Upregulation of Chemokine Ligands and Receptors in the Spinal Cord of Type 2 Diabetic Monkeys

Abstract

Chemokines are a family of small chemoattractant cytokines that have an important role in controlling leukocyte migration and neuron‐glia interactions. Rodent studies have demonstrated that, like other cytokines, chemokine ligands and their cognate receptors in the spinal dorsal horn (SDH) can regulate both acute and chronic/neuropathic pain. Given the high prevalence of pain in patients with type 2 diabetes, it is pivotal to know if chemokine ligand‐receptor systems are upregulated in diabetic primates. Therefore, the aim of this study was to determine and compare the mRNA expression levels of chemokines in the spinal cord of monkeys that had 3–6 years of spontaneously occurring type 2 diabetes (n=7) and age‐matched nondiabetic monkeys (n=6). Chemokine mRNA expressions were analyzed by real‐time RT‐PCR in the SDH of these cynomolgus monkeys. CC‐chemokine ligands, CCL2 (MCP‐1) and CCL3 (MIP‐1alpha), mRNA expression levels were upregulated in the SDH of diabetic monkeys. In addition, their cognate receptors, CC‐chemokine receptors CCR1, CCR2, and CCR5, mRNA levels were upregulated in the SDH. Expression levels of these ligands and receptors mRNA were also higher in the spinal ventral horn of diabetic monkeys. Among numerous chemokines examined, CX3CL1 (Fractalkine) and CX3CR1 are the most highly expressed genes in the spinal cord. However, their expression levels did not differ between diabetic and nondiabetic monkeys. These results indicate that at least two chemokine ligand‐receptor systems (i.e., CCL2‐CCR2 and CCL3‐CCR1/CCR5) were upregulated in the spinal cord of type 2 diabetic monkeys, which is widely regarded as a clinically relevant model. This first‐in‐primate study opens a new avenue to study the functional roles of chemokines and their cognate receptor antagonists for modulating pain in diabetic primates.Support or Funding InformationSupported by US‐PHS grants AR‐059193 and DA‐032568