Pharmacological interactions between calcium/calmodulin-dependent kinase II α and TRPV1 receptors in rat trigeminal sensory neurons

Multiple lines of evidence suggest that calcium/calmodulin-dependent kinase II alpha (CaMKII alpha) plays an important role in the spinal dorsal horn in nociceptive models of chemical, inflammatory and nerve injury. Moreover, CaMKII alpha phosphorylates, the vanilloid receptor type 1 (TRPV1), thereby regulating vanilloid agonist binding to the receptor. Herein, we have explored a possible interaction of CaMKII alpha activity with the TRPV1 receptor in rat trigeminal ganglion (TG) neurons in vitro. Inhibition of CaMKII alpha with KN-93 (5 mu M) inhibited capsaicin (CAP)- and n-arachidonoyl-dopamine (NADA)-evoked calcitonin gene-related peptide (CGRP) release effectively decreasing the E-max for both compounds. This effect was not mimicked by the inactive compound KN-92 (5 mu M), indicating that the effect was mediated by CaMKII alpha inhibition. CAP also stimulated a significant similar to 50% increase in autophosphorylation of CaMKII alpha at Thr(286/287). Immunocytochemistry for phospho-CaMKII alpha indicated that this effect specifically occurred in TRPV1-positive TG neurons. These findings indicate that phopho-CaMKII alpha is likely to play a role in presynaptic primary afferents in animal models of nociceptive hypersensitivity and provide support for CaMKIIa modulation of TRPV1 activity in sensory neurons. (C) 2005 Elsevier Ireland Ltd. All rights reserved.