title: Involvement of corticotropin-releasing hormone receptor subtypes 1 and 2 in peripheral opioid-mediated inhibition of inflammatory pain.
abstract: In painful inflammation, exogenous as well as endogenous corticotropin-releasing hormone (CRH) can release opioid peptides (mainly beta-endorphin) from various types of immune cells and produce antinociception by activating opioid receptors on peripheral sensory nerve endings. CRH mediates its central effects through two high-affinity membrane receptors, the CRH receptor subtypes 1 and 2. It is unclear at present whether the peripheral antinociceptive effects of CRH are mediated through CRH receptor 1 (CRH R1) or CRH receptor 2 (CRH R2). Employing a double-immunocytochemical technique, this study investigated in Wistar rats with Freund's complete adjuvant-induced hind paw inflammation whether immune cells within blood and inflamed subcutaneous tissue express CRH R1 and/or CRH R2 together with the opioid peptide beta-endorphin (END). Additionally, we examined using selective CRH R1 and CRH R2 antagonists whether peripheral CRH-induced antinociception is mediated by the respective CRH receptor subtypes. We found a high degree of co-expression of END together with both CRH R1 and CRH R2 in macrophage/monocytes, granulocytes and lymphocytes within blood and inflamed subcutaneous tissue. Also we observed a high degree of co-localization of CRH R1 and CRH R2 receptors on circulating and resident immune cells. Both the selective CRH R1 antagonist CP-154,526 and the selective CRH R2 antagonist astressin 2B significantly attenuated peripheral antinociceptive effects of CRH indicating the involvement of both CRH receptor subtypes. Taken together, these findings suggest that in inflammatory pain CRH-induced peripheral antinociception is mediated via both CRH R1 and CRH R2 located on END containing immune cells within inflamed sites.
authors.affiliation: Klinik für Anaesthesiologie und operative Intensivmedizin, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany.
authors.forename: Shaaban A
authors.initials: SA
authors.lastname: Mousa
authors.forename: P C
authors.initials: PC
authors.lastname: Bopaiah
authors.forename: Christoph
authors.initials: C
authors.lastname: Stein
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfer
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005620:Freund's Adjuvant / Q000633:toxicity; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D018847:Opioid Peptides / Q000096:biosynthesis; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D001615:beta-Endorphin / Q000096:biosynthesis*; D000099052:CRF Receptor, Type 1
chemical_list: C101531:CRF receptor type 2; D018847:Opioid Peptides; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D001615:beta-Endorphin; D005620:Freund's Adjuvant; D003346:Corticotropin-Releasing Hormone