CRF2 receptor activation prevents colorectal distension induced visceral pain and spinal ERK1 /2 phosphorylation in rats

Million, M.; Wang, L.; Wang, Y.; Adelson, D. W.; Yuan, P-Q.; Maillot, C.; Coutinho, S. V.; Mcroberts, J. A.; Bayati, A.; Mattsson, H.; Wu, V.; Wei, J-Y.; Rivier, J.; Vale, W.; Mayer, E. A.; Taché, V.
February 2006
Gut;Feb2006, Vol. 55 Issue 2, p172
Academic Journal
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 (pc<.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 lb 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 inlection of hUcn 2 blunts CRD induced visceral pain, colonic afferent, and spinal L6-S1 ERK 1/2 activity through CRF2 receptor activation in rats.


Related Articles

  • Can modulating corticotropin releasing hormone receptors alter visceral sensitivity? Fukudo, S.; Saito, K.; Sagami, Y.; Kanazawa, M. // Gut;Feb2006, Vol. 55 Issue 2, p146 

    Activation of corticotropin releasing hormone (CRH) receptor 2 (CRH-R2) reduces visceral sensitivity induced by colorectal distension in conscious rats. This finding is relevant to the increased interest in the potential use of therapeutic agents that act on CRH receptors in the treatment of...

  • Corticotropin-Releasing Factor Receptor Antagonists in Affective Disorders and Drug Dependence - An Update. Steckler, Thomas; Dautzenberg, Frank M. // CNS & Neurological Disorders - Drug Targets;2006, Vol. 5 Issue 2, p147 

    Dysfunctioning of corticotropin-releasing factor (CRF) and its receptors (CRF1 and CRF2) has been linked to the development of stress-related disorders, such as affective disorders and drug abuse. The molecular characterization of CRF1 and CRF2 receptors and their splice variants has generated...

  • The Role of Corticotropin-Releasing Hormone in the Pathophysiology of Depression: Therapeutic Implications. Lloyd, R. Brett; Nemeroff, Charles B. // Current Topics in Medicinal Chemistry;Mar2011, Vol. 11 Issue 6, p609 

    Stress responses have been posited to be a key component of mental health and disease by playing essential roles both in normal adaptive processes and maladaptive physiological responses that in part underlie the pathogenesis of certain subtypes of mood and anxiety disorders. Early research...

  • CRF Receptor Antagonists: Utility in Research and Clinical Practice. Chatzaki, E.; Minas, V.; Zoumakis, E.; Makrigiannakis, A. // Current Medicinal Chemistry;2006, Vol. 13 Issue 23, p2751 

    CRF, CRF-related peptides and CRF receptors constitute a complex physiological system which has a key role in facilitating the adaptation of the organism to the stressful stimuli of the environment. The behavioral, endocrine, autonomic and immune branches of stress response are considered to be...

  • Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans. Licinio, J.; O'Kirwan, F.; Irizarry, K.; Merriman, B.; Thakur, S.; Jepson, R.; Lake, S.; Tantisira, K. G.; Weiss, S. T.; Wong, M.-L. // Molecular Psychiatry;Dec2004, Vol. 9 Issue 12, p1075 

    There are well-replicated, independent lines of evidence supporting a role for corticotropin-releasing hormone (CRH) in the pathophysiology of depression. CRH receptor 1 (CRHR1), which we first mapped in the brain in 1994, has been implicated in the treatment of depression and anxiety. We...

  • Behavioural genetics: Dipsomaniac mice? López, Juan Carlos // Nature Reviews Genetics;Jun2002, Vol. 3 Issue 6, p408 

    Discusses research on the enhanced and delayed stress-induced alcohol drinking in mice lacking functional corticotropin-releasing hormone (CRH). Reference to a study by L. Sillaber and colleagues published in the 2002 issue of "Science" journal; Influence of stress on alcohol intake; CRH...

  • The CRF Receptor Structure, Function and Potential for Therapeutic Intervention. Grigoriadis, D.E.; Haddach, M.; Ling, N.; Saunders, J. // Current Medicinal Chemistry - Central Nervous System Agents;May2001, Vol. 1 Issue 1, p63 

    Two distinct sub-types of receptor encoded by separate genes have been described to date, CRF1 and CRF2, and they belong to the Class-B subdivision within the G-protein coupled receptor (GPCR) super family. All known CRF receptors positively regulate the accumulation of cAMP in response to CRF...

  • Corticotropin-Releasing Factor Binding Protein - A Ligand Trap? Jahn, Olaf; Radulovic, Jelena; Stiedl, Oliver; Tezval, Hossein; Eckart, Klaus; Spiess, Joachim // Mini Reviews in Medicinal Chemistry;Oct2005, Vol. 5 Issue 10, p953 

    The actions of the neuropeptide corticotropin-releasing factor (CRF) are modulated by a CRF binding protein (CRFBP). In view of the memory-enhancing effects of CRF, the release of endogenous CRF from CRFBP by CRFBP inhibitors has been suggested as a therapeutical strategy for the treatment of...

  • The CRF Peptide Family in Appetite Regulation and Energy Balance. Ohata, Hisayuki; Shibasaki, Tamotsu // Current Medicinal Chemistry - Central Nervous System Agents;Sep2003, Vol. 3 Issue 3, p243 

    The physiological roles and pharmacological profile of the corticotropin-releasing factor (CRF) peptide family and their receptors are described. Urocortin, urocortin II, and stresscopin / urcortin III are members of this family in rodents and humans. In the central nervous system, these...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics