New Morphine Analogs Produce Peripheral Antinociception within a Certain Dose Range of Their Systemic Administration
New Morphine Analogs Produce Peripheral Antinociception within a Certain Dose Range of Their Systemic Administration
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DOI：
10.1124/jpet.116.233551
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发表时间：
2016-10-01
影响因子：
3.5
通讯作者：
Al-Khrasani, Mahmoud
中科院分区：
文献类型：
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作者：
Lacko, Erzsebet;Riba, Pal;Al-Khrasani, Mahmoud
越来越多的数据支持外周阿片类药物的镇痛作用，特别是在炎性疼痛模型中。在这里，我们在注射完全弗氏佐剂诱发的炎性疼痛大鼠模型和醋酸诱发的内脏疼痛小鼠模型中检查了最近合成的 14-O-甲基吗啡-6-O-硫酸盐 (14-O-MeM6SU) 与吗啡-6-O-硫酸盐 (M6SU) 皮下注射的镇痛作用。与未发炎的爪子相比，皮下剂量的 14-O-MeM6SU 和 M6SU 分别高达 126 和 547 nmol/kg，在发炎的爪子中产生显着的皮下或足底纳洛酮甲碘化物 (NAL-M) 可逆的镇痛作用。这些剂量均未显着影响硫代丁巴比妥诱导的睡眠时间或大鼠肺部参数。然而，较高剂量的镇痛作用仅被 NAL-M 部分逆转，表明中枢神经系统的作用。在小鼠扭体试验中，皮下或脑室内注射后，14-O-MeM6SU 比 M6SU 更有效。两者均表现出较高的皮下/脑室内 ED50 比率。皮下注射的 14-O-MeM6SU 和 M6SU 的镇痛作用分别高达 136 和 3043 nmol/kg，可被皮下注射的 NAL-M 完全拮抗。此外，测试化合物在抗伤害剂量下抑制小鼠胃肠道转运。总而言之，这些研究结果表明，在特定剂量范围内全身给药与 M6SU 类似的新型化合物 14-O-MeM6SU 在大鼠和小鼠炎症性疼痛模型中显示出外周镇痛作用，而没有中枢不良反应。这些发现适用于雄性动物，并且必须在雌性动物中得到证实。因此，在限制进入大脑的情况下滴定阿片类化合物的全身剂量可能会提供具有临床重要性的外周镇痛作用。
Growing data support peripheral opioid antinociceptive effects, particularly in inflammatory pain models. Here, we examined the antinociceptive effects of subcutaneously administered, recently synthesized 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU) compared with morphine-6-O-sulfate (M6SU) in a rat model of inflammatory pain induced by an injection of complete Freund's adjuvant and in a mouse model of visceral pain evoked by acetic acid. Subcutaneous doses of 14-O-MeM6SU and M6SU up to 126 and 547 nmol/kg, respectively, produced significant and subcutaneous or intraplantar naloxone methiodide (NAL-M)-reversible antinociception in inflamed paws compared with noninflamed paws. Neither of these doses significantly affected thiobutabarbital-induced sleeping time or rat pulmonary parameters. However, the antinociceptive effects of higher doses were only partially reversed by NAL-M, indicating contribution of the central nervous system. In the mouse writhing test, 14-O-MeM6SU was more potent than M6SU after subcutaneous or intracerebroventricular injections. Both displayed high subcutaneous/intracerebroventricular ED50 ratios. The antinociceptive effects of subcutaneous 14-O-MeM6SU and M6SU up to 136 and 3043 nmol/kg, respectively, were fully antagonized by subcutaneous NAL-M. In addition, the test compounds inhibited mouse gastrointestinal transit in antinociceptive doses. Taken together, these findings suggest that systemic administration of the novel compound 14-O-MeM6SU similar to M6SU in specific dose ranges shows peripheral antinociception in rat and mouse inflammatory pain models without central adverse effects. These findings apply to male animals and must be confirmed in female animals. Therefore, titration of systemic doses of opioid compounds with limited access to the brain might offer peripheral antinociception of clinical importance.