Yesilyurt Ozgur, Seyrek Melik, Tasdemir Serdar, Kahraman Serdar, Deveci Mehmet Salih, Karakus Emre, Halici Zekai, Dogrul Ahmet
Dept of Pharmacology, Gulhane Academy of Medicine, Ankara, Turkey.
Dept of Pharmacology, Gulhane Academy of Medicine, Ankara, Turkey.
Eur J Pharmacol. 2015 Sep 5;762:402-10. doi: 10.1016/j.ejphar.2015.04.020. Epub 2015 Apr 25.
The opioid and non-opioid types of stress-induced analgesia have been well defined. One of the non-opioid type involve the endocannabinoid system. We previously reported that the spinal serotonin 7 receptor (5-HT7) blockers inhibit both morphine and cannabinoid-induced analgesia, thus we hypothesized that descending serotonergic pathways-spinal 5-HT7 receptor loop might contribute to stress-induced analgesia. Stress-induced analgesia was induced with warm (32°C) or cold (20°C) water swim stress in male Balb-C mice. The effects of intrathecal injection of a selective 5-HT7 receptor antagonist, SB 269970, of the denervation of serotonergic neurons by intrathecal administration of 5,7-dihydroxytryptamine (5,7-DHT) and of lesions of the dorsolateral funiculus on opioid and non-opioid type stress-induced analgesia were evaluated with the tail-flick and hot plate tests. The expression of 5-HT7 receptors mRNA in the dorsal lumbar region of spinal cord were analyzed by RT-PCR following spinal serotonin depletion or dorsolateral funiculus lesion. The effects of the selective 5-HT7 receptor agonists LP 44 and AS 19 were tested on nociception. Intrathecal SB 269970 blocked both opioid and non-opioid type stress-induced analgesia. Dorsolateral funiculus lesion or denervation of the spinal serotonergic neurons resulted in a marked decrease in 5-HT7 receptor expression in the dorsal lumbar spinal cord, accompanied by inhibition of opioid and non-opioid type stress-induced analgesia. However, the systemic or intrathecal LP 44 and AS 19 alone did not produce analgesia in unstressed mice. These results indicate that descending serotonergic pathways and the spinal 5-HT7 receptor loop play a crucial role in mediating both opioid and non-opioid type stress-induced analgesia.
阿片类和非阿片类应激诱导镇痛已得到明确界定。非阿片类类型之一涉及内源性大麻素系统。我们之前报道过，脊髓5-羟色胺7受体（5-HT7）阻滞剂可抑制吗啡和大麻素诱导的镇痛，因此我们推测下行5-羟色胺能通路-脊髓5-HT7受体环路可能参与应激诱导镇痛。在雄性Balb-C小鼠中，通过温水（32°C）或冷水（20°C）游泳应激诱导应激诱导镇痛。通过甩尾试验和热板试验评估鞘内注射选择性5-HT7受体拮抗剂SB 269970、鞘内注射5,7-二羟色胺（5,7-DHT）使5-羟色胺能神经元去神经支配以及背外侧索损伤对阿片类和非阿片类应激诱导镇痛的影响。在脊髓5-羟色胺耗竭或背外侧索损伤后，通过逆转录聚合酶链反应（RT-PCR）分析脊髓腰背部区域5-HT7受体mRNA的表达。测试选择性5-HT7受体激动剂LP 44和AS 19对伤害感受的影响。鞘内注射SB 269970可阻断阿片类和非阿片类应激诱导镇痛。背外侧索损伤或脊髓5-羟色胺能神经元去神经支配导致脊髓腰背部5-HT7受体表达显著降低，同时伴有阿片类和非阿片类应激诱导镇痛的抑制。然而，单独给予全身或鞘内注射LP 44和AS 19在未应激小鼠中并未产生镇痛作用。这些结果表明，下行5-羟色胺能通路和脊髓5-HT7受体环路在介导阿片类和非阿片类应激诱导镇痛中起关键作用。
