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Intrathecal and intraganglionic injection of calcium/calmodulin-dependent protein kinase II inhibitors as potential treatment of neuropathic pain-related behavior

Introduction: Neuropathic pain is one of the most frustrating and debilitating complications of diabetes mellitus. Despite increasing number of new trials, neuropathic pain treatment remains unsatisfactory. A growing number of studies demonstrate that CaMKII plays a key role in nociceptive transmission. Our previous studies have demonstrated increased expression of the CaMKII in DRG and dorsal horn after diabetes induction in rats (1, 2). The aim of this study was to test effects of intrathecal (i.t.) and intraganglionic (i.g.) injection CaMKII inhibitors on pain-related behavior in diabetic rats. Methods: Sprague-Dawley rats were included in the study. Diabetes induction was achieved by 55 mg/kg of streptozotocin (STZ) intraperitoneally injected. Two weeks following diabetes induction CaMKII inhibitors, myristoylated-AIP (mAIP) and KN93, or saline were injected directly into the subarachnoid space through 5-6th lumbar interspace or into right L5 dorsal root ganglion (DRG) (3). Behavioral testing was performed on the day preceding the STZ injection, on the 15th experimental day, and 2 h and 24 h following the i.t. or i.g. injection. The expression of total CaMKII and its alpha isoform in dorsal horn and dorsal root ganglia neurons was quantified using immunohistochemistry. Results: 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. The expression of CaMKIIα was significantly reduced in DRG neurons after i.g. injection, in contrast the expression of tCaMKII did not change significantly in ipsilateral and contralateral DRG neurons of diabetic rats after injecting saline, mAIP or KN- 93 into the right L5 DRG. Significant reduction in hypersensitivity to cold and mechanical stimuli was observed 2 h after i.g. injection of mAIP, but not following KN93 application. Conclusion: This study showed that CaMKII inhibitors after i.t. and i.g. delivery reduce CaMKII expression in dorsal horn and DRG neurons, but the effect on pain- related behavior of these two injections was the opposite. CaMKII may be potential target for pharmacological agents if injected directly into DRG and should be further explored for treatment of diabetic neuropathy symptoms.

neuropathic pain; CaMKII inhibitors

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