Identification of the Receptor Subtype Involved in the Analgesic Effect of Neurotensin

The neuropeptide neurotensin (NT) elicits hypothermic and naloxone-insensitive analgesic responses after brain injection. Recent pharmacological evidence obtained with NT agonists and antagonists suggests that these effects are mediated by a receptor distinct from the initially cloned high-affinity...

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Bibliographic Details
Published in:The Journal of neuroscience 1999-01, Vol.19 (1), p.503-510
Main Authors: Dubuc, Isabelle, Sarret, Philippe, Labbe-Jullie, Catherine, Botto, Jean-Marie, Honore, Eric, Bourdel, Elisabeth, Martinez, Jean, Costentin, Jean, Vincent, Jean-Pierre, Kitabgi, Patrick, Mazella, Jean
Format: Article
Language:English
Subjects:
Analgesics - pharmacology
Analysis of Variance
Animals
Body Temperature Regulation - drug effects
CHO Cells
Cricetinae
Injections, Intraventricular
Male
Mice
Neurotensin - metabolism
Neurotensin - pharmacology
Oligodeoxyribonucleotides, Antisense
Receptors, Neurotensin - drug effects
Receptors, Neurotensin - metabolism
RNA, Messenger - biosynthesis
Structure-Activity Relationship
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Summary:The neuropeptide neurotensin (NT) elicits hypothermic and naloxone-insensitive analgesic responses after brain injection. Recent pharmacological evidence obtained with NT agonists and antagonists suggests that these effects are mediated by a receptor distinct from the initially cloned high-affinity NT receptor (NTR1). The recent cloning of a second NT receptor (NTR2) prompted us to evaluate its role in NT-induced analgesia. Intracerebroventricular injections in mice of two different antisense oligodeoxynucleotides from the NTR2 markedly decreased NTR2 mRNA and protein and reduced NT-induced analgesia. This effect was specific, because NTR1 levels were unaffected, and sense or scramble oligodeoxynucleotides had no effect. Structure-activity studies revealed a close correlation between the analgesic potency of NT analogs and their affinity for the NTR2 and disclosed potent and selective agonists of this receptor. These data confirm that NTR1 is involved in the NT-elicited turning behavior and demonstrate that the NTR2 mediates NT-induced analgesia.
ISSN:0270-6474
1529-2401
DOI:10.1523/jneurosci.19-01-00503.1999