ABSTRACT
Title
Effect of MCP-1 synthesis inhibitors in a rat model of incisional pain
Authors
A. di Matteo, A. Amato, W. Castaldi, D. Mattei, B. Garrone, A. Guglielmotti
ACRAF-Angelini Research Center, S.Palomba-Pomezia, Rome, Italy
ACRAF-Angelini Research Center, S.Palomba-Pomezia, Rome, Italy
Abstract
Inflammation and nociceptive sensitization are hallmarks of tissue surrounding surgical incision. Recent studies demonstrate that Monocyte Chemotactic Proteins-1 (MCP-1/CCL2) contributes to the maintenance of mechanical hypersensitivity after plantar incision in a rat model of postoperative pain [1].
Small molecules able to inhibit MCP-1 were selected from in-house library and previously characterized for their ability to reduce MCP-1 plasma levels andinflammatory response in mice [2]. Aim of the present study was to investigate whether MCP-1 synthesis inhibitors could modulate mechanical allodynia after plantar incision in a rat model of postoperative pain.
Adult male Sprague-Dawley rats were used. An incision was made on the plantar surface of the left hind paw and AF12 and AF16 were intraperitoneally given, in the range 3-100 mg/kg, 1 h before and 24 h following surgery. Changes in the withdrawal threshold to mechanical stimulation were evaluated with an electronic Von Frey apparatus before the incision (baseline), 24 h post-surgery (pre-dosing) and at 1, 3, 6, 24 and 48 h following drugs administration (post-dosing).Incised rats receiving vehicle were used as positive control.
In the experimental conditions used, 24 h following plantar incision vehicle treated rats displayed profound mechanical allodynia which was significantly reduced in a dose-dependent manner by drugs treatment. In particular, AF12 and AF16 administration displayed a significant antiallodynic effect starting from 3 mg/kg. At the maximum tested dose (100 mg/kg) compounds showed a marked and significant pain threshold increase lasting up to 48 h post-dosing and yielding a 64% and 69% reversal increase, respectively.
In order to confirm that the antiallodynic activity observed was related to an interference with MCP-1 expression and monocyte/macrophage recruitment, histological analysis of paw sections was performed. H&E sections from incised versus control animals revealed the presence of a dense dermal cellular infiltrate that resulted reduced by drugs treatment. In addition, immunohistochemistry performed on paw sections from the same animals revealed macrophages accumulation and a strong MCP-1 immunoreactivity in the rats receiving vehicle that was reduced by treatment with tested compounds.
Obtained results foster the role of MCP-1 and suggest the potential therapeutic use of MCP-1 synthesis inhibitors in postsurgical pain.
[1] C.M. Peters, J.C. Eisenach. Contribution of the chemokine (C-C motif) ligand 2 (CCL2) to mechanical hypersensitivity after surgical incision in rats. Anesthesiology. 2010; 112: 1250-1258.
[2] B. Garrone, A. di Matteo, G. Mangano, C. Bartella, C. Apicella, N. Cazzolla, G. Furlotti, A. Guglielmotti. Novel small molecular weight CCL2 inhibitors reduce inflammatory response in mice. 2010 Worldpharma Congress, Copenhagen.
Small molecules able to inhibit MCP-1 were selected from in-house library and previously characterized for their ability to reduce MCP-1 plasma levels andinflammatory response in mice [2]. Aim of the present study was to investigate whether MCP-1 synthesis inhibitors could modulate mechanical allodynia after plantar incision in a rat model of postoperative pain.
Adult male Sprague-Dawley rats were used. An incision was made on the plantar surface of the left hind paw and AF12 and AF16 were intraperitoneally given, in the range 3-100 mg/kg, 1 h before and 24 h following surgery. Changes in the withdrawal threshold to mechanical stimulation were evaluated with an electronic Von Frey apparatus before the incision (baseline), 24 h post-surgery (pre-dosing) and at 1, 3, 6, 24 and 48 h following drugs administration (post-dosing).Incised rats receiving vehicle were used as positive control.
In the experimental conditions used, 24 h following plantar incision vehicle treated rats displayed profound mechanical allodynia which was significantly reduced in a dose-dependent manner by drugs treatment. In particular, AF12 and AF16 administration displayed a significant antiallodynic effect starting from 3 mg/kg. At the maximum tested dose (100 mg/kg) compounds showed a marked and significant pain threshold increase lasting up to 48 h post-dosing and yielding a 64% and 69% reversal increase, respectively.
In order to confirm that the antiallodynic activity observed was related to an interference with MCP-1 expression and monocyte/macrophage recruitment, histological analysis of paw sections was performed. H&E sections from incised versus control animals revealed the presence of a dense dermal cellular infiltrate that resulted reduced by drugs treatment. In addition, immunohistochemistry performed on paw sections from the same animals revealed macrophages accumulation and a strong MCP-1 immunoreactivity in the rats receiving vehicle that was reduced by treatment with tested compounds.
Obtained results foster the role of MCP-1 and suggest the potential therapeutic use of MCP-1 synthesis inhibitors in postsurgical pain.
[1] C.M. Peters, J.C. Eisenach. Contribution of the chemokine (C-C motif) ligand 2 (CCL2) to mechanical hypersensitivity after surgical incision in rats. Anesthesiology. 2010; 112: 1250-1258.
[2] B. Garrone, A. di Matteo, G. Mangano, C. Bartella, C. Apicella, N. Cazzolla, G. Furlotti, A. Guglielmotti. Novel small molecular weight CCL2 inhibitors reduce inflammatory response in mice. 2010 Worldpharma Congress, Copenhagen.