PT  - JOURNAL ARTICLE
AU  - R T Windh
AU  - C M Kuhn
TI  - Increased sensitivity to mu opiate antinociception in the neonatal rat despite weaker receptor-guanyl nucleotide binding protein coupling.
DP  - 1995 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1353--1360
VI  - 273
IP  - 3
4099  - http://jpet.aspetjournals.org/content/273/3/1353.short
4100  - http://jpet.aspetjournals.org/content/273/3/1353.full
SO  - J Pharmacol Exp Ther1995 Jun 01; 273
AB  - The developmental changes in mu opiate receptor-mediated antinociception and coupling to guanyl nucleotide binding proteins were studied in the rat. ED50 values for morphine- and sufentanil-induced antinociception were determined in the paw-lift assay on days 10 and 27. The ED50 for morphine analgesia in 10-day-old pups was 0.35 mg/kg and increased with age to 5.3 mg/kg on day 27. Similarly, sufentanil was more potent in pups than in weanlings, the ED50 increasing from 1.7 to 7.6 micrograms/kg. Serum and brain morphine levels after 5 mg/kg of morphine were higher in neonates (day 10) than weanlings (day 27), largely due to a more rapid redistribution phase in weanlings (T1/2 = 26 min.) than in pups (T1/2 = 2.5 hr). Additionally, a substantial (70%) antinociceptive response was achieved in neonates at brain morphine levels that were one-half those producing an equal effect in weanlings. Radioligand binding studies indicated that the number of mu receptors increased 2-fold without change in affinity between days 10 and 27, whereas the GTP analog guanylylimidophosphate was nearly twice as effective in shifting the mu receptors from high to low affinity on day 27 than on day 10. These data indicate that neonatal rats are more sensitive to mu opiate antinociception despite apparently weaker receptor-guanyl nucleotide binding protein coupling. This greater sensitivity is enhanced by the pharmacokinetic differences between neonates and weanlings which result in higher drug levels in pups after a similar dose.