Species differences in the behavioral toxicity produced by intrathecal substance P antagonists: relationship to analgesia |
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| Authors: | J L Vaught R Scott |
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| Affiliation: | 1. Centre d’Enseignement et de Recherche en Nutrition Humaine, Centre Hospitalier de Bretagne Sud, 5 Avenue De Choiseul, BP 12233, 56322 Lorient Cedex, France;2. Laboratoires Le Stum, 4 impasse de Kerhoas, 56260 Larmor Plage, France;3. Unité de Biochimie Hormonale et Nutritionnelle, Département de Biochimie, Toxicologie et Pharmacologie, Institut de Biologie et de Pathologie, Centre Hospitalier Universitaire de Grenoble, CS10217, 38043 Grenoble, France;1. Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, 10617, Taiwan;2. Department of Water Resources and Environmental Engineering, Tamkang University, New Taipei City, 25137, Taiwan;3. Research Center for Environmental Changes, Academia Sinica, Taipei, 11529, Taiwan;1. Department of Epidemiology and Biostatistics, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang Province, People’s Republic of China;2. Department of Gynecologic Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning Province, People’s Republic of China;3. Department of Epidemiology and Biostatistics, and National Clinical Research Center for Child Health of the Children''s Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang Province, People’s Republic of China |
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| Abstract: | Intrathecal administration of [D-Pro2,D-Trp7,9]-substance P to rats produced an irreversible flaccid paralysis of the hind limbs (paraplegia) which was irreversible with an ED50 of 2.3 micrograms. At 5 micrograms intrathecally, [D-Pro2,D-Phe7,D-Trp9]-substance P, [D-Trp7,9]-substance P and [D-Pro4,D-Trp7,9,10]-substance P octapeptide also produced paraplegia (70-80%). Surprisingly, intrathecal administration of up to 20 micrograms of these analogs to the mouse produced no paraparesis or paraplegia. In the guinea pig or rabbit, 20 micrograms of [D-Pro2,D-Trp7,9]-substance P or [D-Pro4,D-Trp7,9,10]-substance P octapeptide were also devoid of paraparetic effects. Lidocaine hydrochloride, on the other hand, was equieffective across species in producing paraplegia (which was reversible) suggesting that interspecies susceptibility is not a factor in the marked species differences between substance P analogs. In the mouse, intrathecal [D-Pro2,D-Trp7,9]-substance P was active in tail-flick and hot-plate tests at doses showing no overt behavioral effects but in the rat was not analgesic at sub-paraplegic doses. Lidocaine hydrochloride (i.t.) was analgesic in mouse and rat tail-flick tests at doses two times less than paraplegic doses; however, there was an overlap in analgesic and paraplegic doses. Based on these data, we suggest that the rat is unique in being extremely sensitive to the paraplegic effects of intrathecal neurokinin antagonists and may simply be a poor species in which to study the spinal functionality of neurokinins. |
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