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Intrathecal inhibition of calcium/calmodulin- dependent protein kinase II in diabetic neuropathy adversely affects pain-related behavior

Introduction: 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. Methods: Male Sprague-Dawley rats were used. Diabetes was induced with intraperitoneal injection of 55 mg/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 2 h and 24 h after the intrathecal injection. The expression of total CaMKII and its alpha isoform in dorsal horn was quantified using immunohistochemistry. Results: 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 24 h after i.t. injection. Discussion: A study of two CaMKII inhibitors, employing a full range of behavioral tests, has shown that reduction of CaMKII expression may contribute to increased pain-related behavior in streptozotocin-diabetic rats. Results of this study are opposing current opinion in the field. There are several potential molecular mechanisms that could explain our findings. An increase of CaMKII and its phosphorylation could be protective in short or long run for certain aspects of pain. Additionally, increase of CaMKII and its phosphorylation may be just one of the mechanisms involved in pain- related behavior. Further studies should elucidate the exact role of CaMKII in nociceptive processing in dorsal horn of diabetic models.

Calcium/calmodulin-dependent protein kinase II; intrathecal injection; diabetic neuropathy

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