Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, 39216, USA; School of Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
RTI International, Research Triangle Park, NC, 27709, USA.
Neuropharmacology. 2024 Sep 1;255:110002. doi: 10.1016/j.neuropharm.2024.110002. Epub 2024 May 14.
Recent studies report that fentanyl analogs with relatively low pK 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.
The present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pK values in terms of potency and efficacy in male and female Sprague-Dawley rats.
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.
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.
Low pK fentanyl analogs possess potential as safer analgesics, but determining the optimal degree of difference for pK relative to fentanyl will require further study due to some differences between the current results and findings from prior work with these analogs.
最近的研究报告表明，具有相对较低 pK 值的芬太尼类似物在没有其他 μ 阿片类典型副作用的情况下在啮齿动物中产生镇痛作用，这是由于其活性受到损伤组织中相对较低 pH 值的限制。然而，目前尚不清楚这些化合物在产生镇痛作用所需的剂量以上是否会产生 μ 阿片类典型的副作用（呼吸抑制、强化作用）。
本研究比较了芬太尼和两种具有中等（FF3）和低（NFEPP）pK 值的类似物在雄性和雌性 Sprague-Dawley 大鼠中的炎症性镇痛、呼吸抑制和强化作用，比较了它们的效力和效能。
通过在实验动物的后爪中注射完全弗氏佐剂来产生疼痛，使用电子 Von Frey 测试来测量镇痛作用。使用全身 plethysmography 测量呼吸抑制作用。使用递增比率强化程序在自我给药中测量强化作用。每种药物的测试剂量范围包括无作用至最大作用。
所有化合物在所有测量中都产生了完全的作用，但效力不同。FF3 和芬太尼在镇痛和自我给药方面具有同等效力，但 FF3 在呼吸抑制方面的效力低于芬太尼。NFEPP 在所有测量中都比芬太尼效力低。在镇痛和其他作用之间的效力差异方面，FF3 比 NFEPP 或芬太尼更大，这表明在将镇痛作用与呼吸抑制和强化作用相关联时，FF3 的安全边际更大。
低 pK 值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之前使用这些类似物的研究结果存在一些差异，因此需要进一步研究确定相对于芬太尼的最佳 pK 值差异程度。
