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The effects of intraganglionic injection of calcium/calmodulin-dependent protein kinase II inhibitors on pain-related behavior in diabetic neuropathy

Intoduction: Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in transmission of nociceptive input in diabetic neuropathy. The aim of this study was to test whether intraganglionic injection of CaMKII inhibitors may alleviate pain-related behavior in diabetic rats. Methods: Diabetes was induced in Sprague-Dawley rats using 55 mg/kg streptozotocin intraperitoneally. Two weeks after diabetes induction, CaMKII inhibitors myristoil-AIP and KN93 were injected directly into dorsal root ganglion (DRG). 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 intraganglionic injection. The expression of total CaMKII and its alpha isoform in DRG neurons was analyzed using immunohistochemistry. Results: CaMKII inhibitors attenuated pain-related behavior in a modality-specific fashion. Attenuation of nociceptive behavior was accompanied with corresponding decrease of CaMKII alpha expression in DRG neurons on the side of injection. Significant decrease of CaMKII alpha expression was seen in small and medium-sized neurons. Discussion: Studies using intraganglionic delivery of pharmacological agents have been seldomly used in the basic studies of nociception. Most of the studies are using only one CaMKII inhibitor (KN- 93) and one-time assessment. Pretreatment, posttreatment, as well as combination of both were studied. In this study, only posstreatment approach was used, since diabetic neuropathy occurs after the onset of the disease. We found that two CaMKII inhibitors, with different mechanism of action, may attenuate pain-related behavior in a modality-specific fashion.

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

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