title: 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 (i) the intraperitoneal (i.p.) injection of clonidine reduces mechanical allodynia in mice with an oxaliplatin-induced neuropathy and (ii) concurrent inhibition of p38 mitogen-activated protein kinase (MAPK) activity by the p38 MAPK inhibitor SB203580 enhances clonidine's antiallodynic effect. Clonidine (0.01-0.1 mg kg(-1), i.p.), with or without SB203580(1-10 nmol, intrathecal) was administered two weeks after oxaliplatin injection(10 mg kg(-1), i.p.) to mice. Mechanical withdrawal threshold, motor coordination and blood pressure were measured. Postmortem expression of p38 MAPK and ERK as well as their phosphorylated forms(p-p38 and p-ERK) were quantified 30 min or 4 hr 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 subeffective dose(3 nmol) potentiated the antiallodynic effect of 0.03 mg kg(-1) clonidine and reduced the increased p-p38 MAPK. Coadministration of SB203580 and 0.03 mg kg(-1) clonidine decreased allodynia similar to that of 0.10 mg 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.
authors.affiliation: Department of Oral Physiology and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Ji-Hee
authors.initials: JH
authors.lastname: Yeo
authors.affiliation: Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.|Department of Neurobiology and Physiology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seo-Yeon
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Department of Oral Physiology and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Sol-Ji
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.|Department of Neurobiology and Physiology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seog-Bae
authors.initials: SB
authors.lastname: Oh
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jang-Hern
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN.
authors.forename: Alvin J
authors.initials: AJ
authors.lastname: Beitz
authors.affiliation: Department of Oral Physiology and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Dae-Hyun
authors.initials: DH
authors.lastname: Roh
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006930:Hyperalgesia / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000970:Antineoplastic Agents; D016207:Cytokines; D007093:Imidazoles; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000077150:Oxaliplatin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003000:Clonidine; C093642:SB 203580
keywords: clonidine; mechanical allodynia; oxaliplatin; p38 mitogen-activated protein kinases