Estimation of the affinity of naloxone at supraspinal and spinal opioid receptors in vivo: studies with receptor selective agonists |
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| Authors: | J S Heyman R J Koslo H I Mosberg R J Tallarida F Porreca |
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| Institution: | 4. Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA;1. Bristol-Myers Products, Hillside, NJ 07207, USA;2. College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA;3. Department of Pharmacology, Temple University Medical School, Philadelphia, PA 19102, USA;1. Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland;1. Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea;2. Dental Research Institute and Department of Neurobiology & Physiology, School of Dentistry, Seoul National University, Seoul, Republic of Korea;1. Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia;2. Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia;3. Department of Physiology, Monash University, Clayton, VIC 3800, Australia;4. School of Medicine, IMPACT, Institute for Innovation in Mental and Physical Health and Clinical Translation, Deakin University, Waurn Ponds, VIC 3216, Australia;1. Life Science Research Institute, Kindai University, Osaka-Sayama, Osaka, 589-8511, Japan;2. Department of Neurology, Kindai University, Faculty of Medicine, Osaka-Sayama, Osaka, 589-8511, Japan |
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| Abstract: | The apparent affinity of naloxone at cerebral and spinal sites was estimated using selective mu D-Ala2, Gly-o15]-enkephalin (DAGO) and delta D-Pen2, D-Pen5]enkephalin] (DPDPE) opioid agonists in the mouse warm water tail-withdrawal test in vivo; the mu agonist morphine was employed as a reference compound. The approach was to determine the naloxone pA2 using a time-dependent method with both agonist and antagonist given intracerebroventricularly (i.c.v.) or intrathecally (i.th.); naloxone was always given 5 min before the agonist. Complete time-response curves were determined for each agonist at each site in the absence, and in the presence, of a single, fixed i.c.v. or i.th. dose of naloxone. From these i.c.v. or i.th. pairs of time-response curves, pairs of dose-response lines were constructed at various times; these lines showed decreasing displacement with time, indicative of the disappearance of naloxone. The graph of log (dose ratio-1) vs. time was linear with negative slope, in agreement with the time-dependent form of the equation for competitive antagonism. From this plot, the apparent pA2 and naloxone half-life was calculated at each site and against each agonist. The affinity of naloxone was not significantly different when compared between agonists after i.c.v. administration. A small difference was seen between the affinity of i.th. naloxone against DPDPE and DAGO; the i.th. naloxone pA2 against morphine, however, was not different than that for DPDPE and DAGO. The naloxone half-life varied between 6.6 and 16.9 min, values close to those previously reported for this compound. These results suggest that the agonists studied may produce their i.c.v. analgesic effects at the same receptor type or that alternatively, the naloxone pA2 may be fortuitously similar for mu and delta receptors in vivo. Additionally, while the affinity of naloxone appears different for the receptors activated by i.th. DAGO and DPDPE, further work may be necessary before firm conclusions regarding the nature of the spinal analgesic receptor(s) can be drawn. |
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