Nijsen M, Ongenae N, Meulemans A, Coulie B
Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica N.V., Department of Gastrointestinal and Emerging Diseases, Turnhoutseweg, Beerse, Belgium.
Neurogastroenterol Motil. 2005 Jun;17(3):423-32. doi: 10.1111/j.1365-2982.2005.00644.x.
Both anti- and pro-nociceptive effects of corticotropin-releasing factor (CRF) treatment on visceral pain have been reported. Here, this dual action of CRF was differentiated by selective (in)activation of the CRF1 and CRF2 receptor prior to a visceral pain stimulus. Visceral pain was evaluated out of behavioural and visceromotor (abdominal electromyogram) responses to duodenal distension in the freely moving rat. Intraperitoneal (i.p.) CRF (50 microg kg-1) increased the distension-induced visceromotor and behavioural pain response. The pro-nociceptive effects of CRF on the behavioural response were attenuated by a selective CRF1 (CP-154526; 20 mg kg-1) but not a selective CRF2 [antiSauvagine30 (aSVG30); 100 microg kg-1] antagonist. Selective activation of the CRF2 receptor by stresscopin-related peptide (SRP; i.p. 25 microg kg-1) reduced the distension-induced visceromotor and behavioural response. Intrathecal injection of CRF (2 microg 10 microL-1) or SRP (20 microg 10 microL-1) decreased the distension-induced visceromotor and behavioural response. The antinociceptive effects of intrathecal CRF on the behavioural response were attenuated by aSVG30 (20 microg 10 microL-1) but not with CP-154526 (10 microg 10 microL-1). These findings indicate that the CRF1 receptor is involved in pro-nociception of visceral pain, whereas the CRF2 receptor is mainly involved in antinociception. This divergent role of the CRF subreceptors may explain the bimodal effects of CRF treatment on visceral nociception.
促肾上腺皮质激素释放因子（CRF）治疗对内脏痛既有抗伤害感受作用，也有促伤害感受作用。在此，通过在内脏痛刺激前选择性（失）活CRF1和CRF2受体来区分CRF的这种双重作用。在内脏痛的评估中，观察自由活动大鼠对十二指肠扩张的行为和内脏运动（腹部肌电图）反应。腹腔注射（i.p.）CRF（50微克/千克）增加了扩张诱导的内脏运动和行为疼痛反应。CRF对行为反应的促伤害感受作用被选择性CRF1拮抗剂（CP - 154526；20毫克/千克）减弱，但未被选择性CRF2拮抗剂[抗 sauvagine30（aSVG30）；100微克/千克]减弱。应激肽相关肽（SRP；腹腔注射25微克/千克）对CRF2受体的选择性激活降低了扩张诱导的内脏运动和行为反应。鞘内注射CRF（2微克/10微升）或SRP（2微克/10微升）降低了扩张诱导的内脏运动和行为反应。鞘内注射CRF对行为反应的抗伤害感受作用被aSVG30（20微克/10微升）减弱，但未被CP - 154526（10微克/10微升）减弱。这些发现表明，CRF1受体参与内脏痛的促伤害感受作用，而CRF2受体主要参与抗伤害感受作用。CRF亚型受体的这种不同作用可能解释了CRF治疗对内脏伤害感受的双峰效应。
