Remaury Anne, Vita Natalio, Gendreau Sylvain, Jung Mireille, Arnone Michelle, Poncelet Martine, Culouscou Jean-Michel, Le Fur Gérard, Soubrié Philippe, Caput Daniel, Shire David, Kopf Manfred, Ferrara Pascual
Department of Molecular and Functional Genomics, Sanofi-Synthelabo Recherche, Innopole, 31676 Labège Cedex, France.
Brain Res. 2002 Oct 25;953(1-2):63-72. doi: 10.1016/s0006-8993(02)03271-7.
Three subtypes of neurotensin receptor have been described, two members of the heptahelical transmembrane domain G protein-coupled receptor superfamily NT-1R and NT-2R, and NT-3R unrelated to this family. We have generated NT-1R deficient (NT-1R(-/-)) mice. NT-1R(-/-) mice were born at the expected Mendelian frequency without obvious abnormalities and they were fertile. The NT-induced analgesia on the writhing induced by phenyl-p-benzoquinone administration remained at wild-type levels in the NT-1R(-/-) mice demonstrating that the NT-1R is not implicated in the analgesic effect of NT in this test. The NT-1R(-/-) mice were hyperthermic; their body temperature was not affected by intracerebroventricular (i.c.v.) administration of NT, contrasting with the hypothermia induced in NT-1R(+/+) mice. NT-1R(-/-) mice showed a small significant increase in body weight compared to the NT-1R(+/+) congeners as early as 10 weeks after birth, correlated with a higher food intake. NT-1R(-/-) mice showed similar spontaneous locomotion to the control littermates, but did not respond to i.c.v. NT-induced hypolocomotion. I.c.v. injection of NT inhibited feeding in fasted wild-type mice, but had no effect on feeding of the NT-1R(-/-) mice. I.c.v. administration of the orexigenic neuropeptide Y (NPY) stimulated feeding to the same extent in both wild-type and NT-1R(-/-) mice. This analysis of NT-1R-deficient mice shows that the NT-1R does not play a role in NT-induced analgesia, but that it is clearly implicated in thermal and feeding regulation, weight control, and NT-induced hypolocomotion.
已发现神经降压素受体有三种亚型，其中两种是七螺旋跨膜结构域G蛋白偶联受体超家族的成员，即NT-1R和NT-2R，而NT-3R与该家族无关。我们培育出了NT-1R基因缺陷（NT-1R(-/-)）小鼠。NT-1R(-/-)小鼠以预期的孟德尔频率出生，无明显异常，且具有生育能力。在NT-1R(-/-)小鼠中，由苯对苯醌给药诱导的扭体反应中，神经降压素诱导的镇痛作用仍维持在野生型水平，这表明在该试验中NT-1R与神经降压素的镇痛作用无关。NT-1R(-/-)小鼠体温过高；与NT-1R(+/+)小鼠中诱导的体温过低相反，其体温不受脑室内（i.c.v.）注射神经降压素的影响。与NT-1R(+/+)同窝小鼠相比，NT-1R(-/-)小鼠早在出生后10周体重就有小幅但显著的增加，这与更高的食物摄入量相关。NT-1R(-/-)小鼠表现出与对照同窝小鼠相似的自发活动，但对i.c.v.注射神经降压素诱导的活动减少无反应。i.c.v.注射神经降压素可抑制禁食野生型小鼠的进食，但对NT-1R(-/-)小鼠的进食无影响。i.c.v.给予促食欲神经肽Y（NPY）在野生型和NT-1R(-/-)小鼠中对进食的刺激程度相同。对NT-1R基因缺陷小鼠的这项分析表明，NT-1R在神经降压素诱导的镇痛中不起作用，但显然与体温调节、进食调节、体重控制以及神经降压素诱导的活动减少有关。
