School of Pharmacy, University of Reading, Whiteknights, Reading, PO Box 228, RG6 6AJ, UK.
Pharmaceuticals (Basel). 2013 May 29;6(6):777-87. doi: 10.3390/ph6060777.
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.
佛波酯是二酰基甘油的类似物，可激活 C1 结构域蛋白，如蛋白激酶 C（PKC）。佛波酯/ PKC 途径已被提议作为慢性疼痛状态的潜在治疗靶点，可能通过磷酸化涉及伤害感受的蛋白质，如电压依赖性 Ca2+通道（VDCCs）。在本简要报告中，我们研究了 CaV2 VDCC 亚型在佛波酯（PMA）对脊髓伤害感受传递的功能效应中的潜在作用。在小鼠脊髓切片中，检查了 PMA 和 CaV2 VDCC 亚型的选择性药理学阻滞剂对背角神经元 II 层伤害感受传递的影响。实验扩展到 CaV2.3(-/-)小鼠，以补充药理学研究。PMA 增加了背角神经元中自发性突触后电流（sPSC）的平均频率，而对事件幅度或半宽度没有影响。sPSC 频率被选择性 VDCC 阻滞剂 w-芋螺毒素-IVA（AgTX；CaV2.1）、w-芋螺毒素-GVIA（CTX；CaV2.2）或 SNX-482（CaV2.3）降低。在每种 VDCC 阻滞剂存在下以及在 CaV2.3(-/-)小鼠中，PMA 作用均减弱。这些初步数据表明，PMA 通过作用于不同的 CaV2 亚型增加背角神经元的伤害感受传递，表明该系统中存在潜在的抗伤害感受靶点。
