Involvement of peripheral P2Y1 receptors and potential interaction with IL-1 receptors in IL-1β-induced thermal hypersensitivity in rats

Although interleuldn-1 beta (IL-1 beta) is a prototypical pro-inflammatory cytokine, the specific mechanisms underlying the role of its cognate receptor, the interleuldn-1 receptor (IL-1R) in peripheral sensitization remain to be investigated. Since emerging evidence in the literature indicates that IL-1 beta can modulate membrane-bound receptors, we decided to examine the involvement of P2Y1 receptor (P2Y1R) in IL-1 beta induced pain and the potential interaction of P2Y1Rs and IL-1Rs in both nave and carrageenan injected rats. Intraplantar (i.pl) injection of IL-1 beta dose-dependently produced mechanical and thermal hypersensitivity in nave rats. Pre-treatment with IL-lra (i.pl, 30 and 100 ng), an endogenous IL-1R antagonist, prevented the IL-1 beta induced mechanical and thermal hypersensitivity. Pre-treatment with MRS2500 (i.pl, 1 and 3 nmol), a specific P2Y1R antagonist, dose-dependently reduced IL-1 beta induced thermal hypersensitivity, but did not affect the development of mechanical hypersensitivity. Conversely coadministration of MRS2500 (i.pl, 0.1 nmol, sub-effective dose) together with IL-1ra (10 nmol, sub-effective dose) significantly reduced IL-1 beta induced thermal, but not mechanical hypersensitivity. We next used immunohistochemistry to demonstrate that P2Y1 and IL-1 type I receptors co-localize predominantly in small diameter neurons in the dorsal root ganglion. We also performed experiments to examine the interaction of P2Y1Rs and IL-1Rs under the inflammatory conditions induced by 2% carrageenan. Intraplantar coadministration of MRS2500 (3 nmol, sub-effective dose) and IL-lra (30 ng, sub-effective dose) significantly reduced inflammatory thermal, but not mechanical, hypersensitivity. These data indicate the involvement of P2Y1Rs in IL-1 beta mediated pain in both naive and carrageenan injected rats. There is a positive interaction between peripheral P2Y1Rs and IL-1Rs in both IL-1 beta and carrageenan-induced thermal hypersensitivity. (C) 2017 Elsevier Inc. All rights reserved.