Identification of the receptor subtype involved in the analgesic effect ofneurotensin

The neuropeptide neurotensin (NT) elicits hypothermic and naloxone-insensit ive analgesic responses after brain injection. Recent pharmacological evide nce obtained with NT agonists and antagonists suggests that these effects a re mediated by a receptor distinct from the initially cloned high-affinity MT receptor (NTR1), The recent cloning of a second NT receptor (NTR2) promp ted us to evaluate its role in NT-induced analgesia. Intracerebroventricula r injections in mice of two different antisense oligodeoxynucleotides from the NTR2 markedly decreased NTR2 mRNA and protein and reduced NT-induced an algesia. 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 an alogs and their affinity for the NTR2 and disclosed potent and selective ag onists of this receptor. These data confirm that NTR1 is involved in the NT -elicited turning behavior and demonstrate that the NTR2 mediates NT-induce d analgesia.