of morphine in the 50 degrees C hotplate test and the carrageenan-induced thermal hyperalgesia test. However, involvement of the opiate system in these effects was ruled out as they were blocked by the orexin-1 receptor antagonist SB-334867 but not naloxone. Orexin-1 receptor antagonists had no effect in acute nociceptive tests but under particular inflammatory conditions were pro-hyperalgesic, suggesting a tonic inhibitory orexin drive in these circumstances. These data demonstrate that the orexinergic system has a potential role in the modulation of nociceptive transmission.
MeSH terms
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Abdomen
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Analgesics / pharmacokinetics
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Anesthesia, Intravenous
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Animals
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Behavior, Animal / drug effects
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Benzoxazoles / pharmacology
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Carrageenan
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Carrier Proteins / analysis
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Carrier Proteins / pharmacokinetics*
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Carrier Proteins / physiology*
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Female
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Ganglia, Spinal / chemistry
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Hyperalgesia / chemically induced
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Hyperalgesia / drug therapy*
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Hyperalgesia / physiopathology
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Hypothalamus / chemistry*
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Immunohistochemistry
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Injections, Intraventricular
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Intracellular Signaling Peptides and Proteins*
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Male
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Mice
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Mice, Inbred ICR
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Naloxone / pharmacology
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Naphthyridines
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Narcotic Antagonists / pharmacology
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Neuropeptides / analysis
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Neuropeptides / pharmacokinetics*
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Neuropeptides / physiology*
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Nociceptors / drug effects*
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Orexin Receptors
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Orexins
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Pain Threshold / drug effects
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Rats
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Rats, Wistar
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Receptors, G-Protein-Coupled
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Receptors, Neuropeptide / analysis
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Spinal Cord / chemistry
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Urea / analogs & derivatives
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Urea / pharmacology
Substances
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1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea
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Analgesics
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Benzoxazoles
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Carrier Proteins
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Intracellular Signaling Peptides and Proteins
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Naphthyridines
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Narcotic Antagonists
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Neuropeptides
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Orexin Receptors
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Orexins
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Receptors, G-Protein-Coupled
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Receptors, Neuropeptide
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Naloxone
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Urea
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Carrageenan