Targeted inactivation of the neurotensin type 1 receptor reveals its role in body temperature control and feeding behavior but not in analgesia.
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.
Remaury
Anne
A
Department of Molecular and Functional Genomics, Sanofi-Synthelabo Recherche, Innopole, 31676 Labège Cedex, France.
Vita
Natalio
N
Gendreau
Sylvain
S
Jung
Mireille
M
Arnone
Michelle
M
Poncelet
Martine
M
Culouscou
Jean-Michel
JM
Le Fur
Gérard
G
Soubrié
Philippe
P
Caput
Daniel
D
Shire
David
D
Kopf
Manfred
M
Ferrara
Pascual
P
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001833:Body Temperature Regulation / Q000502:physiology*; D005247:Feeding Behavior / Q000502:physiology*; D005260:Female; D017353:Gene Deletion; D007035:Hypothermia / Q000139:chemically induced / Q000503:physiopathology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009478:Neuropeptide Y / Q000494:pharmacology; D009496:Neurotensin / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology; D018028:Receptors, Neurotensin / Q000235:genetics* / Q000378:metabolism*
D000700:Analgesics; D009478:Neuropeptide Y; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin