Clonidine, an alpha-2 adrenoceptor agonist relieves mechanical allodynia in oxaliplatin-induced neuropathic mice; potentiation by spinal p38 MAPK inhibition without motor dysfunction and hypotension

Abstract

Cancer chemotherapy with platinum-based antineoplastic agents including oxaliplatin frequently results in a debilitating and painful peripheral neuropathy. We evaluated the antinociceptive effects of the alpha-2 adrenoceptor agonist, clonidine on oxaliplatin-induced neuropathic pain. Specifically, we determined if (1) the intraperitoneal(i.p.) injection of clonidine reduces mechanical allodynia in mice with an oxaliplatin-induced neuropathy, and (2) concurrent inhibition of p38 mitogen-activated protein kinase(MAPK) activity by the p38 MAPK inhibitor SB203580 enhances clonidine's anti-allodynic effect. Clonidine(0.01-0.1mg kg⁻¹, i.p.), with or without SB203580(1-10nmol, intrathecal) was administered two weeks after oxaliplatin injection(10mg kg⁻¹, i.p.) to mice. Mechanical withdrawal threshold, motor coordination and blood pressure were measured. Post-mortem expression of p38 MAPK and ERK as well as their phosphorylated forms(p-p38 and p-ERK) were quantified 30 min or 4 hours after drug injection in the spinal cord dorsal horn of treated and control mice. Clonidine dose-dependently reduced oxaliplatin-induced mechanical allodynia and spinal p-p38 MAPK expression, but not p-ERK. At 0.1 mg kg⁻¹, clonidine also impaired motor coordination and decreased blood pressure. A 10 nmol dose of SB203580 alone significantly reduced mechanical allodynia and p-p38 MAPK expression, while a sub-effective dose(3nmol) potentiated the anti-allodynic effect of 0.03mg kg⁻¹ clonidine and reduced the increased p-p38 MAPK. Coadministration of SB203580 and 0.03mg kg⁻¹ clonidine decreased allodynia similar to that of 0.10mg kg⁻¹ clonidine, but without significant motor or vascular effects. These findings demonstrate that clonidine treatment reduces oxaliplatin-induced mechanical allodynia. The concurrent administration of SB203580 reduces the dosage requirements for clonidine, thereby alleviating allodynia without producing undesirable motor or cardiovascular effects. This article is protected by copyright. All rights reserved.

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