Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, China.
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou, China.
J Pharm Pharmacol. 2017 Sep;69(9):1244-1251. doi: 10.1111/jphp.12761. Epub 2017 Jun 16.
Chimeric peptide MCRT, based on morphiceptin and PFRTic-NH , was a bifunctional ligand of μ- and δ-opioid receptors (MOR-DOR) and produced potent analgesia in tail-withdrawal test. The study focused on the supraspinal effects of morphiceptin, PFRTic-NH and MCRT on gastrointestinal motility. Moreover, opioid receptor antagonists, naloxone (non-selective), cyprodime (MOR selective) and naltrindole (DOR selective) were utilized to explore the mechanisms.
Intracerebroventricular administration was achieved via the implanted cannula. Gastric emptying and intestinal transit were measured to evaluate gastrointestinal motility.
(1) At supraspinal level, morphiceptin, PFRTic-NH and MCRT significantly decreased gastric emptying and intestinal transit; (2) MCRT at 1 nmol/mouse, far higher than its analgesic dose (ED = 29.8 pmol/mouse), failed to regulate the gastrointestinal motility; (3) MCRT-induced gastrointestinal dysfunction could be completely blocked by naloxone and naltrindole, but not affected by cyprodime.
(1) Morphiceptin and PFRTic-NH played important roles in the regulation of gastrointestinal motility; (2) MCRT possessed higher bioactivity of pain relief than gastrointestinal regulation, suggesting its promising analgesic property; (3) MCRT-induced motility disorders were sensitive to DOR but not to MOR blockade, indicating the pain-relieving specificity of speculated MOR subtype or splice variant or MOR-DOR heterodimer.
基于吗啡肽和 PFRTic-NH 的嵌合肽 MCRT 是 μ 和 δ 阿片受体（MOR-DOR）的双功能配体，在尾部退缩试验中产生强烈的镇痛作用。本研究侧重于吗啡肽、PFRTic-NH 和 MCRT 对胃肠道动力的中枢效应。此外，还利用阿片受体拮抗剂纳洛酮（非选择性）、环丙甲羟二羟吗啡酮（MOR 选择性）和纳曲吲哚（DOR 选择性）来探讨其机制。
通过植入的套管进行脑室内给药。胃排空和肠传输用于评估胃肠道动力。
（1）在中枢水平，吗啡肽、PFRTic-NH 和 MCRT 显著降低胃排空和肠传输；（2）MCRT 以 1 nmol/只（远远高于其镇痛剂量 ED = 29.8 pmol/只）给药，不能调节胃肠道动力；（3）MCRT 诱导的胃肠道功能障碍可被纳洛酮和纳曲吲哚完全阻断，但不受环丙甲羟二羟吗啡酮影响。
（1）吗啡肽和 PFRTic-NH 在调节胃肠道动力方面发挥着重要作用；（2）MCRT 具有比胃肠道调节更高的镇痛生物活性，表明其具有很好的镇痛特性；（3）MCRT 诱导的运动障碍对 DOR 敏感而不受 MOR 阻断的影响，提示推测的 MOR 亚型或剪接变体或 MOR-DOR 异二聚体的镇痛特异性。
