Journal Article

Different mechanisms underlie the analgesic actions of paracetamol and dipyrone in a rat model of inflammatory pain

Menezes, G B, Francischi, J N, Rezende, R M, França, D S, Reis, W G P, Bakhle, Y S

2008

Overview

Background and purpose: The analgesics, paracetamol and dipyrone are weak inhibitors of the cyclooxygenase isoforms 1 or 2 (COX‐1, COX‐2) but more potent on COX‐3. Both are also weak anti‐inflammatory agents, relative to their analgesic and antipyretic activities. In a model of inflammatory pain mediated by prostaglandins, both compounds were analgesic. We have analysed this shared effect further in order to elucidate the underlying mechanisms. Experimental approach: Inflammation was induced in one hind paw of rats by intraplantar injection of 250 μg λ‐carrageenan (CG) and the contralateral paw injected with saline. Nociceptive thresholds to mechanical stimulation were measured immediately before and for 6 h after, injection of CG. The analgesics were s.c. or locally (intraplantar) injected either 30 min before or 2 h after CG. In some groups, naltrexone was injected (s.c. or intraplantar), 1 h before CG. Key results: Pretreatment with paracetamol or dipyrone (60–360 mg kg−1) reversed hyperalgesia induced by CG and increased nociceptive threshold in the inflamed paw above the basal level (hypoalgesia). Paracetamol, but not dipyrone, also raised nociceptive thresholds in the non‐inflamed paw. Subcutaneous, but not local, administration of naltrexone, a specific opioid antagonist, reversed the hypoalgesia induced by paracetamol, but similar naltrexone treatment had no effect on dipyrone‐induced analgesia. Conclusions and implications: Although both paracetamol and dipyrone are inhibitors of COX isoforms and thus of prostaglandin biosynthesis and were analgesic in our model, their analgesic actions were functionally and mechanistically different. Satisfactory mechanisms of action for these analgesics still remain to be established. British Journal of Pharmacology (2008) 153, 760–768; doi:10.1038/sj.bjp.0707630; published online 24 December 2007

• Publisher: Blackwell Publishing Ltd,Nature Publishing,Nature Publishing Group
• Subject: Acetaminophen - administration & dosage / Acetaminophen - pharmacology / Analgesics, Non-Narcotic - administration & dosage / Analgesics, Non-Narcotic - pharmacology / Animals / Biological and medical sciences / Carrageenan / dipyrone / Dipyrone - administration & dosage / Dipyrone - pharmacology / Disease Models, Animal / endogenous opioids / Hyperalgesia - etiology / Hyperalgesia - metabolism / Hyperalgesia - physiopathology / Hyperalgesia - prevention & control / hypoalgesia / Inflammation - chemically induced / Inflammation - complications / Inflammation - drug therapy / Inflammation - metabolism / Inflammation - physiopathology / Injections, Intralesional / Injections, Subcutaneous / Male / Medical sciences / Naltrexone - pharmacology / Narcotic Antagonists - pharmacology / Opioid Peptides - antagonists & inhibitors / Opioid Peptides - metabolism / Pain - etiology / Pain - metabolism / Pain - physiopathology / Pain - prevention & control / Pain Measurement / Pain Threshold - drug effects / paracetamol / Pharmacology. Drug treatments / Rats / Rats, Sprague-Dawley / Rats, Wistar / Research Design / Research Papers / Time Factors