Gergen K A, Zadina J E, Paul D
Tulane University School of Medicine, New Orleans, LA 70146, USA.
Eur J Pharmacol. 1996 Nov 28;316(1):33-8. doi: 10.1016/s0014-2999(96)00656-5.
Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) is a naturally occurring neuropeptide that displays high selectivity for mu-opioid receptors. Recently, intrathecal (i.t.) Tyr-W-MIF-1 was shown to induce potent analgesia mediated through spinal mu2-opioid receptors in mice. In the current study, we investigated the supraspinal analgesic effects of Tyr-W-MIF-1 using intracerebroventricular (i.c.v.) administration in mice. I.c.v. Tyr-W-MIF-1 induced a dose-dependent analgesic response with an ED50 of 31.4 micrograms that was antagonized by i.c.v. naloxone (ED50 = 4.46 nmol) and the mu-opioid receptor antagonist beta-funaltrexamine but not by the mu1-opioid receptor-selective antagonist naloxonazine. I.t. naloxone (ED50 = 0.12 nmol), however, was nearly 40-fold more potent than i.c.v. naloxone at antagonizing i.c.v. Tyr-W-MIF-1-induced analgesia. Tyr-W-MIF-1 also possesses antagonist activity at mu1-opioid receptors in brain. Coadministration of i.c.v. Tyr-W-MIF-1 with i.c.v. morphine or i.c.v. [D-Ala2, MePhe4, Gly(ol)5]enkephalin (DAMGO) significantly decreased the analgesic response to either drug administered alone. Thus, Tyr-W-MIF-1 functions as a mixed mu2-opioid receptor agonist/mu1-opioid receptor antagonist after i.c.v. administration in mice.
酪氨酰 - 色氨酰 - 甲硫氨酸脑啡肽 -1（Tyr - Pro - Trp - Gly - NH2）是一种天然存在的神经肽，对μ - 阿片受体具有高度选择性。最近研究表明，鞘内注射（i.t.）酪氨酰 - 色氨酰 - 甲硫氨酸脑啡肽 -1可通过小鼠脊髓μ2 - 阿片受体诱导强效镇痛。在本研究中，我们通过向小鼠脑室内（i.c.v.）给药来研究酪氨酰 - 色氨酰 - 甲硫氨酸脑啡肽 -1的脊髓上镇痛作用。脑室内注射酪氨酰 - 色氨酰 - 甲硫氨酸脑啡肽 -1可诱导剂量依赖性镇痛反应，半数有效剂量（ED50）为31.4微克，脑室内注射纳洛酮（ED50 = 4.46纳摩尔）和μ - 阿片受体拮抗剂β - 氟纳曲明可拮抗该反应，但μ1 - 阿片受体选择性拮抗剂纳洛酮嗪则不能。然而，鞘内注射纳洛酮（ED50 = 0.12纳摩尔）在拮抗脑室内注射酪氨酰 - 色氨酰 - 甲硫氨酸脑啡肽 -1诱导的镇痛作用方面，效力比脑室内注射纳洛酮强近40倍。酪氨酰 - 色氨酰 - 甲硫氨酸脑啡肽 -1在脑中的μ1 - 阿片受体上也具有拮抗活性。脑室内注射酪氨酰 - 色氨酰 - 甲硫氨酸脑啡肽 -1与脑室内注射吗啡或脑室内注射[D - Ala2，MePhe4，Gly(ol)5]脑啡肽（DAMGO）共同给药时，可显著降低单独给予任何一种药物时的镇痛反应。因此，在小鼠脑室内给药后，酪氨酰 - 色氨酰 - 甲硫氨酸脑啡肽 -1作为一种混合的μ2 - 阿片受体激动剂/μ1 - 阿片受体拮抗剂发挥作用。
