PDF(Pubmed)
Abstract：
BACKGROUND: Recent studies report that fentanyl analogs with relatively low pKa values produce antinociception in rodents without other mu opioid-typical side effects due to the restriction of their activity to injured tissue with relatively low pH values. However, it is unclear if and to what degree these compounds may produce mu opioid-typical side effects (respiratory depression, reinforcing effects) at doses higher than those required to produce antinociception.
OBJECTIVE: The present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pKa values in terms of potency and efficacy in male and female Sprague-Dawley rats.
METHODS: Nociception was produced by administration of Complete Freund\'s Adjuvant into the hind paw of subjects, and antinociception was measured using an electronic Von Frey test. Respiratory depression was measured using whole-body plethysmography. Reinforcing effects were measured in self-administration using a progressive-ratio schedule of reinforcement. The dose ranges tested for each drug encompassed no effect to maximal effects.
RESULTS: All compounds produced full effects in all measures but varied in potency. FF3 and fentanyl were equipotent in antinociception and self-administration, but FF3 was less potent than fentanyl in respiratory depression. NFEPP was less potent than fentanyl in every measure. The magnitude of potency difference between antinociception and other effects was greater for FF3 than for NFEPP or fentanyl, indicating that FF3 had the widest margin of safety when relating antinociception to respiratory-depressant and reinforcing effects.
CONCLUSIONS: Low pKa fentanyl analogs possess potential as safer analgesics, but determining the optimal degree of difference for pKa relative to fentanyl will require further study due to some differences between the current results and findings from prior work with these analogs.
OBJECTIVE: The present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pKa values in terms of potency and efficacy in male and female Sprague-Dawley rats.
METHODS: Nociception was produced by administration of Complete Freund\'s Adjuvant into the hind paw of subjects, and antinociception was measured using an electronic Von Frey test. Respiratory depression was measured using whole-body plethysmography. Reinforcing effects were measured in self-administration using a progressive-ratio schedule of reinforcement. The dose ranges tested for each drug encompassed no effect to maximal effects.
RESULTS: All compounds produced full effects in all measures but varied in potency. FF3 and fentanyl were equipotent in antinociception and self-administration, but FF3 was less potent than fentanyl in respiratory depression. NFEPP was less potent than fentanyl in every measure. The magnitude of potency difference between antinociception and other effects was greater for FF3 than for NFEPP or fentanyl, indicating that FF3 had the widest margin of safety when relating antinociception to respiratory-depressant and reinforcing effects.
CONCLUSIONS: Low pKa fentanyl analogs possess potential as safer analgesics, but determining the optimal degree of difference for pKa relative to fentanyl will require further study due to some differences between the current results and findings from prior work with these analogs.
摘要：
背景:最近的研究报道,具有相对低的pKa值的芬太尼类似物在啮齿动物中产生抗伤害感受,而没有其他μ阿片样物质典型的副作用,这是由于它们对具有相对低的pH值的损伤组织的活性的限制。然而,目前尚不清楚这些化合物是否以及在多大程度上可能产生阿片类药物典型的副作用(呼吸抑制，增强作用）的剂量高于产生镇痛作用所需的剂量。
目的：本研究比较了炎性镇痛，呼吸抑制剂,以及芬太尼和两种中间（FF3）和低（NFEPP）pKa值类似物在雄性和雌性Sprague-Dawley大鼠中的效力和功效方面的增强作用。
方法：通过向受试者的后爪施用完全弗氏佐剂来产生伤害感受，使用电子VonFrey试验测量抗伤害感受。使用全身体积描记术测量呼吸抑制。使用渐进比例的增强方案在自我给药中测量增强效果。每种药物测试的剂量范围包括对最大效果没有影响。
结果：所有化合物在所有措施中均产生完全效果，但效力不同。FF3和芬太尼在镇痛和自我给药方面是等效的，但FF3在呼吸抑制方面不如芬太尼有效。在所有措施中，NFEPP的效力均低于芬太尼。FF3的抗伤害感受和其他作用之间的效力差异幅度大于NFEPP或芬太尼，表明FF3在将抗伤害感受与呼吸抑制和增强作用相关联时具有最广泛的安全范围。
结论：低pKa芬太尼类似物具有作为更安全的镇痛药的潜力，但由于目前的结果与这些类似物的先前研究结果之间存在一些差异,因此确定pKa相对于芬太尼的最佳差异程度需要进一步研究.
目的：本研究比较了炎性镇痛，呼吸抑制剂,以及芬太尼和两种中间（FF3）和低（NFEPP）pKa值类似物在雄性和雌性Sprague-Dawley大鼠中的效力和功效方面的增强作用。
方法：通过向受试者的后爪施用完全弗氏佐剂来产生伤害感受，使用电子VonFrey试验测量抗伤害感受。使用全身体积描记术测量呼吸抑制。使用渐进比例的增强方案在自我给药中测量增强效果。每种药物测试的剂量范围包括对最大效果没有影响。
结果：所有化合物在所有措施中均产生完全效果，但效力不同。FF3和芬太尼在镇痛和自我给药方面是等效的，但FF3在呼吸抑制方面不如芬太尼有效。在所有措施中，NFEPP的效力均低于芬太尼。FF3的抗伤害感受和其他作用之间的效力差异幅度大于NFEPP或芬太尼，表明FF3在将抗伤害感受与呼吸抑制和增强作用相关联时具有最广泛的安全范围。
结论：低pKa芬太尼类似物具有作为更安全的镇痛药的潜力，但由于目前的结果与这些类似物的先前研究结果之间存在一些差异,因此确定pKa相对于芬太尼的最佳差异程度需要进一步研究.
