Kosoyan Hovsep P, Grigoriadis Dimitri E, Taché Yvette
CURE: Digestive Diseases Research Center and Center for Neurovisceral Sciences and Women's Health, Veterans Affairs Medical Center, Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
Brain Res. 2005 Sep 14;1056(1):85-96. doi: 10.1016/j.brainres.2005.07.010.
Corticotropin-releasing factor (CRF) receptors have been reported to play a role in tonic colorectal distension (CRD)-induced activation of locus coeruleus (LC) neurons. We examined the influence of repeated phasic CRDs and intracisternal (ic) CRF on the spontaneous discharge rate of LC neurons in chloral hydrate-anesthetized rats and the role of CRF receptors using the nonselective CRF(1)/CRF(2) antagonist, astressin, and the water-soluble CRF(1) receptor antagonist, NBI-35965. Two consecutive phasic CRDs (43.7 +/- 1.1 mm Hg, 30 s each) at a 10-min interval increased LC activity to 184.9 +/- 15% and 171.9 +/- 12.2%, respectively. There was no difference in magnitude, onset (within 1 s), and duration (5-7 min) of the LC responses between the 1st and 2nd CRDs. CRF (300 ng/rat, ic) injected 10 min after the 2nd CRD increased LC activity to 191.1 +/- 11.2%. Astressin (3 mug, ic) completely blocked the 2nd CRD- and ic CRF-induced LC activation. Neither ic vehicle nor astressin influenced basal LC neuronal activity. NBI-35965 (10 mg/kg, iv) prevented the 2nd CRD- and ic CRF-induced LC neuronal activation, while at 5 mg significantly reduced the LC response to the 2nd CRD by 80%, but did not block that of ic CRF injected 30 min later. These findings indicate a primary role of brain CRF interacting with CRF(1) receptors in mediating the activation of LC neurons in response to a phasic CRD within the nociceptive range (>40 mm Hg). This activation may have relevance to irritable bowel syndrome characterized by lower pain threshold to CRD and hypervigilance to colonic input.
据报道，促肾上腺皮质激素释放因子（CRF）受体在强直性结肠扩张（CRD）诱导的蓝斑（LC）神经元激活中发挥作用。我们研究了重复的阶段性CRD和脑池内（ic）注射CRF对水合氯醛麻醉大鼠LC神经元自发放电率的影响，以及使用非选择性CRF(1)/CRF(2)拮抗剂阿斯特辛和水溶性CRF(1)受体拮抗剂NBI-35965研究CRF受体的作用。以10分钟的间隔连续两次阶段性CRD（43.7±1.1毫米汞柱，每次30秒）分别使LC活性增加到184.9±15%和171.9±12.2%。第一次和第二次CRD之间LC反应的幅度、起始时间（1秒内）和持续时间（5-7分钟）没有差异。在第二次CRD后10分钟注射CRF（300纳克/大鼠，ic）使LC活性增加到191.1±11.2%。阿斯特辛（3微克，ic）完全阻断了第二次CRD和ic CRF诱导的LC激活。ic注射的溶剂和阿斯特辛均不影响基础LC神经元活性。NBI-35965（10毫克/千克，静脉注射）可预防第二次CRD和ic CRF诱导的LC神经元激活，而5毫克时可使LC对第二次CRD的反应显著降低80%，但不能阻断30分钟后注射的ic CRF的反应。这些发现表明，在痛觉范围内（>40毫米汞柱），脑内CRF与CRF(1)受体相互作用在介导LC神经元对阶段性CRD的激活中起主要作用。这种激活可能与肠易激综合征有关，该综合征的特征是对CRD的疼痛阈值较低，对结肠输入过度警觉。
