Reduction of inflammation in rats by diazepam: tolerance development.
High doses of diazepam (10-20 mg/kg) were shown to reduce the volume of acute carrageenan-induced inflammatory paw edema in rats. This effect was not observed after adrenalectomy or long-term use of similar doses of diazepam. The present experiment was undertaken to analyze the effects of long-term (21 daily injections) treatment with diazepam (10 mg/kg) on both carrageenan-induced paw edema (CIPE) and corticosterone serum levels. For comparison, the effects of a single and acute 10 mg/kg dose of diazepam were also analyzed. Results showed that: 1- long-term diazepam treatment induced no changes in CIPE values and corticosterone serum levels; 2- acute diazepam treatment reduced CIPE values and increased corticosterone serum levels; 3- the plasmatic levels of diazepam measured 1 hour after the single treatment or 1 hour after the last dose of long-term diazepam administration were not different. These results indicate the development of tolerance to diazepam effects on both CIPE and corticosterone serum levels and suggest a relevant role for corticosterone on diazepam-induced inhibition of acute inflammation. Data were discussed in the light of peripheral benzodiazepine receptor site (PBR) activation within adrenal gland cells by diazepam, thereby increasing the serum levels of corticosterone and thus reducing CIPE. Possible actions of diazepam on HPA axis activity and/or on cytokine network were also discussed.
Lazzarini
Ricardo
R
Laboratories of Applied Pharmacology, Toxicology and Experimental Pathology, School of Veterinary Medicine, University of São Paulo, Av. Prof. Dr. Orlando M. de Paiva, 87, CEP: 05508-900, SP, São Paulo, Brazil
Malucelli
Benjamin Eurico
BE
Muscará
Marcelo Nicolas
MN
de Nucci
Gilberto
G
Palermo-Neto
João
J
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D002351:Carrageenan / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D003975:Diazepam / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology*; D004487:Edema / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D006614:Hindlimb / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008297:Male; D051381:Rats; D013047:Specific Pathogen-Free Organisms
D000893:Anti-Inflammatory Agents; D002351:Carrageenan; D003975:Diazepam; D003345:Corticosterone