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ANALGESIA

Increased Tumor Necrosis Factor- and Prostaglandin E₂ Concentrations in the Cerebrospinal Fluid of Rats with Inflammatory Hyperalgesia: The Effects of Analgesic Drugs

From the Department of Pharmacology, University of Milan, Milan, Italy.

Address correspondence and reprint requests to Mauro Bianchi, MD, Department of Pharmacology, Via Vanvitelli, 32, 20129 Milano, Italy. Address e-mail to mauro.bianchi{at}unimi.it.

Abstract

BACKGROUND: We examined the changes in cerebrospinal fluid (CSF) concentrations of prostaglandin E₂ (PGE₂) and tumor necrosis factor- (TNF-) after intraplantar administration of complete Freund’s adjuvant (CFA) in rats. In addition, we investigated whether different analgesic drugs orally administered at antihyperalgesic doses were able to prevent the changes in PGE₂ and TNF- spinal levels associated with hindpaw inflammation.

METHODS: The Randall–Selitto paw-withdrawal test was used to measure inflammatory hyperalgesia. Tramadol (7.5 mg/kg), paracetamol (65 mg/kg), tramadol plus paracetamol and nimesulide (5 mg/kg) were administered orally twice a day, starting from the first day after the CFA injection. PGE₂ in the CSF was measured by enzyme immunoassay, and TNF- by ELISA. Behavioral and biochemical parameters were measured on Day 7 after intraplantar injection of CFA or saline.

RESULTS: Withdrawal thresholds to mechanical stimuli decreased markedly in the CFA-treated paw. In these animals the quantification of proinflammatory mediators in the CSF revealed a significant increase in both PGE₂ and TNF- concentrations. All the pharmacological treatments prevented the development of the hyperalgesia as well as the PGE₂ increase in the CSF. Conversely, a prevention of the increase in TNF- levels was observed only in rats treated with nimesulide or tramadol and paracetamol in combination.

CONCLUSIONS: Our results demonstrate that peripheral inflammatory hyperalgesia is associated with significant changes of proinflammatory mediators in the CSF. It is important to note, however, that spinal PGE₂ and TNF- proved to be differently affected by pharmacological treatments able to fully abolish the hyperalgesia.

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