Cegielska-Perun Krystyna, Tatarkiewicz Jan, Siwek Agata, Dybała Małgorzata, Bujalska-Zadrożny Magdalena
Department of Pharmacodynamics, Centre for Preclinical Research and Technology (CePT) Laboratory, Medical University of Warsaw, Warszawa, Poland.
Department of Pharmacodynamics, Centre for Preclinical Research and Technology (CePT) Laboratory, Medical University of Warsaw, Warszawa, Poland.
Pharmacol Rep. 2015 Feb;67(1):90-6. doi: 10.1016/j.pharep.2014.08.008. Epub 2014 Aug 21.
we investigated the possible mechanisms involved in the interactions of venlafaxine (VFX), a selective serotonin and noradrenaline reuptake inhibitor, and morphine (MRF), an opioid receptor agonist, after acute and chronic VFX treatment in diabetic neuropathic pain model (DNPM).
The studies were performed on male rats. The changes in nociceptive thresholds were determined by using mechanical stimuli (the Randall-Selitto and the von Frey tests). Diabetes was induced by intramuscular administration of streptozotocin. In order to investigate the mechanism of interaction, animals were also pretreated with naloxone (NLX), a nonselective opioid antagonist, yohimbine (YOH), a nonselective α2-adrenergic antagonist, and p-chloroamphetamine (PCA), a neurotoxin that destroys serotonergic neurons. The μ-opioid receptors' density was determined with the use of radioligand binding assay.
VFX potentiated antinociceptive action of MRF after acute administration of VFX and this effect was decreased by pretreatment of NLX, YOH and PCA. On the contrary, VFX administered for 21 days prior to MRF significantly decreased the analgesic action of MRF; this effect was augmented only after YOH pretreatment. Also, 21-days administration of VFX caused decreasing tendency in the number of μ-opioid receptors in the brain stem.
The results of our study show that single administration of VFX potentiates antinociceptive action of morphine in DNPM. This effect is probably mediated by both, noradrenergic and serotonergic systems. On the other hand, 21-days administration of VFX significantly decreases analgesic action of MRF. Moreover, there is a possibility that VFX acts as an antagonist of N-methyl-d-aspartate receptors.
我们研究了在糖尿病性神经病理性疼痛模型（DNPM）中，急性和慢性服用文拉法辛（VFX，一种选择性5-羟色胺和去甲肾上腺素再摄取抑制剂）与吗啡（MRF，一种阿片受体激动剂）相互作用的可能机制。
实验选用雄性大鼠。通过机械刺激（Randall-Selitto和von Frey试验）测定伤害性感受阈值的变化。通过肌肉注射链脲佐菌素诱导糖尿病。为了研究相互作用的机制，动物还预先接受了非选择性阿片拮抗剂纳洛酮（NLX）、非选择性α2-肾上腺素能拮抗剂育亨宾（YOH）以及破坏5-羟色胺能神经元的神经毒素对氯苯丙胺（PCA）的预处理。使用放射性配体结合试验测定μ-阿片受体的密度。
急性服用VFX后，VFX增强了MRF的抗伤害感受作用，而NLX、YOH和PCA预处理可降低这种作用。相反，在给予MRF前21天服用VFX可显著降低MRF的镇痛作用；仅在YOH预处理后这种作用增强。此外，连续21天服用VFX导致脑干中μ-阿片受体数量有减少趋势。
我们的研究结果表明，单次服用VFX可增强DNPM中吗啡的抗伤害感受作用。这种作用可能由去甲肾上腺素能和5-羟色胺能系统介导。另一方面，连续21天服用VFX可显著降低MRF的镇痛作用。此外，VFX有可能作为N-甲基-D-天冬氨酸受体的拮抗剂发挥作用。
