Rojewska Ewelina, Ciapała Katarzyna, Piotrowska Anna, Makuch Wioletta, Mika Joanna
Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Front Pharmacol. 2018 Jul 11;9:724. doi: 10.3389/fphar.2018.00724. eCollection 2018.
Neuropathic pain caused by a primary injury or dysfunction in the peripheral or central nervous system is a tremendous therapeutic challenge. Here, we have collected the first evidence from a single study on the potential contributions to neuropathic pain development by enzymes in the kynurenine pathway [tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO1/2), kynurenine 3-monooxygenase (KMO); kynureninase, 3-hydroxyanthranilate-3,4-dioxygenase (HAOO)] at the spinal cord and dorsal root ganglia (DRG) levels. At the spinal cord, mRNA levels of , and were elevated as measured on day 7 after chronic constriction injury in a rat model, parallel to the C1q-positive cell activation. According to our data obtained from primary microglial cell cultures, all enzymes of the kynurenine pathway except TDO were derived from these cells; however, the activation of microglia induced stronger changes in IDO2 and KMO. Our pharmacological studies gave evidence that the repeated intraperitoneal administration of minocycline, a microglia/macrophage inhibitor, not only attenuated tactile and thermal hypersensitivity but also diminished the levels of and mRNA. Our further pharmacological studies confirmed that IDO2 and KMO enzymes take part in the development of neuropathic pain, since we observed that the repeated administration of IDO2 (1-methyl-D-tryptophan) and KMO [UPF 648 - (1S,2S)-2-(3,4-dichlorobenzoyl)cyclopropanecarboxylic acid] inhibitors diminished hypersensitivity development as measured on days 2 and 7. The results of our studies show that the kynurenine pathway is an important mediator of neuropathic pain pathology in rats and indicate that IDO2 and KMO represent novel pharmacological targets for treating neuropathy.
由外周或中枢神经系统的原发性损伤或功能障碍引起的神经性疼痛是一个巨大的治疗挑战。在此，我们从一项单一研究中收集到了首个证据，该研究涉及犬尿氨酸途径中的酶[色氨酸2,3-双加氧酶（TDO）、吲哚胺2,3-双加氧酶（IDO1/2）、犬尿氨酸3-单加氧酶（KMO）；犬尿氨酸酶、3-羟基邻氨基苯甲酸-3,4-双加氧酶（HAOO）]在脊髓和背根神经节（DRG）水平对神经性疼痛发展的潜在作用。在脊髓，大鼠模型慢性缩窄损伤后第7天测量发现，TDO、IDO2和KMO的mRNA水平升高，与C1q阳性细胞活化平行。根据我们从原代小胶质细胞培养物中获得的数据，犬尿氨酸途径中除TDO外的所有酶均来源于这些细胞；然而，小胶质细胞的活化在IDO2和KMO中引起了更强的变化。我们的药理学研究表明，小胶质细胞/巨噬细胞抑制剂米诺环素的反复腹腔注射不仅减弱了触觉和热超敏反应，还降低了IDO2和KMO的mRNA水平。我们进一步的药理学研究证实，IDO2和KMO酶参与了神经性疼痛的发展，因为我们观察到IDO2抑制剂（1-甲基-D-色氨酸）和KMO抑制剂[UPF 648 - （1S,2S）-2-（3,4-二氯苯甲酰基）环丙烷羧酸]的反复给药减弱了第2天和第7天测量的超敏反应发展。我们的研究结果表明，犬尿氨酸途径是大鼠神经性疼痛病理的重要介质，并表明IDO2和KMO是治疗神经病变的新药理学靶点。
