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.

The effect of gestational diabetes mellitus on sufentanil consumption after cesarean section: a prospective cohort study

“…In animal models of diabetes mellitus (DM), high blood glucose has been shown to reduce the effectiveness of opioid receptor agonists [14][15][16]. Studies on relevant mechanisms have shown that high blood glucose is associated with changes in the expression of opioid receptor genes [17,18], the body's metabolism [9], and neurotransmitter levels [11,12].…”

Differential mRNA expression of neuroinflammatory modulators in the spinal cord and thalamus of type 2 diabetic monkeys

“…CCR4, CCR6, CCR8, CCR10, CXCR3, CXCR5, and CXCR6) are simultaneously upregulated . In addition, mRNA expression levels of classical opioid receptor subtypes μ, κ, and δ are downregulated . These findings demonstrate that there is potential cross‐talk between chemokines and opioids in the spinal cord of diabetic monkeys .…”

“…In addition, mRNA expression levels of classical opioid receptor subtypes μ, κ, and δ are downregulated . These findings demonstrate that there is potential cross‐talk between chemokines and opioids in the spinal cord of diabetic monkeys . However, potential changes in other ligand–receptor systems associated with neuroinflammation in primates with T2DM are virtually unknown.…”

“…Detailed procedures for tissue collection and reverse transcription and quantitative real‐time polymerase chain reaction (RT‐qPCR) have been described elsewhere . Briefly, the skull and spinal column were cut open to expose the brain and spinal cord.…”

“…In addition to activated microglia and astrocytes, three chemokine ligand–receptor systems, namely CCL2–CCR2, CCL3–CCR1/5, and CCL4–CCR5, and multiple chemokine receptors (i.e. CCR4, CCR6, CCR8, CCR10, CXCR3, CXCR5, and CXCR6) are simultaneously upregulated . In addition, mRNA expression levels of classical opioid receptor subtypes μ, κ, and δ are downregulated .…”