We determined the susceptibility of two ages of rat pups to become tolerant to and dependent on morphine infusions from osmotic minipumps. Neonatal rats (postnatal day 6; P6) were infused for 72 h with morphine at 0.175 or 0.7 mg/kg/h. On P9, morphine’s antinociceptive efficacy was reduced in both groups. P14 infant rats were also infused at 0.7 mg/kg/h. Unlike P9 neonates, morphine’s potency was reduced in P17 infant rats, without a loss in efficacy. Yet raising the infusion rate to 1.1 mg/kg/h reduced morphine’s efficacy. ³H-DAMGO D-Ala2, N-MePhe4, Gly5-ol-enkephalin) binding revealed no change in the affinity or density of mu-opioid receptors at any age or in any treatment group. P9 and P17 pups were physically dependent on each infusion dose. Thus, chronic infusion of morphine affected both ages to such an extent that acutely administered morphine doses of even 1,000 mg/kg failed to restore antinociception. However, this effect cannot be attributed to changes in mu-opioid receptor number or affinity.

We have previously noted that the antinociceptive efficacy of morphine was significantly decreased in rat pups chronically infused with morphine from implanted osmotic minipumps. In this study, morphine was fully efficacious (i.e., 100% maximum possible effect, %MPE) in the 52 ºC tail-immersion test after a 72-h infusion from implanted saline-filled osmotic minipumps. However, administration of up to 1000 mg/kg s.c. morphine failed to elicit greater than a 27% MPE in rats infused with morphine at 2 mg/kg/h. Morphine was more efficacious when the water bath temperature was decreased to 49 ºC. Experiments were conducted to determine the mechanisms whereby chronic morphine administration leads to a decrease in antinociceptive efficacy. The kappa-opioid antagonist nor-binalorphimine completely blocked the antinociceptive effects of morphine in morphine-infused rat pups. The kappa agonist U50,488 elicited antinociception however, the requirement to use higher doses in morphine-than saline-infused rats indicates that kappa cross-tolerance was present. Thus, in tolerant rats the antinociceptive effects of high doses of morphine appear to be mediated through kappa-opioid receptors. The deltaopioid antagonist naltrindole was inactive in both treatment groups. DAMGO-stimulated [ 35 S]GTPγS and [ 3 H]naloxone binding reveal that the anatomical distribution of the mu-opioid receptor was consistent with that of the adult rat brain. In adult rats, the mu-opioid receptor is desensitized during morphine tolerance. However, desensitization was not evident in P17 rats based on the lack of significant decreases in [ 35 S]GTPγS binding. Furthermore, [ 3 H]naloxone binding indicated a lack of mu receptor downregulation in morphine-tolerant rat pups.

Buprenorphine may prove to be a suitable drug for treating opioid withdrawal in human infants.