Dubuc I, Sarret P, Labbé-Jullié C, Botto J M, Honoré E, Bourdel E, Martinez J, Costentin J, Vincent J P, Kitabgi P, Mazella J
Unité de Neuropsychopharmacologie Expérimentale, Centre National de la Recherche Scientifique (CNRS), 76803 Saint Etienne du Rouvray, France.
J Neurosci. 1999 Jan 1;19(1):503-10. doi: 10.1523/JNEUROSCI.19-01-00503.1999.
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.
神经肽神经降压素（NT）脑内注射后可引发体温降低和对纳洛酮不敏感的镇痛反应。近期使用NT激动剂和拮抗剂获得的药理学证据表明，这些效应是由一种不同于最初克隆的高亲和力NT受体（NTR1）的受体介导的。第二种NT受体（NTR2）的近期克隆促使我们评估其在NT诱导的镇痛中的作用。在小鼠脑室内注射来自NTR2的两种不同反义寡脱氧核苷酸，显著降低了NTR2 mRNA和蛋白质水平，并减弱了NT诱导的镇痛作用。这种效应具有特异性，因为NTR1水平未受影响，而正义或随机寡核苷酸则无作用。构效关系研究揭示了NT类似物的镇痛效力与其对NTR2的亲和力之间密切相关，并发现了该受体的强效和选择性激动剂。这些数据证实NTR1参与了NT引发的转向行为，并表明NTR2介导了NT诱导的镇痛作用。
