Background: It has been reported that opioid antinociceptive effects are enhanced in animal models of inflammation, but it remains unclear whether this sensitization to morphine is related to predominant central or peripheral increased effects.
Methods: The authors compared the behavioral effects of intraplantar and intravenous morphine and naloxone in a rat model of repeated acute carrageenan-induced inflammation in which enhanced responses to noxious stimuli result from sensitization in peripheral tissues or central sensitization. The antinociceptive effects of intraplantar morphine (50, 75, 100, 150, and 200 microg), intravenous morphine (0.3, 0.6, and 1 mg/kg), and the pronociceptive effects of intraplantar naloxone methiodide (150 microg) and intravenous naloxone (1 mg/kg) against noxious pressure (vocalization thresholds to paw pressure) in rats were assessed 3 h after one or two carrageenan plantar injections performed 7 days apart.
Results: After the first carrageenan injection, intraplantar and intravenous morphine produced significant increase of vocalization thresholds to paw pressure in inflamed but not in noninflamed paws. After the second carrageenan injection, the antinociceptive effects of intraplantar morphine were significantly reduced compared with those obtained after the first carrageenan injection, whereas effects of intravenous morphine were significantly enhanced and present in both hind paws. Intravenous naloxone demonstrated similar pronociceptive patterns after the first and second carrageenan injection. Intraplantar naloxone methiodide produced pronociceptive effects in inflamed hind paw that were significantly enhanced after the second carrageenan injection.
Conclusions: When inflammation is enhanced by recurrent stimulations, the antinociceptive effects of systemic morphine are enhanced. This increase is more likely related to central than peripheral sites of action, beyond endogenous opioid system activation.