Antinociceptive action of a p38alpha MAPK inhibitor, SD-282, in a diabetic neuropathy model.
Diabetes can induce a bewildering list of sensory changes, including alteration in pain sensitivity. Painful diabetic neuropathy is refractory to most common analgesics. This study examined the effect of a p38alpha MAPK inhibitor, SD-282, on mechanical allodynia, thermal hyperalgesia, and formalin-evoked nociception in streptozotocin-induced diabetic rats. Four-week diabetic rats exhibited mechanical allodynia, decreased mechanical thresholds, and C- and Adelta-fiber mediated thermal hyperalgesia. Mechanical and thermal responses were measured in diabetic rats following acute and repeated intraperitoneal administration of vehicle, 15 or 45 mg/kg SD-282. Mechanical allodynia was reversed by acute and repeated administration of 15 and 45 mg/kg SD-282. Repeated administration of 15 or 45 mg/kg SD-282 prevented the exacerbation of C-, but not Adelta-fiber, mediated thermal hyperalgesia. Repeated administration of 45 mg/kg SD-282 attenuated flinching behaviors during the quiescent period and the second phase of the formalin response in diabetic rats. Acute and repeated administration of 15 or 45 mg/kg SD-282 had no effect on mechanical, thermal or formalin responses in age-matched control rats. These results indicate a potential therapeutic value of p38alpha MAPK inhibitors in the treatment of aberrant pain sensitivity produced by diabetes.
Sweitzer
Sarah M
SM
Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305-5117, USA Scios, Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA.
Medicherla
Satyanarayana
S
Almirez
Ramona
R
Dugar
Sundeep
S
Chakravarty
Sarvajit
S
Shumilla
Jennifer A
JA
Yeomans
David C
DC
Protter
Andrew A
AA
D000700:Analgesics / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006930:Hyperalgesia / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000201:enzymology; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000201:enzymology; D009437:Neuralgia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D010147:Pain Measurement / Q000187:drug effects; D010525:Peripheral Nerves / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases
D000700:Analgesics; D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases