title: Altered expression of glial markers, chemokines, and opioid receptors in the spinal cord of type 2 diabetic monkeys.
abstract: Neuroinflammation is a pathological condition that underlies diabetes and affects sensory processing. Given the high prevalence of pain in diabetic patients and crosstalk between chemokines and opioids, it is pivotal to know whether neuroinflammation-associated mediators are dysregulated in the central nervous system of diabetic primates. Therefore, the aim of this study was to investigate whether mRNA expression levels of glial markers, chemokines, and opioid receptors are altered in the spinal cord and thalamus of naturally occurring type 2 diabetic monkeys (n=7) compared with age-matched non-diabetic monkeys (n=6). By using RT-qPCR, we found that mRNA expression levels of both GFAP and IBA1 were up-regulated in the spinal dorsal horn (SDH) of diabetic monkeys compared with non-diabetic monkeys. Among all chemokines, expression levels of three chemokine ligand-receptor systems, i.e., CCL2-CCR2, CCL3-CCR1/5, and CCL4-CCR5, were up-regulated in the SDH of diabetic monkeys. Moreover, in the SDH, seven additional chemokine receptors, i.e., CCR4, CCR6, CCR8, CCR10, CXCR3, CXCR5, and CXCR6, were also up-regulated in diabetic monkeys. In contrast, expression levels of MOP, KOP, and DOP, but not NOP receptors, were down-regulated in the SDH of diabetic monkeys, and the thalamus had fewer changes in the glial markers, chemokines and opioids. These findings indicate that neuroinflammation, manifested as glial activation and simultaneous up-regulation of multiple chemokine ligands and receptors, seems to be permanent in type 2 diabetic monkeys. As chemokines and opioids are important pain modulators, this first-in-primate study provides a translational bridge for determining the functional efficacy of spinal drugs targeting their signaling cascades.
authors.affiliation: Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Department of Pharmacology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Kiguchi
authors.affiliation: Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: Huiping
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Peters
authors.affiliation: Department of Pathology, Center for Comparative Medicine Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Kock
authors.affiliation: Department of Pharmacology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Shiroh
authors.initials: S
authors.lastname: Kishioka
authors.affiliation: Department of Pathology, Center for Comparative Medicine Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Cline
authors.affiliation: Department of Pathology, Center for Comparative Medicine Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: Janice D
authors.initials: JD
authors.lastname: Wagner
authors.affiliation: Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA. Electronic address: mko@wakehealth.edu.
authors.forename: Mei-Chuan
authors.initials: MC
authors.lastname: Ko
mesh_terms: D000818:Animals; D018925:Chemokines / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D015536:Down-Regulation; D005260:Female; D007249:Inflammation / Q000150:complications / Q000235:genetics*; D008252:Macaca fascicularis / Q000235:genetics; D008297:Male; D017628:Microglia / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011957:Receptors, Opioid / Q000235:genetics*; D013116:Spinal Cord / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018925:Chemokines; D012333:RNA, Messenger; D011957:Receptors, Opioid
keywords: Astrocytes; Chemokines; Chronic pain; Diabetes; Macaques; Microglia; Neuroinflammation; Opioids; Spinal cord; Thalamus