Cyclosporin inhibits hyperalgesia and edema in arthritic rats: role of the central nervous system.
Since arthritis induced by Mycobacterium products (adjuvant) in rats is considered to be immunologically driven, the objective of the present study was to determine if the immunosuppressor drug cyclosporin could affect hindpaw edema and joint hyperalgesia simultaneously. Female Holtzman rats (140-170 g) presented hyperalgesia and edema on the 8th and 12th day following adjuvant injection. Daily systemic (oral or intramuscular) administration of cyclosporin (0.5-5.0 mg kg (-1) day (-1)) or dexamethasone (0.01-0.1 mg kg (-1) day (-1)) for 15 days starting on day zero dose-dependently inhibited the hindpaw edema and hyperalgesia in arthritic rats. However, hyperalgesia but not edema could be detected two days after cyclosporin withdrawal. We concluded that a) the continuous presence of cyclosporin is essential to reduce the development of joint hyperalgesia and that b) different mechanisms underlie the appearance of hyperalgesia and edema in this model. The intracerebroventricular (i.c.v.) administration of 5-50-fold smaller doses of cyclosporin (1.5-150 micrograms/day) or dexamethasone (15 micrograms/day) also reduced the arthritic hindpaw edema and hyperalgesia. Peripheral blood from animals injected with effective systemic cyclosporin doses showed detectable levels of the drug, whereas peripheral blood from those injected with i.c.v. cyclosporin did not, as measured by specific RIA. Our results indicate that cyclosporin administered by the central route is as effective as by the systemic route to reduce joint hyperalgesia and hindpaw edema in arthritic rats. The antiarthritic effect induced by low doses of cyclosporin in the central nervous system (CNS) could be explored to avoid it often associated systemic side effects during chronic therapy. However, the mechanism(s) involved in the antiarthritic response to cyclosporin in the CNS remain to be elucidated.
Francischi
J N
JN
Departamento de Farmacologia, Universidade Federal de Minas Gerais, Brasil. janettif@mono.icb.ufmg.br
Pereira
L S
LS
Castro
M S
MS
D000818:Animals; D001168:Arthritis / Q000150:complications / Q000188:drug therapy*; D002490:Central Nervous System / Q000187:drug effects*; D016572:Cyclosporine / Q000627:therapeutic use*; D004487:Edema / Q000188:drug therapy*; D005260:Female; D006930:Hyperalgesia / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016572:Cyclosporine