Dissociable effects of ultralow-dose naltrexone on tolerance to the antinociceptive and cataleptic effects of morphine

Abstract

Ultralow-dose opioid antagonists augment the antinociceptive effect of morphine and block the development of tolerance to repeated morphine injections in rodents, but the effects are not reliably reproduced in humans. One explanation for this discrepancy is that preclinical studies of ultralow-dose antagonism in rodents generally use reflex-withdrawal tests of antinociception, which may be affected by cataleptic effects of morphine. We tested this hypothesis by examining whether ultralow-dose naltrexone alters the cataleptic effect of morphine or the development of tolerance to morphine-induced catalepsy. Rats (N=56) were randomly assigned to saline, morphine (10 mg/kg), cotreatments of morphine plus naltrexone (molar ratios of 1,000,000 : 1; 500,000 : 1; 100,000 : 1), or naltrexone-alone groups. Rats were injected with drug for 7 consecutive days; on each day, catalepsy and antinociception were assessed 30 and 60 min postinjection, using the bar and tail-flick tests, respectively. Ultralow-dose naltrexone (500,000 : 1) extended the antinociceptive effect of morphine within a session and attenuated the development of tolerance to the antinociceptive effect of morphine across sessions. Naltrexone alone had no effect on either test. These data show that the paradoxical effect of ultralow-dose naltrexone on antinociception is not the product of morphine-induced catalepsy, pointing to an important role for agonist-antagonist combinations in the clinical treatment of pain.