title: Intrathecal inhibition of calcium/calmodulin-dependent protein kinase II in diabetic neuropathy adversely affects pain-related behavior.
abstract: Calcium/calmodulin-dependent protein kinase II (CaMKII) is considered an important enzyme contributing to the pathogenesis of persistent pain. The aim of this study was to test whether intrathecal injection of CaMKII inhibitors may reduce pain-related behavior in diabetic rats. Male Sprague-Dawley rats were used. Diabetes was induced with intraperitoneal injection of 55mg/kg streptozotocin. Two weeks after diabetes induction, CaMKII inhibitor myristoil-AIP or KN-93 was injected intrathecally. Behavioral testing with mechanical and thermal stimuli was performed before induction of diabetes, the day preceding the injection, as well as 2h and 24h after the intrathecal injection. The expression of total CaMKII and its alpha isoform in dorsal horn was quantified using immunohistochemistry. Intrathecal injection of mAIP and KN-93 resulted in significant decrease in expression of total CaMKII and CaMKII alpha isoform activity. Also, mAIP and KN93 injection significantly increased sensitivity to a mechanical stimulus 24h after i.t. injection. Intrathecal inhibition of CaMKII reduced the expression of total CaMKII and its CaMKII alpha isoform activity in diabetic dorsal horn, which was accompanied with an increase in pain-related behavior. Further studies about the intrathecal inhibition of CaMKII should elucidate its role in nociceptive processes of diabetic neuropathy.
authors.affiliation: Laboratory for Pain Research, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia.
authors.forename: Antonia
authors.initials: A
authors.lastname: Jelicic Kadic
authors.forename: Matija
authors.initials: M
authors.lastname: Boric
authors.forename: Lejla
authors.initials: L
authors.lastname: Ferhatovic
authors.forename: Adriana
authors.initials: A
authors.lastname: Banozic
authors.forename: Damir
authors.initials: D
authors.lastname: Sapunar
authors.forename: Livia
authors.initials: L
authors.lastname: Puljak
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology*; D007278:Injections, Spinal; D008297:Male; D010146:Pain / Q000201:enzymology / Q000503:physiopathology*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology; D010812:Physical Stimulation; D020671:Posterior Horn Cells / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D013696:Temperature; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D010455:Peptides; D013449:Sulfonamides; C489863:myristoylated autocamtide-2-related inhibitory peptide; C072105:KN 93; D000096926:Benzenesulfonamides
keywords: CaMKII; Diabetes mellitus; Inhibitor; KN-93; Myristoil-AIP; Pain-related behavior