CRF2 receptor activation prevents colorectal distension induced visceral pain and spinal ERK1/2 phosphorylation in rats
CRF2 receptor activation prevents colorectal distension induced visceral pain and spinal ERK1/2 phosphorylation in rats
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DOI：
10.1136/gut.2004.051391
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发表时间：
2006-02-01
期刊：
影响因子：
24.5
通讯作者：
Taché, Y
中科院分区：
文献类型：
--
作者：
Million, M;Wang, L;Taché, Y
背景与目的：促肾上腺皮质激素释放因子1 （CRF1）受体的激活参与应激相关反应和内脏疼痛，而CRF2受体的激活则抑制内分泌和一些行为应激反应。我们假设CRF2受体激活可能影响有意识大鼠结肠直肠膨胀（CRD）引起的内脏疼痛，并评估了可能的作用部位和机制。方法：雄性Sprague-Dawley大鼠注射crd （60 mm Hg，两次10分钟，休息时间10分钟）。用肌电图或目测法测定内脏运动反应（VMR）。测定脊髓（L6-S1）细胞外信号调节激酶1/2 （ERK 1/2）的激活与体内T13-S1背根神经节（DRG）和脊髓中CRD和CRF2受体基因的表达。下内脏传入（ISA）对CRD （0.4 ml， 20秒）的活性在体外ISA神经-肠系膜下动脉（动脉内）-结肠直肠制备中通过电生理记录进行评估。结果：对照组第二次CRD的VMR平均比第一次高31 % (SEM 4)% （p < 0.05）。选择性CRF2激动剂，人尿皮质素2 (huhn 2，浓度分别为10和20 μ g/kg)，在第一次膨胀后静脉注射，与第一次反应相比，分别防止致敏和减少第二次反应8%和30% (5%)% （p, 0.05）。RT-PCR检测DRG和脊髓中CRF2受体基因的表达。CRD （60 mm Hg， 10分钟）诱导腰骶椎板I和IIo神经元ERK 1/2磷酸化，静脉注射huhn 2可抑制该反应。CRD在体外诱导了强大的ISA峰活性，并被huhn 2 （1-3 μ g，动脉内）剂量依赖性地减弱。CRF2受体拮抗剂应激素(2)-B（皮下注射200 μ g/kg或动脉注射20 mg）在体内和体外阻断了hun2的抑制作用。结论：外周注射huhn - 2通过激活CRF2受体，使CRD诱导的大鼠内脏疼痛、结肠传入和脊髓L6-S1 ERK /2活性减弱。
Background and aims: Activation of corticotropin releasing factor 1 ( CRF1) receptors is involved in stress related responses and visceral pain, while activation of CRF2 receptors dampens the endocrine and some behavioural stress responses. We hypothesised that CRF2 receptor activation may influence visceral pain induced by colorectal distension ( CRD) in conscious rats, and assessed the possible sites and mechanisms of action.Methods: Male Sprague-Dawley rats were exposed to CRDs ( 60 mm Hg, 10 minutes twice, with a 10 minute rest interval). Visceromotor responses ( VMR) were measured by electromyography or visual observation. Spinal ( L6-S1) extracellular signal regulated kinase 1/2 ( ERK 1/2) activation following in vivo CRD and CRF2 receptor gene expression in the T13-S1 dorsal root ganglia ( DRG) and spinal cord were determined. Inferior splanchnic afferent ( ISA) activity to CRD ( 0.4 ml, 20 seconds) was assessed by electrophysiological recording in an in vitro ISA nerve-inferior mesenteric artery ( intra-arterial)-colorectal preparation.Results: In controls, VMR to the second CRD was mean 31 ( SEM 4)% higher than that of the first ( p < 0.05). The selective CRF2 agonist, human urocortin 2 ( hUcn 2, at 10 and 20 mu g/kg), injected intravenous after the first distension, prevented sensitisation and reduced the second response by 8 ( 1)% and 30 ( 5)% ( p, 0.05) compared with the first response, respectively. RT-PCR detected CRF2 receptor gene expression in the DRG and spinal cord. CRD ( 60 mm Hg for 10 minutes) induced phosphorylation of ERK 1/2 in neurones of lumbosacral laminae I and IIo and the response was dampened by intravenous hUcn 2. CRD, in vitro, induced robust ISA spike activity that was dose dependently blunted by hUcn 2 ( 1-3 mu g, intra-arterially). The CRF2 receptor antagonist, astressin(2)-B ( 200 mu g/kg subcutaneously or 20 mg intra-arterially) blocked the hUcn 2 inhibitory effects in vivo and in vitro.Conclusions: Peripheral injection of hUcn 2 blunts CRD induced visceral pain, colonic afferent, and spinal L6-S1 ERK 1/2 activity through CRF2 receptor activation in rats.