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.
Subject(s)
Carrier Proteins/physiology , Carrier Proteins/pharmacokinetics , Hyperalgesia/drug therapy , Hypothalamus/chemistry , Intracellular Signaling Peptides and Proteins , Neuropeptides/physiology , Neuropeptides/pharmacokinetics , Nociceptors/drug effects , Abdomen , Analgesics/pharmacokinetics , Anesthesia, Intravenous , Animals , Behavior, Animal/drug effects , Benzoxazoles/pharmacology , Carrageenan , Carrier Proteins/analysis , Female , Ganglia, Spinal/chemistry , Hyperalgesia/chemically induced , Hyperalgesia/physiopathology , Immunohistochemistry , Injections, Intraventricular , Male , Mice , Mice, Inbred ICR , Naloxone/pharmacology , Naphthyridines , Narcotic Antagonists/pharmacology , Neuropeptides/analysis , Orexin Receptors , Orexins , Pain Threshold/drug effects , Rats , Rats, Wistar , Receptors, G-Protein-Coupled , Receptors, Neuropeptide/analysis , Spinal Cord/chemistry , Urea/analogs & derivatives , Urea/pharmacologyABSTRACT
NGF is an important link between inflammation and hyperalgesia and interacts with many different mediators of inflammation, including the MAPK signaling pathway. In these studies, carrageenan-induced thermal hyperalgesia was evaluated in the mouse and the role of NGF and the MAPK pathway investigated. Carrageenan induced a time-dependent inflammation and thermal hyperalgesia, which was maximal 4 h post administration. Both indomethacin (0.3, 1.0 and 10 mg/kg s.c., 30 min pre-carrageenan) and morphine (0.4, 1.2, 4.0 mg/kg; s.c., 30 min pre-hyperalgesia measurement) significantly inhibited carrageenan-induced thermal hyperalgesia and indomethicin inhibited paw inflammation, demonstrating the model as suitable for the assessment of anti-hyperalgesic and anti-inflammatory agents. Anti-NGF (0.67 mg/kg sc, 60 min pre-carrageenan) produced a significant inhibition of thermal hyperalgesia, but not inflammation. NGF itself produced a time-dependent hyperalgesia, but not inflammation, following intraplantar injection. The specific MAPK pathway inhibitor, PD98059 (0.1, 0.3 and 1 mg/kg sc, 30 min pre-carrageenan) significantly inhibited carrageenan-induced hyperalgesia, but not inflammation. These data demonstrate a role for both NGF and the MAPK signaling pathway in the production of thermal hyperalgesia, but not inflammation, in the mouse.
