神经性疼痛是实验和临床糖尿病中的一种有据可查的现象;然而,目前的治疗不能令人满意。含5-羟色胺能的神经元是下降的自抑制途径的关键组成部分,并且其活性的降低可能至少部分地导致糖尿病性神经性疼痛(DNP)。使用链脲佐菌素(STZ)治疗的大鼠作为1型糖尿病(T1DM)的模型。使用公认的基于伤害性的技术评估疼痛传播,包括哈格里夫斯装置,冷板和动态足底美感仪。使用qRT-PCR,西方印迹,免疫组织化学,和基于HPLC的技术,我们还测量了糖尿病动物中枢神经系统和周围神经系统中5-HT1A受体(5-HT1AR)的表达和定位,参与色氨酸和5-HT合成和降解的关键酶的水平,包括色氨酸羟化酶-2(Tph-2),色氨酸2,3-双加氧酶(Tdo),吲哚胺2,3-双加氧酶1(Ido1)和Ido2。此外,脊髓5-HT的浓度,5-羟基吲哚乙酸(5-HIAA,5-HT的代谢物)和喹啉酸(QA,色氨酸的代谢物)也被定量。糖尿病大鼠出现热痛觉过敏和冷/机械性异常疼痛,这些行为异常似乎与与5-羟色胺能神经系统相关的关键分子表达水平的上调有关,包括突触前5-HT1AR和酶Tph-2,Tdo,Ido1和Ido2。有趣的是,在STZ诱导的T1DM中,突触后5-HT1AR水平保持不变。用8-羟基-2-(二丙基氨基)四氢萘(8-OH-DPAT)慢性治疗糖尿病动物,选择性5-HT1AR激动剂,下调神经元突触前5-HT1AR的上调,5-HT的脊髓释放增加(^5-HIAA/5-HT)并降低QA的浓度,Tdo的mRNA表达降低,Ido1和Ido2抑制了神经元变性并改善了疼痛相关行为,例如热痛觉过敏和冷/机械异常性疼痛。这些数据表明,8-OH-DPAT减轻DNP和5-羟色胺能系统的其他成分,包括5-HIAA/5-HT和5-HT1AR的比例,并且可能是管理DNP的有用治疗剂。
Neuropathic pain is a well-documented phenomenon in experimental and clinical diabetes; however, current treatment is unsatisfactory. Serotoninergic-containing neurons are key components of the descending autoinhibitory pathway, and a decrease in their activity may contribute at least in part to diabetic neuropathic pain (DNP). A streptozotocin (STZ)-treated rat was used as a model for type 1 diabetes mellitus (T1DM). Pain transmission was evaluated using well-established nociceptive-based techniques, including the Hargreaves apparatus, cold plate and dynamic plantar aesthesiometer. Using qRT-PCR, Western blotting, immunohistochemistry, and HPLC-based techniques, we also measured in the central nervous system and peripheral nervous system of diabetic animals the expression and localization of 5-HT1A receptors (5-HT1AR), levels of key enzymes involved in the synthesis and degradation of tryptophan and 5-HT, including tryptophan hydroxylase-2 (Tph-2), tryptophan 2,3-dioxygenase (Tdo), indoleamine 2,3-dioxygenase 1 (Ido1) and Ido2. Moreover, spinal concentrations of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA, a metabolite of 5-HT) and quinolinic acid (QA, a metabolite of tryptophan) were also quantified. Diabetic rats developed thermal hyperalgesia and cold/mechanical allodynia, and these behavioral abnormalities appear to be associated with the upregulation in the levels of expression of critical molecules related to the serotoninergic nervous system, including presynaptic 5-HT1AR and the enzymes Tph-2, Tdo, Ido1 and Ido2. Interestingly, the level of postsynaptic 5-HT1AR remains unaltered in STZ-induced T1DM. Chronic treatment of diabetic animals with 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT), a selective 5-HT1AR agonist, downregulated the upregulation of neuronal presynaptic 5-HT1AR, increased spinal release of 5-HT (↑ 5-HIAA/5-HT) and reduced the concentration of QA, decreased mRNA expression of Tdo, Ido1 and Ido2, arrested neuronal degeneration and ameliorated pain-related behavior as exemplified by thermal hyperalgesia and cold/mechanical allodynia. These data show that 8-OH-DPAT alleviates DNP and other components of the serotoninergic system, including the ratio of 5-HIAA/5-HT and 5-HT1AR, and could be a useful therapeutic agent for managing DNP.