‘Peripheral CRH’, which is identical to central CRH, found in immune organs and inflammatory sites is present at high levels in many sites of experimental inflammation in the rat (65,59) and mouse (26,64) and in a variety of aseptic or septic inflammatory sites examined thus far in humans. The latter include the inflamed joints of patients with rheumatoid arthritis and osteoarthritis (56).

Multiple research groups have demonstrated during the last decade the expression of CRH and their receptors in several components of the immune system and their participation in the regulation of inflammatory phenomena suggesting that administration of CRH antagonists/inhibitors might improve the clinical profile of such conditions. Αntalarmin, N-butyl-N-ethyl-[2,5,6-trimethyl-7-(2,4,6)-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl] amine has been recently synthesized as a therapeutic tool for both CNS and inflammatory disorders associated with central and peripheral CRH hypersecretion, respectively (99). Regarding the anti-inflammatory properties of this CRH-R1 antagonist on peripheral CRH activity, antalarmin has ameliorated carrageenin-induced aseptic inflammation in rats, and acute and chronic streptococcal cell wall- and adjuvant-induced arthritis in Lewis rats (99, 100). In addition, antalarmin prolonged survival of mice subjected to LPS-induced septic shock by lowering pro-inflammatory cytokine levels (30).

Given the ability of peripheral CRH to degranulate mast cells, CRH-R1 antagonist could be considered for the treatment of allergic conditions such as asthma, eczema, urticaria or even stress-induced brain inflammatory disorders that increase blood-brain-barrier permeability (101, 102). In the gastrointestinal tract, these compounds open new therapeutic options in the treatment of lower-GI inflammatory diseases associated to CRH, such as the chronic inflammatory bowel syndromes, irritable bowel disease and ulcerative colitis (103, 104). In human endometrium, CRH-R1 antagonists may be used as anti-implantation agents interfering with the inflammatory phenomena taking place during implantation (104). Administration of antalarmin to early pregnant rats (day 1 of pregnancy) results in a 70% reduction in implantation sites (105, 91). These examples illustrate the potential therapeutic significance of the CRH in regulating inflammatory phenomena without affecting the rest of the immune system.