Endogenous opioids mediate analgesia due to selective inhibitors of cyclo-oxygenase-2 (COX-2) in rat inflamed paws

J.N. Francischi, D.S. França, D.L. Ferreira-Alves, I.D.G. Duarte & Y.S. Bakhle1; Depto. de Farmacologia, ICB, UFMG, Belo Horizonte, MG, Brazil and 1Leukocyte Biology, NHLI, Imperial College, London, SW7 2AZ.

Injection of carrageenan (CG) into the rat hind paw lowers the nociceptive threshold in that paw (hyperalgesia). This lowered threshold is restored to normal by pre-treatment with non-selective inhibitors of COX. Pre-treatment with selective inhibitors of COX-2 also prevents hyperalgesia but raises the threshold above normal values. We have referred to this condition of raised nociceptive threshold as “hypoalgesia” (Francischi et al, 2002). Here, we have analysed the mechanisms underlying such hypoalgesic states.

Groups of male Holtzman rats (at least 5 rats per group; 140- 200 g body weight) were injected with CG (250 μg/paw) in the right hind paw and saline injected into the left hind paw. Every hour, the mechanical nociceptive threshold was measured (Francischi et al, 2002); hyperalgesia peaked at 3-4 h after CG and disappeared by about 6 h. The area under the curve (AUC) of threshold values during the hyperalgesia was used to quantitate the responses; results are shown as means±-s.e.m; significant differences between means (P<0.05) were assessed by Student t test or ANOVA, with post hoc analysis, when indicated. Pre treatment (30 min before CG) with indomethacin ( s.c.; 2 mg.kg-1) decreased hyperalgesia but did not raise the threshold above normal. Pre-treatment with selective inhibitors of COX-2, SC 236 (12mg.kg-1) or celecoxib (12mg.kg-1), prevented development of hyperalgesia and raised the threshold above normal values, yielding positive values for the AUC (CG alone, -337 +19 AUC units; CG+ celecoxib, 127 +13; CG+SC236, 103 +25). A selective inhibitor of COX-1, SC560 (1–10 mg.kg-1) prevented hyperalgesia but did not induce hypoalgesia. Intra-plantar injection of prostaglandin E 2 (PGE 2; 200ng per paw) also induced hyperalgesia comparable in duration to that induced by CG. This hyperalgesia was converted to a state of hypoalgesia by pre-treatment of the rats with celecoxib (PGE2, -238 +22; PGE2 + celecoxib, 147 +24 units). Pre-treatment (30 min before CG) of rats with the opioid antagonist, naltrexone (s.c , 3mg.kg-1), totally abolished the analgesic effects of celecoxib, without affecting the anti-hyperalgesic effects of indomethacin. In rats made tolerant to morphine by daily injections (s.c, 10mg.kg-1, two divided doses) over 5 days, paw hyperalgesia induced by PGE2 was tested daily, after the morning morphine injection. Analgesic effects of morphine decreased progressively and, on the 5 th day, there was no effect of morphine on PGE2 hyperalgesia. In these morphine tolerant rats, pre-treatment with SC236 was now ineffective in reversing hyperalgesia due to PGE2. From these results we conclude that the anti-hyperalgesic effects of selective inhibitors of COX-2 were not related to inhibition of PG biosynthesis. Rather, there is evidence that endogenous opioids were involved in the analgesic actions of the COX-2 inhibitors in this model of inflammatory pain.

Francischi et al, (2002). Br. J. Pharmacol. 137 , 837-844.

We thank CNPq and CAPES for support.