Department of Human Physiology and Pharmacology "Vittorio Erspamer", University of Roma "La Sapienza", P.za A. Moro 5, 00185 Roma, Italy.
Neurosci Lett. 2012 Jul 11;521(1):40-5. doi: 10.1016/j.neulet.2012.05.055. Epub 2012 May 26.
Bv8 is a pronociceptive peptide that binds to two G-protein coupled prokineticin receptors, PK-R1 and PK-R2. These receptors are localized in the dorsal horn of the spinal cord and dorsal root ganglia (DRG) of nociceptive neurons in rodents. Systemic administration of Bv8 elicits a biphasic reduction in nociceptive thresholds to thermal and mechanical stimuli. Here, the possibility that Bv8 might directly modulate the expression and release of excitatory transmitters within the early and late phases of hyperalgesia was evaluated. Administration of Bv8 to mouse lumbar spinal cord sections produced a direct, significant and concentration-related release of CGRP. Bv8- or capsaicin-stimulated CGRP release was markedly enhanced in tissues taken from Bv8-pretreated mice during the late, but not the early, phase of hyperalgesia. Pretreatment of rats with protein synthesis inhibitors blocked the expression of the late, but not early, phase of Bv8-induced hyperalgesia. Finally, during the late-phase of hyperalgesia, there was an upregulation of CGRP and substance P immunoreactivity in the rat lumbar dorsal horn and DRG. Such upregulation was prevented by pretreatment with protein synthesis inhibitors. These data suggest that Bv8 induces hyperalgesia by direct release of excitatory transmitters in the spinal cord, consistent with the first phase of hyperalgesia. Additionally, Bv8 elicits a subsequent, protein-synthesis dependent increase in expression and release of excitatory transmitters that may underlie the long-lasting second phase of hyperalgesia. Activation of prokineticin receptors may therefore contribute to persistent hyperalgesia occurring as a consequence of tissue injury further suggesting that these receptors are attractive targets for development of therapeutics for pain treatment.
Bv8 是一种伤害感受性肽，与两种 G 蛋白偶联促动力素受体，PK-R1 和 PK-R2 结合。这些受体定位于伤害感受神经元的背角和背根神经节（DRG）的啮齿动物。Bv8 的全身给药会引起热和机械刺激的伤害感受阈值的双相降低。在这里，评估了 Bv8 可能直接调节伤害感受早期和晚期阶段兴奋性递质表达和释放的可能性。在小鼠腰椎脊髓切片中给予 Bv8 会导致 CGRP 的直接、显著和浓度相关的释放。在伤害感受晚期，但不在早期，Bv8 预处理小鼠组织中，Bv8 或辣椒素刺激的 CGRP 释放明显增强。用蛋白质合成抑制剂预处理大鼠阻断了 Bv8 诱导的伤害感受的晚期，但不是早期阶段的表达。最后，在伤害感受的晚期，大鼠腰椎背角和 DRG 中 CGRP 和 P 物质免疫反应性上调。这种上调可通过蛋白质合成抑制剂预处理来预防。这些数据表明，Bv8 通过在脊髓中直接释放兴奋性递质诱导伤害感受，与伤害感受的早期阶段一致。此外，Bv8 引起随后的、依赖蛋白质合成的兴奋性递质表达和释放增加，这可能是伤害感受的第二阶段持续时间延长的基础。促动力素受体的激活可能因此导致组织损伤后持续的伤害感受，这进一步表明这些受体是开发用于疼痛治疗的治疗方法的有吸引力的靶标。
