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Phorbol Ester Modulation of Ca2+ Channels Mediates Nociceptive Transmission in Dorsal Horn Neurones
School of Pharmacy, University of Reading, Whiteknights, Reading, PO Box 228, RG6 6AJ, UK
School of Basic Medical Science, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China
Institute of Neurophysiology, University of Cologne, Robert-Koch-Strasse 39, Köln D-50931, Germany
* Author to whom correspondence should be addressed.
Received: 25 February 2013; in revised form: 13 May 2013 / Accepted: 14 May 2013 / Published: 29 May 2013
Abstract: Phorbol esters are analogues of diacylglycerol which activate C1 domain proteins, such as protein kinase C (PKC). Phorbol ester/PKC pathways have been proposed as potential therapeutic targets for chronic pain states, potentially by phosphorylating proteins involved in nociception, such as voltage-dependent Ca2+ channels (VDCCs). In this brief report, we investigate the potential involvement of CaV2 VDCC subtypes in functional effects of the phorbol ester, phorbol 12-myristate 13-acetate (PMA) on nociceptive transmission in the spinal cord. Effects of PMA and of selective pharmacological blockers of CaV2 VDCC subtypes on nociceptive transmission at laminae II dorsal horn neurones were examined in mouse spinal cord slices. Experiments were extended to CaV2.3(−/−) mice to complement pharmacological studies. PMA increased the mean frequency of spontaneous postsynaptic currents (sPSCs) in dorsal horn neurones, without an effect on event amplitude or half-width. sPSC frequency was reduced by selective VDCC blockers, w-agatoxin-IVA (AgTX; CaV2.1), w-conotoxin-GVIA (CTX; CaV2.2) or SNX-482 (CaV2.3). PMA effects were attenuated in the presence of each VDCC blocker and, also, in CaV2.3(−/−) mice. These initial data demonstrate that PMA increases nociceptive transmission at dorsal horn neurones via actions on different CaV2 subtypes suggesting potential anti-nociceptive targets in this system.
Keywords: phorbol ester; protein kinase C; Ca2+ channel; nociception; patch-clamp
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Yang, L.; Topia, I.; Schneider, T.; Stephens, G.J. Phorbol Ester Modulation of Ca2+ Channels Mediates Nociceptive Transmission in Dorsal Horn Neurones. Pharmaceuticals 2013, 6, 777-787.
Yang L, Topia I, Schneider T, Stephens GJ. Phorbol Ester Modulation of Ca2+ Channels Mediates Nociceptive Transmission in Dorsal Horn Neurones. Pharmaceuticals. 2013; 6(6):777-787.
Yang, Li; Topia, Iqbal; Schneider, Toni; Stephens, Gary J. 2013. "Phorbol Ester Modulation of Ca2+ Channels Mediates Nociceptive Transmission in Dorsal Horn Neurones." Pharmaceuticals 6, no. 6: 777-787.