The amphibian Bv8 and the mammalian prokineticin 1 (PROK1) and 2 (PROK2) are new chemokine-like protein ligands acting on two G protein-coupled receptors, prokineticin receptor 1 (PKR1) and 2 (PKR2), participating to the mediation of diverse physiological and pathological processes. Prokineticins (PKs), specifically activating the prokineticin receptors (PKRs) located in several areas of the central and peripheral nervous system associated with pain, play a fundamental role in nociception. In this paper, to improve the understanding of the prokineticin system in the neurobiology of pain, we investigated the role of PKR2 in pain perception using pkr2 gene-deficient mice. We observed that, compared to wildtype, pkr2-null mice were more resistant to nociceptive sensitization to temperatures ranging from 46 to 48 °C, to capsaicin and to protons, highlighting a positive interaction between PKR2 and the non-selective cation channels TRPV1. Moreover, PKR2 knock-out mice showed reduced nociceptive response to cold temperature (4 °C) and to mustard oil-induced inflammatory hyperalgesia, suggesting a functional interaction between PKR2 and transient receptor potential ankyrin 1 ion (TRPA1) channels. This notion was supported by experiments in dorsal root ganglia (DRG) cultures from pkr1 and-pkr2-null mice, demonstrating that the percentage of Bv8-responsive DRG neurons which were also responsive to mustard oil was much higher in PKR1-/- than in PKR2-/- mice. Taken together, these findings suggest a functional interaction between PKR2 and TRP channels in the development of hyperalgesia. Drugs able to directly or indirectly block these targets and/or their interactions may represent potential analgesics.

中文翻译：

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缺乏促动蛋白受体PKR2的小鼠的异常疼痛感：PKR2与瞬态受体电位TRPV1和TRPA1的相互作用。

两栖动物Bv8和哺乳动物prokineticin 1（PROK1）和2（PROK2）是新的趋化因子样蛋白配体，作用于两个G蛋白偶联受体prokineticin receptor 1（PKR1）和2（PKR2），参与多种介导作用生理和病理过程。Prokineticins（PKs），特别是激活位于中枢和周围神经系统与疼痛相关的多个区域的prokineticin受体（PKR），在伤害感受中起着基本作用。在本文中，为了增进对疼痛神经生物学中促动力素系统的了解，我们使用pkr2基因缺陷型小鼠研究了PKR2在疼痛感知中的作用。我们观察到，与野生型相比，无pkr2的小鼠对46至48°C的温度，辣椒素和质子的伤害性敏化具有更强的抵抗力，强调了PKR2与非选择性阳离子通道TRPV1之间的正相互作用。此外，敲除PKR2的小鼠对寒冷温度（4°C）和芥子油诱导的炎性痛觉过敏的伤害性反应降低，表明PKR2与瞬时受体电位锚蛋白1离子（TRPA1）通道之间存在功能性相互作用。在pkr1和-pkr2-null小鼠的背根神经节（DRG）培养物中进行的实验支持了这一观点，表明在PKR1-/-中对芥子油也有响应的Bv8响应DRG神经元的百分比要比在PKR1 / PKR2-/-小鼠。两者合计，这些发现表明痛觉过敏的发展中PKR2和TRP通道之间的功能相互作用。