Kassuya C A L, Ferreira J, Claudino R F, Calixto J B
Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
Br J Pharmacol. 2007 Mar;150(6):727-37. doi: 10.1038/sj.bjp.0707149. Epub 2007 Feb 19.
Receptor subtypes involved in PGE(2)-induced nociception are still controversial. The present study investigated the prostanoid E receptor (EP) subtypes and the protein kinase (PK) pathways involved in the nociception induced by PGE(2) injection in the mouse paw.
Paw-licking and mechanical allodynia were measured in vivo and protein kinase activation ex vivo by Western blots of extracts of paw skin.
Intraplantar (i.pl.) injection of PGE(2) into the mouse paw caused nociceptive behaviour of short duration with mean ED(50) of 1.43 nmol. PGE(2) produced a longer-lasting mechanical allodynia, with an ED(50) of 0.05 nmol. Intraplantar injection of antagonists at EP(3) or EP(4), but not at EP(1) or EP(2) receptors inhibited PGE(2)-induced paw-licking. Paw-licking caused by PGE(2) was blocked by an inhibitor of PKA but only partially decreased by inhibition of the extracellular-regulated kinase (ERK). Selective inhibitors of PKC, c-Jun N-terminal kinase (JNK) or p38, all failed to affect PGE(2)-induced paw-licking. An EP(3) antagonist inhibited PGE(2)-induced mechanical allodynia. However, inhibitors of PKA, PKC or ERK, but not p38 or JNK, also partially inhibited PGE(2)-induced mechanical allodynia. Western blot analyses confirmed that i.pl. injection of PGE(2) activated PKA, PKCalpha, and mitogen activated kinases (MAPKs) in the paw. Co-treatment with EP(3) or EP(4) receptor antagonists reduced PGE(2)-induced PKA and ERK, but not PKCalpha activation.
The present results indicate that the nociceptive behaviour and mechanical allodynia caused by i.pl. PGE(2) are mediated through activation of distinct EP receptors and PK-dependent mechanisms.
参与前列腺素E2（PGE2）诱导伤害感受的受体亚型仍存在争议。本研究调查了前列腺素E受体（EP）亚型以及蛋白激酶（PK）途径在PGE2注射小鼠爪部诱导的伤害感受中的作用。
通过体内测量舔爪行为和机械性异常性疼痛，并通过爪部皮肤提取物的蛋白质印迹法在体外检测蛋白激酶激活情况。
向小鼠爪部足底注射PGE2会引起持续时间较短的伤害性反应，平均半数有效剂量（ED50）为1.43 nmol。PGE2会产生持续时间更长的机械性异常性疼痛，ED50为0.05 nmol。足底注射EP3或EP4受体拮抗剂，但不是EP1或EP2受体拮抗剂，可抑制PGE2诱导的舔爪行为。PGE2引起的舔爪行为被蛋白激酶A（PKA）抑制剂阻断，但仅被细胞外调节激酶（ERK）抑制部分降低。蛋白激酶C（PKC）、c-Jun氨基末端激酶（JNK）或p38的选择性抑制剂均未能影响PGE2诱导的舔爪行为。EP3拮抗剂可抑制PGE2诱导的机械性异常性疼痛。然而，PKA、PKC或ERK抑制剂，但不是p38或JNK抑制剂，也可部分抑制PGE2诱导的机械性异常性疼痛。蛋白质印迹分析证实，足底注射PGE2可激活爪部的PKA、PKCα和丝裂原活化激酶（MAPK）。与EP3或EP4受体拮抗剂共同处理可降低PGE2诱导的PKA和ERK激活，但不影响PKCα激活。
目前的结果表明，足底注射PGE2引起的伤害性反应和机械性异常性疼痛是通过不同的EP受体激活和PK依赖性机制介导的。
