Differential behavioral effects of peripheral and systemic morphine and naloxone in a rat model of repeated acute inflammation. (Unité de Physiopharmacologie du Système Nerveux, Paris, France) Anesthesiology. 2001;94:870–875.
Authors: Perrot Serge , Guilbaud Gisèle , Kayser Valérie 
Published: March 2003

This study compared the behavioral effects of intraplantar and intravenous morphine and naloxone in a rat model of repeated acute carrageenan‐induced inflammation in which enhanced response to noxious stimuli result from sensitization in peripheral tissues or central sensitization. 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. Conclude that when the 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.

Comment by Octavio Calvillo, M.D., Ph.D. There is evidence that opioid antinociception is enhanced in the presence of inflammation. In fact, there is evidence that opioids produce analgesia through peripheral opioid receptors within inflamed tissue. Primary afferent neurons are known to contain opioid receptors. It remains unclear whether the antinociceptive effects of opioids are related predominantly to central, peripheral sites of action or both. The authors compared the effects of intraplantar and intravenous morphine and naloxone in a rat model of carrageenan‐induced inflammation. In this model, hyperalgesia is due probably to both peripheral and central sensitization. The antinociceptive effects of intraplantar morphine, intravenous morphine, intraplantar naloxone, and intravenous naloxone were assessed on the vocalization thresholds to noxious pressure 3 hours after carrageenan plantar injections. Intraplantar and intravenous morphine increased the vocalization thresholds after carrageenan injection in inflamed but not on noninflamed paws. The antinociceptive effects of intraplantar morphine were reduced compared to the first response whereas the effects of intravenous morphine were significantly enhanced and present on both inflamed and noninflamed paws. Intravenous naloxone demonstrated similar pronociceptive patterns after the first and second carrageenan injection. Intraplantar naloxone produced pronociceptive effects in inflamed hind paws that were significantly enhanced after the second carrageenan injection. The authors concluded that when inflammation is enhanced by recurrent stimulation the antinociceptive effects of systemic morphine are enhanced. This is more probably related to central than to peripheral sites of action.