Reduction of acute inflammation in rats by diazepam: role of peripheral benzodiazepine receptors and corticosterone.
Carrageenin causes a reproducible inflammatory reaction and remains the standard irritant for examining acute inflammation and anti-inflammatory drugs. High doses of diazepam (10.0-20.0 mg/Kg) were shown to reduce the volume of acute inflammatory paw edema in rats as a response to carrageenin administration. The present experiment was undertaken to investigate the possible roles of peripheral-type benzodiazepine receptors (PBRs) and corticosterone on the anti-inflammatory effects of diazepam. Five experiments were conducted to assess the effects of a single dose (10.0 mg/Kg) of diazepam on carrageenin-induced paw edema (CIPE), pleurisy and increase in vascular permeability in rats. Results showed that: 1. diazepam or Ro5-4864 (a PBR agonist) treatment reduced CIPE values; 2. prior treatment with PK11195 (a non-benzodiazepine PBR antagonist) suppressed the effects of either diazepam or Ro5-4864 on CIPE; 3. diazepam reduced the volume of the pleural exudate in carrageenin-injected rats, as well as its leukocyte count; 4. diazepam treatment reduced the magnitude of the increase in vascular permeability caused by carrageenin; 5. adrenalectomy suppressed the effects of diazepam on CIPE; and 6. diazepam treatment increased the serum concentration of corticosterone. These results suggest a relevant role of PBR and corticosterone on diazepam-induced changes in inflammation. They are discussed in the light of a possible activation of mitochondrial PBRs within the adrenal gland cells by diazepam, thereby increasing the serum levels of corticosterone and thus reducing CIPE.
Lazzarini
R
R
Laboratory of Applied Pharmacology and Toxicology, School of Veterinary Medicine, University of São Paulo, Brazil.
Malucelli
B E
BE
Palermo-Neto
J
J
D000208:Acute Disease; D000315:Adrenalectomy; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology; D002199:Capillary Permeability; D002351:Carrageenan / Q000633:toxicity; D003345:Corticosterone / Q000502:physiology*; D003975:Diazepam / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D007509:Irritants / Q000633:toxicity; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001570:Benzodiazepinones; D058785:GABA-A Receptor Agonists; D007509:Irritants; D007546:Isoquinolines; D011963:Receptors, GABA-A; C028513:4'-chlorodiazepam; D002351:Carrageenan; D003975:Diazepam; D003345:Corticosterone; C037850:PK 11195