Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA.
Neuroscience. 2012 Oct 11;222:392-403. doi: 10.1016/j.neuroscience.2012.07.004. Epub 2012 Jul 13.
In heterozygous mice, attenuation of G-protein-coupled receptor kinase 2 (GRK2) level in nociceptors is associated with enhanced and prolonged inflammatory hyperalgesia. To further elucidate the role of GRK2 in nociceptor function we reversibly decreased GRK2 expression using intrathecal antisense oligodeoxynucleotide (AS-ODN). GRK2 AS-ODN administration led to an enhanced and prolonged hyperalgesia induced by prostaglandin E(2), epinephrine and carrageenan. Moreover, this effect persisted unattenuated 2weeks after the last dose of antisense, well after GRK2 protein recovered, suggesting that transient attenuation of GRK2 produced neuroplastic changes in nociceptor function. Unlike hyperalgesic priming induced by transient activation of protein kinase C epsilon (PKCε), (Aley et al., 2000; Parada et al., 2003b), the enhanced and prolonged hyperalgesia following attenuation of GRK2 is PKCε- and cytoplasmic polyadenylation element binding protein (CPEB)-independent and is protein kinase A (PKA)- and Src tyrosine kinase (Src)-dependent. Finally, rats treated with GRK2 AS-ODN exhibited enhanced and prolonged hyperalgesia induced by direct activation of second messengers, adenyl cyclase, Epac or PKA, suggesting changes downstream of G-protein-coupled receptors. Because inflammation can produce a decrease in GRK2, such a mechanism could help explain a predilection to develop chronic pain, after resolution of acute inflammation.
在杂合子小鼠中，伤害感受器中 G 蛋白偶联受体激酶 2（GRK2）水平的衰减与炎症性痛觉过敏的增强和延长有关。为了进一步阐明 GRK2 在伤害感受器功能中的作用，我们使用鞘内反义寡核苷酸（AS-ODN）可逆地降低了 GRK2 的表达。GRK2 AS-ODN 给药导致前列腺素 E2、肾上腺素和角叉菜胶诱导的痛觉过敏增强和延长。此外，这种效应在最后一次反义治疗后 2 周仍未减弱，远远超过 GRK2 蛋白的恢复，表明 GRK2 的短暂衰减导致伤害感受器功能的神经可塑性变化。与短暂激活蛋白激酶 C epsilon（PKCε）诱导的痛觉过敏预激不同（Aley 等人，2000；Parada 等人，2003b），GRK2 衰减后增强和延长的痛觉过敏与 PKCε和细胞质多聚腺苷酸化元件结合蛋白（CPEB）无关，而是依赖于蛋白激酶 A（PKA）和Src 酪氨酸激酶（Src）。最后，用 GRK2 AS-ODN 治疗的大鼠表现出直接激活第二信使、腺苷酸环化酶、Epac 或 PKA 诱导的增强和延长的痛觉过敏，表明 G 蛋白偶联受体下游发生了变化。由于炎症可导致 GRK2 减少，这种机制可能有助于解释急性炎症消退后慢性疼痛易发性增加的原因。
