title: Involvement of cholecystokininergic systems in anxiety-induced hyperalgesia in male rats: behavioral and biochemical studies.
abstract: Keeping in mind the increased pain complaints reported in anxious or depressive patients, our goal was to investigate in rats the consequences of an experimentally provoked state of anxiety/depression on pain behavior and on its underlying mechanisms. We therefore used a model of social defeat consisting of a 30 min protected confrontation followed by a 15 min physical confrontation, repeated during 4 d, that elicited symptoms close to those observed in humans with anxiety or depression. Indeed, 5 d later, animals subjected to social-defeat confrontation were characterized by a decrease of sweet-water consumption and of body weight, and a hyperactivity of the hypothalamic-pituitary-adrenal axis, suggesting that the social-defeat procedure induced a prolonged state of anxiety. Rats subjected to the social-defeat procedure showed an enhanced nociceptive behavior to the subcutaneous administration of formalin, 5 d after the last confrontation session. Because chronic treatment with the established anxiolytic chlordiazepoxide (10 mg.kg(-1).d(-1)) prevented hyperalgesia, this strongly suggested that this experimental procedure might be a suitable animal model of "anxiety-induced hyperalgesia." Hyperalgesia associated with anxiety not only was related to a significant increase of CCKLM [cholecystokinin (CCK)-like material] in frontal cortex microdialysates but also was prevented by a CCK-B receptor antagonist [4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2[[(tricyclo[3.3[12,17]dec-2-yloxy)-carbonyl]amino]-propyl]amino]-1-phenyethyl]amino]-4-oxo-[R-(R*, R*)]-butanoate N-methyl-D-glucamine (CI-988)] (2 mg/kg), strongly supporting the involvement of central CCKergic systems in these phenomena. Finally, combined treatments with CI-988 and morphine completely suppressed pain-related behavior, supporting the idea that the association of both compounds might represent a new therapeutic approach to reduce the increase of pain complaints highly prevalent among anxious or depressive patients.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale E0331, Douleurs et Stress, Faculté de Médecine Pitié-Salpêtrière, 75634 Paris Cedex 13, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Andre
authors.forename: Brigitte
authors.initials: B
authors.lastname: Zeau
authors.forename: Michel
authors.initials: M
authors.lastname: Pohl
authors.forename: François
authors.initials: F
authors.lastname: Cesselin
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Benoliel
authors.forename: Chrystel
authors.initials: C
authors.lastname: Becker
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism* / Q000523:psychology*; D001835:Body Weight / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism*; D002766:Cholecystokinin / Q000378:metabolism*; D006930:Hyperalgesia / Q000378:metabolism* / Q000523:psychology*; D008297:Male; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000502:physiology*
chemical_list: D011949:Receptors, Cholecystokinin; D002766:Cholecystokinin