Noda Y, Mamiya T, Nabeshima T
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Japan.
Nihon Shinkei Seishin Yakurigaku Zasshi. 1999 Apr;19(2):73-8.
Nociceptin and nociceptin receptor, which show structural similarities to opioid peptides and opioid receptors, respectively, have been recently found to constitute a novel neuromodulatory system. In the central nervous system, however, the physiological role of modulation via the nociceptin receptor is still unclear. Here, we report the behavioral pharmacological characterization of mice lacking the nociceptin receptor. Nociceptin produced hyperalgesia and hypolocomotion, whereas the nociceptin receptor-knockout mice showed no significant abnormalities in nociceptive thresholds (tail-flick, hot-plate, electric, and acetic acid-induced writhing tests) and locomotion. In the learning and memory tests, nociceptin induced impairment of learning and memory in wild-type mice. Nociceptin receptor-knockout mice possessed greater learning ability and had better memory than wild-type mice. These results suggest that the nociceptin system plays a role in regulation of nociception or locomotion and seems to play negative roles in learning and memory. Next, we compared nociceptive responses induced by various opioids between the nociceptin receptor-knockout and wild-type mice. As previously reported, morphine (mu-opioid receptor agonist), U-50,488 H (kappa 1-opioid receptor agonist), and naloxone benzoylhydrazone (NalBzoH; kappa 3-opioid receptor agonist) induced antinociceptive effects in wild-type mice. Surprisingly, knockout mice lacked the antinociceptive effect induced by NalBzoH, but not by morphine and U-50,488H. Further, NalBzoH completely inhibited nociceptin-induced hyperalgesia and hypolocomotion in wild-type mice. Experiments on the cultured cells transfected with the nociceptin receptor cDNA showed that NalBzoH competed in [3H]-nociceptin binding and attenuated the nociceptin-induced inhibition of cyclic AMP accumulation induced by forskolin. These results clearly suggest that NalBzoH acts as a potent antagonist for the nociceptin receptor. Our studies suggest that the nociceptive system and/or learning and memory processes could be modulated by ligands to the nociceptin receptor, and further that the antagonists are worth testing for the alleviation of pain and memory disorders.
痛敏肽和痛敏肽受体分别与阿片肽和阿片受体在结构上具有相似性，最近发现它们构成了一个新的神经调节系统。然而，在中枢神经系统中，通过痛敏肽受体进行调节的生理作用仍不清楚。在此，我们报告了缺乏痛敏肽受体的小鼠的行为药理学特征。痛敏肽可产生痛觉过敏和运动减少，而痛敏肽受体基因敲除小鼠在痛觉阈值（甩尾、热板、电刺激和醋酸诱导扭体试验）和运动方面未表现出明显异常。在学习和记忆测试中，痛敏肽可导致野生型小鼠学习和记忆受损。痛敏肽受体基因敲除小鼠比野生型小鼠具有更强的学习能力和更好的记忆力。这些结果表明，痛敏肽系统在痛觉或运动调节中发挥作用，且似乎在学习和记忆中起负面作用。接下来，我们比较了痛敏肽受体基因敲除小鼠和野生型小鼠对各种阿片类药物诱导的痛觉反应。如先前报道，吗啡（μ阿片受体激动剂）、U-50,488 H（κ1阿片受体激动剂）和纳洛酮苯甲酰腙（NalBzoH；κ3阿片受体激动剂）在野生型小鼠中诱导产生镇痛作用。令人惊讶的是，基因敲除小鼠缺乏NalBzoH诱导的镇痛作用，但吗啡和U-50,488H诱导的镇痛作用不受影响。此外，NalBzoH可完全抑制野生型小鼠中痛敏肽诱导的痛觉过敏和运动减少。对转染了痛敏肽受体cDNA的培养细胞进行的实验表明，NalBzoH可竞争[3H]-痛敏肽结合，并减弱痛敏肽诱导的由福司可林引起的环磷酸腺苷积累的抑制作用。这些结果清楚地表明，NalBzoH可作为痛敏肽受体的有效拮抗剂。我们的研究表明，痛觉系统和/或学习与记忆过程可通过痛敏肽受体的配体进行调节，而且进一步表明，拮抗剂在缓解疼痛和记忆障碍方面值得进行测试。
