Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation.
Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation.
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DOI：
10.1097/j.pain.0000000000000341
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发表时间：
2016-01
期刊：
影响因子：
7.4
通讯作者：
Sorkin LS
中科院分区：
文献类型：
--
作者：
Pritchard RA;Falk L;Larsson M;Leinders M;Sorkin LS
PI 3 K-α、-δ和-γ均参与炎症诱导。仅PI 3 K-γ的拮抗作用阻断伤害性感受，这表明该亚型在传入内的作用。磷脂酰肌醇3-激酶（PI 3 Ks）参与信号转导级联反应，可直接激活和致敏伤害感受器并增强疼痛传递。它们还在导致炎症的趋化性和免疫细胞浸润中发挥重要作用。我们希望确定哪些PI 3 K亚型参与这些过程。轻度麻醉的大鼠（异氟烷）在其后爪皮下注射角叉菜胶。在此之前，局部注射1% DMSO溶剂或PI 3 K-α（化合物15-e）、-β（TGX 221）、-δ（Cal-101）或-γ（AS 252424）的亚型特异性拮抗剂。我们测量了机械痛阈和脊髓c-Fos表达（注射后4小时）的变化作为伤害性感受的指标。爪体积、血浆外渗（伊文思蓝，注射后0.3小时）和中性粒细胞（髓过氧化物酶;注射后1小时）和巨噬细胞（CD 11b +;注射后4小时）浸润爪组织是测量的炎症终点。PI 3 K-γ拮抗剂治疗前仅能降低角叉菜胶诱导的痛行为和脊髓c-Fos表达（P ≤ 0.01）。相反，用PI 3 K-α、-δ和-γ拮抗剂预处理可降低早期炎症指数。与溶媒给药前相比，血浆外渗PI 3 K-α（P ≤ 0.05）、-δ（P ≤ 0.05）和-γ（P ≤ 0.01）、早期（0-2小时）水肿-α（P ≤ 0.05）、-δ（P ≤ 0.001）和-γ（P ≤ 0.05）以及中性粒细胞浸润（均P ≤ 0.001）均减少。随后（2-4小时），仅PI 3 K-δ和-γ亚型拮抗剂即可减轻水肿和巨噬细胞浸润（P ≤ 0.05），其中PI 3 K-δ拮抗剂对水肿的影响更大。PI 3 K-β拮抗作用在所有范例中均无效。这些数据表明，疼痛和临床炎症是不可分离的，并可能有助于解释炎症自然减弱或缓解，但疼痛持续不减的临床条件。
PI3K-α, -δ, and -γ all participate in inflammation induction. Antagonism of only PI3K-γ blocks nociception, which is indicative of a role for this isoform within the afferent. Phosphoinositide 3-kinases (PI3Ks) participate in signal transduction cascades that can directly activate and sensitize nociceptors and enhance pain transmission. They also play essential roles in chemotaxis and immune cell infiltration leading to inflammation. We wished to determine which PI3K isoforms were involved in each of these processes. Lightly anesthetized rats (isoflurane) were injected subcutaneously with carrageenan in their hind paws. This was preceded by a local injection of 1% DMSO vehicle or an isoform-specific antagonist to PI3K-α (compound 15-e), -β (TGX221), -δ (Cal-101), or -γ (AS252424). We measured changes in the mechanical pain threshold and spinal c-Fos expression (4 hours after injection) as indices of nociception. Paw volume, plasma extravasation (Evans blue, 0.3 hours after injection), and neutrophil (myeloperoxidase; 1 hour after injection) and macrophage (CD11b+; 4 hour after injection) infiltration into paw tissue were the measured inflammation endpoints. Only PI3K-γ antagonist before treatment reduced the carrageenan-induced pain behavior and spinal expression of c-Fos (P ≤ 0.01). In contrast, pretreatment with PI3K-α, -δ, and-γ antagonists reduced early indices of inflammation. Plasma extravasation PI3K-α (P ≤ 0.05), -δ (P ≤ 0.05), and -γ (P ≤ 0.01), early (0-2 hour) edema -α (P ≤ 0.05), -δ (P ≤ 0.001), and -γ (P ≤ 0.05), and neutrophil infiltration (all P ≤ 0.001) were all reduced compared to vehicle pretreatment. Later (2-4 hour), edema and macrophage infiltration (P ≤ 0.05) were reduced by only the PI3K-δ and -γ isoform antagonists, with the PI3K-δ antagonist having a greater effect on edema. PI3K-β antagonism was ineffective in all paradigms. These data indicate that pain and clinical inflammation are pharmacologically separable and may help to explain clinical conditions in which inflammation naturally wanes or goes into remission, but pain continues unabated.