The increase in morphine antinociceptive potency produced by carrageenan-induced hindpaw inflammation is blocked by naltrindole, a selective δ-opioid antagonist

Abstract

Carrageenan-induced inflammation of the rat hindpaw has been used as a model for persistent pain of inflammatory origin. The induction of inflammation resulting from carrageenan injection in the rat hindpaw has been shown to elicit an increase in the antinociceptive potency of morphine, an effect postulated to be related to reduced levels of spinal cholecystokinin (CCK). Recent findings have related the anti-opioid effect of CCK to a decrease in activation of δ-opioid receptors. For this reason, we have examined the effects of the δ-opioid antagonist naltrindole (NTI) on the modulation of morphine antinociceptive potency resulting from carrageenan-induced inflammation. Rats with carrageenan-induced hindpaw inflammation received several doses of morphine in the absence or presence of NTI and were tested in the hot plate (HP) and tail flick (TF) tests. These results were compared to those of non-carrageenan injected rats. Morphine was significantly more potent in inflamed, than in control, rats in both tests. While NTI did not affect morphine antinociceptive potency in control rats in either test, this opioid δ antagonist blocked the increase in morphine potency resulting from carrageenan inflammation in nearly every case. The blockade of the enhancement of morphine potency was such that the effect of a given dose of morphine was similar in control rats and carrageenan-injected rats with NTI. We suggest that carrageenan-induced indlammation may alter endogenous enkephalin levels, perhaps by a decrease in CCK availability. The enhancement of morphine antinociceptive potency may result from the well-established synergism seen following the activation of opioid δ receptors by enkephalins.