CRF1 receptors as a therapeutic target for irritable bowel syndrome.
The characterization of the corticotropin-releasing factor (CRF) family of neuroendocrine regulatory peptides, the cloning and pharmacological characterization of two CRF receptor subtypes (CRF(1) and CRF(2)), and the development of selective CRF receptor antagonists provided new insight to unravel the mechanisms of stress and the potential involvement of the CRF system in different pathophysiological conditions, including functional gastrointestinal disorders, mainly irritable bowel syndrome (IBS), and psychopathologies such as anxiety/depression. Compelling pre-clinical data showed that brain CRF administration mimics acute stress-induced colonic responses and enhances colorectal distension-induced visceral pain in rats through CRF(1) receptors. Similarly, peripheral CRF reduced the pain threshold to colonic distension and increased colonic motility in humans and rodents. These observations mimic the manifestations of IBS, characterized by abdominal bloating/discomfort and altered bowel habits. Moreover, CRF-CRF(1) pathways have been implicated in the development of anxiety/depression. These psychopathologies, together with stressful life events, have high comorbidity with IBS, and are considered significant components of the disease. From these observations, CRF(1) receptors have been suggested as a target to treat IBS. Peripherally acting CRF(1) antagonists might directly improve IBS symptoms, as related to motility, secretion and immune response. On the other hand, central actions will be beneficial as to prevent the psychopathologies that co-exist with IBS and as a way to modulate the central processing of stress- and visceral pain-related signals. Here, we review the pre-clinical and clinical data supporting these assumptions, and address the efforts done at a pharmaceutical level to develop effective therapies targeting CRF(1) receptors for functional gastrointestinal disorders.
Martinez
V
V
Integrative Pharmacology--Gastrointestinal Biology, AstraZeneca R&D, Mölndal, Sweden.
Taché
Y
Y
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005769:Gastrointestinal Motility / Q000187:drug effects; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D043183:Irritable Bowel Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism; D054832:Urocortins; D000099052:CRF Receptor, Type 1
D006727:Hormone Antagonists; D010446:Peptide Fragments; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; C103016:antalarmin; C104416:astressin; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; C045089:corticotropin releasing hormone (9-41)