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Ontogeny of mu opioid agonist anti-nociception in postnatal rats
S R Thornton1, D R Compton, F L Smith
1Department of Pharmacology, Medical College of Virginia/Virginia Commonwealth University Richmond 23298-0613, USA.
Insights
Age significantly impacts opioid effectiveness in young rats. Morphine and fentanyl showed consistent efficacy, while meperidine
Area of Science:
- Pharmacology
- Neuroscience
- Pediatric Medicine
Background:
- Mu opiate agonists like morphine, fentanyl, and meperidine are used in pediatric patients.
- Limited data exists on how age affects opioid efficacy and concentration-response in humans.
- Animal studies correlating opioid analgesia with tissue levels are scarce.
Purpose of the Study:
- To investigate the role of age in opioid antinociceptive potency and efficacy.
- To determine the relationship between age, brain/plasma opioid levels, and analgesic effects.
- To provide predictive insights into opioid effects in developing organisms.
Main Methods:
- Used postnatal rats (PND 3-21) to assess age-related opioid effects.
- Employed the tail-flick test for antinociception measurement.
- Measured brain and plasma drug-equivalent levels using radiolabeled tracers.
Main Results:
- Morphine and fentanyl were fully efficacious across all ages, with age-dependent potency and drug levels.
- Strong correlations were found between morphine/fentanyl ED50 and brain/plasma EC50 values.
- Meperidine efficacy varied with age, showing limited effect in young rats and seizures in older ones.
Conclusions:
- Opioid efficacy and potency are influenced by age in developing rats.
- Pharmacokinetics, blood-brain barrier development, and opioid receptor ontogeny are key factors.
- These findings offer predictive information for opioid use in pediatric populations.
Abstract:
Mu opiate agonists morphine, fentanyl and meperidine are administered short-term to pediatric patients, from the neonatal period through adolescence. However, there has been no assessment of the effect of age on the analgesic efficacy or the concentration-response relationship for these opioids in human pediatric patients. Few studies in animals have correlated opioid anti-nociception and tissue levels of these opioids commonly administered to pediatric patients. The present study was conducted to examined the role of age on opioid anti-nociceptive potency and efficacy and brain and plasma opioid levels to provide predictive information on the effect of opioids in developing humans. Administration of trace amounts of tritiated drug with anti-nociceptive doses of unlabeled drug was used for the assessment of anti-nociception in the tail-flick test and for the measurement of brain and plasma drug equivalent levels in postnatal rats (PND 3-21). Morphine and fentanyl were completely efficacious in all postnatal ages examined, although age-related differences in drug potency, as well as, differences in brain and plasma levels were observed. There was a good correlation between morphine (r = 0.96) and fentanyl (r = 0.89) ED(50) values and their respective brain and plasma EC(50) equivalent levels. Meperidine had limited efficacy in young rats (PND 3-9) but was completely efficacious in older rats (PND 14-17). However, PND 21 rats experienced tonic-clonic seizures which limited its efficacy to 70% anti-nociception. Our data suggest that pharmacokinetics, the development of the blood-brain barrier and ontogeny of opioid receptor function may play important roles in the sensitivity of postnatal rats to mu receptor agonists.