Noda Y, Mamiya T, Nabeshima T, Nishi M, Higashioka M, Takeshima H
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Showa-ku, Nagoya 466-8560, Japan.
J Biol Chem. 1998 Jul 17;273(29):18047-51. doi: 10.1074/jbc.273.29.18047.
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 brain, however, the physiological role of the modulation via the nociceptin receptor is still unclear. Administered nociceptin produces hyperalgesia and hypolocomotion, whereas the nociceptin receptor-knockout mice show no significant abnormalities in nociceptive thresholds and locomotion. To clarify possible involvement of the nociceptin receptor in the regulation of nociception and locomotion, we made use of the knockout mice and naloxone benzoylhydrazone (NalBzoH) identified originally as a ligand for opioid receptors. Experiments on the cultured cells transfected with the nociceptin receptor cDNA showed that NalBzoH competed with [3H]nociceptin binding and attenuated the nociceptin-induced inhibition of cAMP accumulation. Furthermore, behavioral studies demonstrated that NalBzoH completely inhibited nociceptin-induced hyperalgesia and hypolocomotion. It is therefore likely that NalBzoH can act as a potent antagonist for the nociceptin receptor in vivo. In wild-type mice, NalBzoH induced antinociception but did not affect locomotor activity. In contrast, in the knockout mice, no significant changes in nociception and locomotion were induced by NalBzoH. These results clearly suggest that the nociceptin system takes part in the physiological regulation of nociceptive thresholds but not in the basal modulation of locomotion.
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，最近被发现构成一种新型神经调节系统。然而，在大脑中，通过痛敏肽受体进行调节的生理作用仍不清楚。给予痛敏肽会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和运动方面未表现出明显异常。为了阐明痛敏肽受体在痛觉和运动调节中可能的作用，我们利用了基因敲除小鼠和最初被鉴定为阿片受体配体的纳洛酮苯甲酰腙（NalBzoH）。对转染了痛敏肽受体cDNA的培养细胞进行的实验表明，NalBzoH与[3H]痛敏肽结合竞争，并减弱了痛敏肽诱导的cAMP积累抑制。此外，行为学研究表明，NalBzoH完全抑制了痛敏肽诱导的痛觉过敏和运动减少。因此，NalBzoH在体内可能作为痛敏肽受体的有效拮抗剂。在野生型小鼠中，NalBzoH诱导镇痛，但不影响运动活性。相反，在基因敲除小鼠中，NalBzoH未诱导痛觉和运动的显著变化。这些结果清楚地表明，痛敏肽系统参与痛觉阈值的生理调节，但不参与运动的基础调节。
