The Involvement of Calcitonin Gene-Related Peptide and Toll-Like Receptor 4 in the Development of Diabetic Sensory Neuropathy

Background: This study was designed to investigate the course and mechanism of diabetes-induced sensory abnormalities in a type 1 diabetic mouse model. Dynamic neuropeptide calcitonin gene-related peptide (CGRP) expression and involvement of toll-like receptor 4 (TLR4) were explored.Methods: C57BL/6J mice were divided in two groups, a normal control group and a diabetes mellitus (DM) group which was induced with streptozotocin (STZ). Thermal and mechanical nociceptive behavioral techniques were utilized to measure the development of sensitivities. Mice lumbar L4-L6 spinal cord and dorsal root ganglia (DRG) were taken to evaluate the molecular mechanisms of diabetic neuropathy (DN) by using immunocytochemistry and reverse transcription polymerase chain reaction (RT-PCR) methods.Results: DM mice developed both thermal and mechanical hypersensitivities. Thermal sensitivity returned to "normal" levels at 6 weeks as the mice then gradually developed thermal hypoalgesia in the late stages of DM. However, mechanical allodynia remained from 2 to 10 weeks post-DM, and mice later developed mechanical hypoalgesia. CGRP expression levels in DRG and the dorsal horn of the spinal cord showed a transient increase post-DM, followed by a significant decrease. In DM mice, TLR4 expression level increased in the dorsal horn of the spinal cord and co-localized with microglia and astrocytes in the spinal cord. The TLR4 specific inhibitor, TAK242, alleviated the symptoms of DM-induced pain.Conclusions: Our results demonstrated that hyperglycemia-induced diabetic neuropathic behavior includes early-stage hypersensitivity and late-stage hyposensitivity. CGRP and TLR4 pathways may play a role in early-stage of diabetic neuropathic pain.  Citation: Yan-Ping Zhang, Jin-Feng Yang, Yue Yuan, Karla Gomez, Shan-Shan Mei, Yiliam Rodriguez, et al. The involvement of calcitonin gene-related peptide and toll-like receptor 4 in the development of diabetic sensory neuropathy. J Anesth Perioper Med 2016; 3: 18-26. doi: 10.24015/JAPM.2016.0003This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.