Local inhibition of inflammatory pain by naloxone and its N-methyl quaternary analogue

Inflammation was induced in rats by intraplantar administration of carrageenan (500 micrograms in 0.1 ml). Nociceptive thresholds were measured on both inflamed and contralateral hindpaws with the pressure test of Randal and Sellito. Low doses (0.03-10 micrograms/kg) of naloxone hydrochloride (Nx) or of methylnaloxone methylsulfonate (MeNx) were injected 4 h after carrageenan in the inflamed paw: Nx (3 micrograms) and MeNx (1-10 micrograms) diminished inflammatory pain; a slight, nonspecific hyperalgesia was observed in the contralateral paw after Nx, MeNx or NaCl. Neither drug was effective when injected s.c. at the same doses and time; however activities were shown to be influenced by the experimental schedule. Low s.c. doses of Nx antagonized the analgesia produced by s.c. morphine whereas MeNx did not. This work demonstrates the local site of the analgesic action of the doses of Nx and MeNx used here, bringing new evidence in favour of the existence of cutaneous opioid receptors. Opiate antagonists might inhibit inflammatory pain by interacting with a particular population of cutaneous receptors and (or) by being dealkylated locally into agonists.