Paracetamol is analgesic in a rat model of local inflammatory pain through activation of a systemic endogenous opioid response

Rafael M Rezende, Y.S.Bakhle1 , Janetti N Francischi, Dept of Pharmacology, ICB, UFMG, Belo Horizonte, MG, Brazil and 1Leukocyte Biology, NHLI, Imperial College, London, SW7 2AZ.

Paracetamol is a mild, non-narcotic, analgesic exerting minimal inhibition of either cyclooxygenase (COX)-1 or COX-2. Latterly, inhibition of prostaglandin (PG) biosynthesis catalysed by another COX isoform, COX-3, has been proposed as the mechanism underlying the analgesic effects of paracetamol (Simmons, 2003; Ayoub et al., 2006). In a model of inflammatory pain (rat hind paw injected with carrageenan, CG), we noted that paracetamol shared with celecoxib, a selective inhibitor of COX-2, the ability to raise nociceptive thresholds above normal (hypoalgesia) and here we present a fuller comparison of these two compounds in this model.

We used male Holtzman rats (140-170g), under IASP guidelines (Zimmermann, 1983). Intraplantar injection of CG (250 μg per paw) induced hyperalgesia to a mechanical stimulus, developing and resolving over 6h and expressed only in the injected (right) paw. Paracetamol (60-360 mg kg-1, s.c, 30 min before CG) reversed hyperalgesia and raised thresholds above normal (saline injected paw) levels; thresholds (g weight) at 2h after CG, (mean ± s.e. mean); CG+paracetamol, 60mg kg–1, 164 ± 19; 180mg kg–1, 205 ± 10*; 360mg kg–1, 280 ± 25*; saline, 170 ± 2; * P<0.05 vs saline; (n=5-6). This was comparable to the effect of celecoxib (12mg kg–1, s.c, 30min before CG); 2h thresholds, CG+celecoxib, 210 ± 17*: saline, 136 ± 6). However, unlike celecoxib, paracetamol also raised thresholds in the non-inflamed (left) paw (left paw, CG+paracetamol, 360mg kg–1, 275 ± 22). Naltrexone (3mg/kg, s.c., 60min before CG), known to prevent the analgesic effects of celecoxib in this model (França et al., 2006), also prevented those of paracetamol, in both CG (right) and saline treated (left) paws (saline only, 148 ± 3: right, 166 ± 6; left, 174 ± 7). Intraplantar injection of naltrexone (100 μg, 30min before CG) also reversed the effects of celecoxib (12mg kg–1 s.c.) but did not affect the analgesic effects of paracetamol (360mg kg–1 s.c.).

Although both celecoxib and paracetamol induced naltrexone-sensitive, anti-hyperalgesic effects, celecoxib acted locally and was dependent on inflammation whereas paracetamol acted systemically and in the absence of inflammation. If inhibition of PG biosynthesis via COX-3 is critical for the analgesic actions of paracetamol, then our results would imply that lack of those COX-3 derived PGs, or paracetamol itself, activates an endogenous opioid system to mediate the observed analgesia.

Ayoub S S et al (2006). Eur J Pharmacol. 538: 57-65.
França D et al (2006). Neuropharmacology 51:37-43.
Simmons D L (2003). Thromb Res 110: 265-268.
Zimmermann M (1983). Pain 6, 109-110.

We thank CAPES, CNPq and FAPEMIG for their support of this work.