Augmentation of spinal morphine analgesia and inhibition of tolerance by low doses of μ- And δ-opioid receptor antagonists

Background and purpose: Ultralow doses of naltrexone, a non-selective opioid antagonist, have previously been found to augment acute morphine analgesia and block the development of tolerance to this effect. Since morphine tolerance is dependent on the activity of μ and δ receptors, the present study investigated the effects of ultralow doses of antagonists selective for these receptor types on morphine analgesia and tolerance in tests of thermal and mechanical nociception. Experimental approach: Effects of intrathecal administration of μ-receptor antagonists, CTOP (0.01 ng) or CTAP (0.001 ng), or a δ-receptor antagonist, naltrindole (0.01 ng), on spinal morphine analgesia and tolerance were evaluated using the tail-flick and paw-pressure tests in rats. Key results: Both μ and δ antagonists augmented analgesia produced by a sub-maximal (5 μg) or maximal (15 μg) dose of morphine. Administration of the antagonists with morphine (15 μg) for 5 days inhibited the progressive decline of analgesia and prevented the loss of morphine potency. In animals exhibiting tolerance to morphine, administration of the antagonists with morphine produced a recovery of the analgesic response and restored morphine potency. Conclusions and implications: Combining ultralow doses of μ- or δ-receptor antagonists with spinal morphine augmented the acute analgesic effects, inhibited the induction of chronic tolerance and reversed established tolerance. The remarkably similar effects of μ- and δ-opioid receptor antagonists on morphine analgesia and tolerance are interpreted in terms of blockade of the latent excitatory effects of the agonist that limit expression of its full activity.