Upadhya Manoj A, Dandekar Manoj P, Kokare Dadasaheb M, Singru Praful S, Subhedar Nishikant K
Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University Campus, Nagpur 440 033, India.
Neuropeptides. 2009 Aug;43(4):303-14. doi: 10.1016/j.npep.2009.05.003. Epub 2009 Jun 24.
Although morphine is a potent antinociceptive agent, its chronic use developed tolerance in neuropathic pain (NP). Furthermore, opioid antagonist naloxone attenuated the antinociceptive effect of neuropeptide Y (NPY). The present study investigated the role of NPY and NPY Y1/Y5 receptors in acute and chronic actions of morphine in neuropathic rats using thermal paw withdrawal test and immunocytochemistry. In acute study, intracerebroventricular (icv) administration of morphine, NPY or NPY Y1/Y5 receptors agonist [Leu(31),Pro(34)]-NPY produced antinociception, whereas selective NPY Y1 receptors antagonist BIBP3226 caused hyperalgesia. While NPY or [Leu(31),Pro(34)]-NPY potentiated, BIBP3226 attenuated morphine induced antinociception. Chronic icv infusion of morphine via osmotic minipumps developed tolerance to its antinociceptive effect, and produced hyperalgesia following withdrawal. However, co-administration of NPY or [Leu(31),Pro(34)]-NPY prevented the development of tolerance and withdrawal hyperalgesia. Sciatic nerve ligation resulted in significant increase in the NPY-immunoreactive (NPY-ir) fibers in ventrolateral periaqueductal gray (VLPAG) and locus coeruleus (LC); fibers in the dorsal part of dorsal raphe nucleus (DRD) did not respond. While chronic morphine treatment significantly reduced NPY-ir fibers in VLPAG and DRD, morphine withdrawal triggered significant augmentation in NPY-immunoreactivity in the VLPAG. NPY-immunoreactivity profile of LC remained unchanged in all the morphine treatment conditions. Furthermore, removal of sciatic nerve ligation reversed the effects of NP, increased pain threshold and restored NPY-ir fiber population in VLPAG. NPY, perhaps acting via Y1/Y5 receptors, might profoundly influence the processing of NP information and interact with the endogenous opioid system primarily within the framework of the VLPAG.
尽管吗啡是一种强效的抗伤害感受剂，但其长期使用会导致在神经性疼痛（NP）中产生耐受性。此外，阿片类拮抗剂纳洛酮会减弱神经肽Y（NPY）的抗伤害感受作用。本研究使用热足退缩试验和免疫细胞化学方法，研究了NPY和NPY Y1/Y5受体在吗啡对神经性大鼠急性和慢性作用中的作用。在急性研究中，脑室内（icv）注射吗啡、NPY或NPY Y1/Y5受体激动剂[Leu(31),Pro(34)]-NPY可产生抗伤害感受作用，而选择性NPY Y1受体拮抗剂BIBP3226则会引起痛觉过敏。当NPY或[Leu(31),Pro(34)]-NPY增强吗啡诱导的抗伤害感受作用时，BIBP3226则会减弱这种作用。通过渗透微型泵进行慢性icv输注吗啡会使其抗伤害感受作用产生耐受性，并在撤药后产生痛觉过敏。然而，同时给予NPY或[Leu(31),Pro(34)]-NPY可防止耐受性和撤药性痛觉过敏的发生。坐骨神经结扎导致腹外侧导水管周围灰质（VLPAG）和蓝斑（LC）中NPY免疫反应性（NPY-ir）纤维显著增加；中缝背核背侧部分（DRD）的纤维无反应。虽然慢性吗啡治疗可显著减少VLPAG和DRD中的NPY-ir纤维，但吗啡撤药会引发VLPAG中NPY免疫反应性的显著增强。在所有吗啡治疗条件下，LC的NPY免疫反应性特征保持不变。此外，去除坐骨神经结扎可逆转NP的影响，提高疼痛阈值并恢复VLPAG中NPY-ir纤维数量。NPY可能通过Y1/Y5受体发挥作用，可能会深刻影响NP信息的处理，并主要在VLPAG的框架内与内源性阿片系统相互作用。
