Effects of μ-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of μ-Agonist Efficacy and Noxious Stimulus Intensity
Effects of μ-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of μ-Agonist Efficacy and Noxious Stimulus Intensity
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DOI：
10.1124/jpet.114.219873
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发表时间：
2015-02-01
影响因子：
3.5
通讯作者：
Negus, S. Stevens
中科院分区：
文献类型：
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作者：
Altarifi, Ahmad A.;Rice, Kenner C.;Negus, S. Stevens
疼痛与某些行为的刺激和其他行为的抑制有关，Mu-阿片受体激动剂是最广泛使用的止痛药之一。本研究通过对雄性SD大鼠疼痛刺激和疼痛抑制行为的平行分析，比较了六种不同的MU激动剂在MU阿片受体上的药效差异(从高到低依次为：美沙酮、芬太尼、吗啡、氢可酮、丁丙诺啡和纳布芬)。在颅内自我刺激(ICSS)中，腹腔注射稀释乳酸可作为急性伤害性刺激，刺激伸展或抑制由电刺激维持的操作者反应。所有MU激动剂均可阻断1.8%乳酸对ICSS的收缩和抑制作用。高效激动剂美沙酮和芬太尼在阻断酸诱导的ICSS抑制方面比酸刺激的伸展更有效，而低效激动剂在不同试验中显示出类似的效力。除吗啡外，所有MU激动剂在无伤害性刺激的情况下也促进ICSS，其剂量与阻断酸诱导的ICSS抑制的剂量相似。当伤害性刺激强度增加到5.6%时，低效Mu激动剂纳布芬(Nalbuphine)对ICSS酸诱导的抑制的阻断力显著降低，而高效Mu激动剂美沙酮(MAP)的阻断力不明显。这些结果证明了酸诱导的ICSS抑制对一系列临床有效的u阿片类止痛剂的敏感性，并揭示了基于u受体有效性的阿片类药物之间的差异。这些结果也支持使用疼痛刺激和抑郁行为的平行分析来评估候选药物的止痛效果。
Pain is associated with stimulation of some behaviors and depression of others, and mu-opioid receptor agonists are among the most widely used analgesics. This study used parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats to compare antinociception profiles for six mu-agonists that varied in efficacy at mu-opioid receptors (from highest to lowest: methadone, fentanyl, morphine, hydrocodone, buprenorphine, and nalbuphine). Intraperitoneal injection of diluted lactic acid served as an acute noxious stimulus to either stimulate stretching or depress operant responding maintained by electrical stimulation in an intracranial self-stimulation (ICSS). All mu-agonists blocked both stimulation of stretching and depression of ICSS produced by 1.8% lactic acid. The high-efficacy agonists methadone and fentanyl were more potent at blocking acid-induced depression of ICSS than acid-stimulated stretching, whereas lower-efficacy agonists displayed similar potency across assays. All mu-agonists except morphine also facilitated ICSS in the absence of the noxious stimulus at doses similar to those that blocked acid-induced depression of ICSS. The potency of the low-efficacy mu-agonist nalbuphine, but not the high-efficacy mu-agonist methadone, to block acid-induced depression of ICSS was significantly reduced by increasing the intensity of the noxious stimulus to 5.6% acid. These results demonstrate sensitivity of acid-induced depression of ICSS to a range of clinically effective mu-opioid analgesics and reveal distinctions between opioids based on efficacy at the mu-receptor. These results also support the use of parallel assays of pain-stimulated and -depressed behaviors to evaluate analgesic efficacy of candidate drugs.