Effect of fentanyl on 5-HT efflux involves both opioid and 5-HT1A receptors.
Effect of fentanyl on 5-HT efflux involves both opioid and 5-HT1A receptors.
复制标题
芬太尼对 5-HT 流出的影响涉及阿片类受体和 5-HT1A 受体。
DOI：
10.1038/sj.bjp.0705378
复制
发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Auerbach,SidneyB
中科院分区：
文献类型：
--
作者：
Tao,Rui;Karnik,Meghana;Ma,Zhiyuan;Auerbach,SidneyB
芬太尼是一种 aμ-阿片类镇痛药，可能会抑制 5-HT 神经元，从而增加 5-HT 外流。然而，芬太尼也与 5-HT1A 受体结合，如果它激活 5-HT1A 体树突自身受体，所产生的抑制作用可能会抵消阿片类药物介导的 5-HT 外流增加。为了检验这一假设，我们使用微透析来研究芬太尼对未麻醉大鼠中缝背核（DRN）细胞外 5-HT 的影响。全身给予芬太尼（0.01-0.2 mg kg−1，s.c.）增加了 DRN 中的 5-HT 流出。中等剂量的芬太尼（0.05 mg kg−1）使 DRN 中 5-HT 的最大增加达到基线水平的约 180%。纳曲酮 (10 mg kg−1, s.c.) 阻断了对全身芬太尼 (0.05 mg kg−1) 反应的增加。相反，在输注到 DRN 期间，芬太尼 (10–1000μM) 诱导 5-HT 剂量依赖性下降。纳曲酮和去甲-联托菲明未能阻止这种下降，表明μ-和κ-阿片受体没有介导这种作用。全身性(−)-吲哚洛尔（8 mg kg−1，s.c.）或将WAY-100635（100μM）输注到DRN中可以阻断这种下降，相反，局部输注芬太尼（100μM）后5-HT增加。 WAY-100635（0.3 mg kg−1，s.c.）也增强了全身芬太尼（0.2 mg kg−1，s.c.）的作用。 (−)-Pindolol 和 WAY-100635 阻断 5HT1A 受体，表明芬太尼与体细胞树突自身受体结合而抑制 5-HT 神经元活性，减弱了阿片类药物介导的 5-HT 外流增加。这些结果提供了新的证据，证明芬太尼除了刺激 μ-阿片类受体外，还是一种 5-HT1A 受体激动剂。这可能会导致芬太尼过量的致死率。英国药理学杂志(2003)139, 1498–1504。 doi:10.1038/sj.bjp.0705378
Fentanyl is aμ‐opioid analgesic that might disinhibit 5‐HT neurons and thus increase 5‐HT efflux. However, fentanyl also binds to 5‐HT1Areceptors, and if it activates 5‐HT1Asomatodendritic autoreceptors, the resultant inhibition might offset opioid‐mediated increases in 5‐HT efflux. To test this hypothesis, we used microdialysis to study effects of fentanyl on extracellular 5‐HT in the dorsal raphe nucleus (DRN) of unanesthetized rats.Systemic administration of fentanyl (0.01–0.2 mg kg−1, s.c.) increased 5‐HT efflux in the DRN. An intermediate dose of fentanyl (0.05 mg kg−1) produced the maximum increase in 5‐HT to ∼180% of baseline levels in the DRN. Naltrexone (10 mg kg−1, s.c.) blocked the increase in response to systemic fentanyl (0.05 mg kg−1).In contrast, during infusion into the DRN, fentanyl (10–1000μM) induced a dose‐dependent decrease in 5‐HT. Naltrexone andnor‐binaltorphimine failed to block the decrease suggesting thatμ‐ andκ‐opioid receptors did not mediate this effect.Systemic (−)‐pindolol (8 mg kg−1, s.c.) or infusion of WAY‐100635 (100μM) into the DRN blocked the decrease, and instead 5‐HT increased in response to local infusion of fentanyl (100μM). WAY‐100635 (0.3 mg kg−1, s.c.) also potentiated the effect of systemic fentanyl (0.2 mg kg−1, s.c.). (−)‐Pindolol and WAY‐100635 block 5HT1Areceptors, indicating that inhibition of 5‐HT neuronal activity resulting from fentanyl binding to somatodendritic autoreceptors attenuated opioid‐mediated increases in 5‐HT efflux.These results provide novel evidence that besides stimulatingμ‐opioid receptors, fentanyl is a 5‐HT1Areceptor agonist. Possibly, this contributes to lethality of fentanyl overdose.British Journal of Pharmacology(2003)139, 1498–1504. doi:10.1038/sj.bjp.0705378