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CRF2 receptor activation prevents colorectal distension induced visceral pain and spinal ERK1/2 phosphorylation in rats
  1. M Million1,
  2. L Wang1,
  3. Y Wang1,
  4. D W Adelson1,
  5. P-Q Yuan1,
  6. C Maillot1,
  7. S V Coutinho1,
  8. J A Mcroberts1,
  9. A Bayati3,
  10. H Mattsson3,
  11. V Wu1,
  12. J-Y Wei1,
  13. J Rivier2,
  14. W Vale2,
  15. E A Mayer1,
  16. Y Taché1
  1. 1CURE/Digestive Diseases Research Center, and Center for Neurovisceral Sciences and Women’s Health, Department of Medicine, Division of Digestive Diseases, University of California Los Angeles, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
  2. 2Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California, USA
  3. 3AstraZeneca R&D, Mölndal, Sweden
  1. Correspondence to:
    Dr M Million
    CURE Bldg, 115, Rm # 203, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA; mmuluget{at}ucla.edu

Abstract

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 μg/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 μg, intra-arterially). The CRF2 receptor antagonist, astressin2-B (200 μg/kg subcutaneously or 20 μg 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.

  • AUC, area under the curve
  • CRD, colorectal distension
  • CRF, corticotropin releasing factor
  • DRG, dorsal root ganglia
  • EMG, electromyogram
  • hUcn 2, human urocortin 2
  • IBS, irritable bowel syndrome
  • IML, intermediolateral column
  • ISA, inferior splanchnic afferent
  • MAPK, mitogen activated protein kinase
  • pERK, phosphorylated extracellular signal regulated kinase
  • RF, receptive field
  • RT-PCR, reverse transcriptase-polymerase chain reaction
  • VMR, visceromotor response
  • IIo, laminae II outer layer
  • corticotrophin releasing factor
  • urocortin 2
  • astressin2-B
  • visceral pain
  • colon
  • ERK 1/2
  • inferior splanchnic afferents
  • colorectal distension

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Footnotes

  • Published online first 28 June 2005

  • Conflict of interest: None declared.

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