Ontogeny of mu opioid agonist anti-nociception in postnatal rats.
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.
Thornton
S R
SR
Department of Pharmacology, Medical College of Virginia/Virginia Commonwealth University Richmond 23298-0613, USA.
Compton
D R
DR
Smith
F L
FL
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000254:growth & development*; D001923:Brain Chemistry / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005283:Fentanyl / Q000494:pharmacology; D008297:Male; D008614:Meperidine / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists*
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D009020:Morphine; D008614:Meperidine; D005283:Fentanyl