Dose-related opposite modulation by nociceptin/orphanin FQ of substance P nociception in the nociceptors and spinal cord

作     者：Inoue, M Shimohira, I Yoshida, A Zimmer, A Takeshima, H Sakurada, T Ueda, H 

作者机构：Nagasaki Univ Sch Pharmaceut Sci Dept Mol Pharmacol & Neurosci Nagasaki 8528521 Japan NIMH Genet Sect Bethesda MD 20892 USA Univ Tokyo Fac Med Dept Pharmacol Tokyo 113 Japan Daiichi Coll Pharmaceut Sci Dept Biochem Fukuoka 815 Japan 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：1999年第291卷第1期

页      面：308-313页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

主　　题：镇痛药/药理学 剂量效应关系 药物 药物相互作用 神经元/药物作用 神经元/代谢 疼痛感受器/药物作用 疼痛感受器/代谢 阿片样肽类/药理学 疼痛测定 脊髓/药物作用 脊髓/代谢 P物质/代谢 突触/药物作用 突触/代谢 血管舒张药/药理学 动物 男(雄)性 小鼠 

摘      要：We previously reported that the intraplantar (***.) application of nociceptin/orphanin FQ (N/OFQ) at extremely low doses elicited a nociception through a substance P (SP) release from nociceptor endings. In the present study, the nociception induced by SP (and N/OFQ) was abolished by intrathecal (i.t.) injection of neurokinin(1) (SP receptor) antagonist, suggesting the involvement of the stimulation of nociceptive primary SP neuron and SP release into spinal synapses. On the other hand, similar low doses of N/OFQ (i.t.) exerted nociceptive responses, characterized by scratching, biting, and licking, and these responses were blocked by an neurokinin(1) antagonist (i.t.) or capsaicin pretreatment or in tachykinin 1 gene knockout mice (tac1(-/-) mice), suggesting that N/OFQ receptor (NOR) also exists on the spinal terminals of SP neurons. When wide ranges of N/OFQ doses were used, a typical bell-shaped dose-response relationship was observed in both peripheral and central nociception tests. Furthermore, N/OFQ (1 nmol) administered ***. blocked SP (***.)-induced flexor responses, which were abolished by pertussis toxin pretreatment or in NOR gene knockout (NOR-/-) mice. On the other hand, N/OFQ administered i.t. blocked SP (i.t.)-induced scratching, biting, and licking in capsaicin-pretreated and tac1(-/-) mice, and this antinociception was abolished in NOR-/- mice. All these findings suggest that N/OFQ has biphasic actions depending on doses in the nociceptors and spinal synapses and has postsynaptic antinociceptive actions in spinal cord by modulating SP signaling.