Increased tumor necrosis factor-alpha and prostaglandin E2 concentrations in the cerebrospinal fluid of rats with inflammatory hyperalgesia: the effects of analgesic drugs.
BACKGROUND
We examined the changes in cerebrospinal fluid (CSF) concentrations of prostaglandin E2 (PGE2) and tumor necrosis factor-alpha (TNF-alpha) 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-alpha 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-alpha 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-alpha 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-alpha 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-alpha proved to be differently affected by pharmacological treatments able to fully abolish the hyperalgesia.
Bianchi
Mauro
M
Department of Pharmacology, University of Milan, Milan, Italy. mauro.bianchi@unimi.it
Martucci
Cataldo
C
Ferrario
Paolo
P
Franchi
Silvia
S
Sacerdote
Paola
P
D000082:Acetaminophen / Q000494:pharmacology; D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000134:cerebrospinal fluid*; D004195:Disease Models, Animal; D004338:Drug Combinations; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000134:cerebrospinal fluid / Q000209:etiology / Q000517:prevention & control* / Q000523:psychology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications*; D008297:Male; D010146:Pain / Q000134:cerebrospinal fluid / Q000209:etiology / Q000517:prevention & control* / Q000523:psychology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D014110:Touch; D014147:Tramadol / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid*
D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D016861:Cyclooxygenase Inhibitors; D004338:Drug Combinations; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D000082:Acetaminophen; D014147:Tramadol; D005620:Freund's Adjuvant; D015232:Dinoprostone; C012655:nimesulide