Malin David H, Henceroth Mallori M, Izygon Jonathan J, Nghiem Duyen M, Moon Will D, Anderson Andrea P, Madison Caitlin A, Goyarzu Pilar, Ma Jian-Nong, Burstein Ethan S
University of Houston-Clear Lake, Houston, TX 77058, United States.
University of Houston-Clear Lake, Houston, TX 77058, United States.
Neurosci Lett. 2015 Jan 1;584:141-5. doi: 10.1016/j.neulet.2014.10.018. Epub 2014 Oct 20.
Neuropeptide FF (NPFF) modulates opiate actions. It has pro-nociceptive effects, primarily through the NPFF receptor 1 subtype, and anti-nociceptive effects, primarily through the NPFFR2 subtype. AC-263093 is a small l, organic, systemically active molecule that was previously shown to functionally activate NPFFR2, but not NPFFR1. It was hypothesized that AC-263093 would attenuate morphine tolerance. Rats were tested for radiant heat tail-flick latency before and after 5 mg/kg morphine sulfate s.c. They were then rendered morphine-tolerant by continuous subcutaneous infusion of 17.52 mg/kg/day morphine sulfate. On the seventh day of infusion, they were retested for analgesia 10 and 20 min after 5mg/kg morphine sulfate s.c. Tolerance was indicated by reduction of morphine analgesia from the pre-infusion test. Fifty minutes prior to morphine challenge, rats received either 10 mg/kg i.p. AC-263093 or injection vehicle alone. AC-2623093-treated rats had far smaller tolerance scores than control rats. This drug effect was significant, p = 0.015. The same dose of AC-263093 had almost no analgesic effect in non-tolerant, saline-infused rats. In vitro experiments revealed that AC-263093 had equal affinity for NPFFR1 and NPFFR2, and functionally inactivated NPFFR1, in addition to its previously shown ability to activate NPFFR2. Thus, altering the balance between activation of NPFF receptor subtypes may provide one approach to reversing opiate tolerance.
神经肽FF（NPFF）可调节阿片类药物的作用。它具有促痛觉过敏作用，主要通过NPFF受体1亚型发挥作用；也具有抗痛觉过敏作用，主要通过NPFFR2亚型发挥作用。AC - 263093是一种小分子有机化合物，具有全身活性，先前的研究表明它可功能性激活NPFFR2，但不能激活NPFFR1。据推测，AC - 263093可减轻吗啡耐受性。对大鼠进行皮下注射5mg/kg硫酸吗啡前后的辐射热甩尾潜伏期测试。然后通过持续皮下输注17.52mg/kg/天的硫酸吗啡使大鼠产生吗啡耐受性。在输注的第7天，再次对大鼠进行皮下注射5mg/kg硫酸吗啡后10分钟和20分钟的镇痛测试。吗啡镇痛作用较输注前测试降低表明产生了耐受性。在吗啡激发前50分钟，大鼠腹腔注射10mg/kg的AC - 263093或仅注射溶媒。接受AC - 2623093治疗的大鼠的耐受性评分远低于对照大鼠。这种药物效应具有显著性，p = 0.015。相同剂量的AC - 263093对未产生耐受性、输注生理盐水的大鼠几乎没有镇痛作用。体外实验表明，AC - 263093对NPFFR1和NPFFR2具有同等亲和力，除了其先前显示的激活NPFFR2的能力外，还可使NPFFR1功能失活。因此，改变NPFF受体亚型激活之间的平衡可能是一种逆转阿片类药物耐受性的方法。
