The ontogeny of mu opiate tolerance and dependence in the rat: antinociceptive and biochemical studies.
The ontogeny of tolerance to mu opiate antinociception and the behavioral and endocrine profiles of the opiate withdrawal syndrome were studied in rats. Animals were treated with saline or an increasing dose regimen of morphine for 5 days (5-25 mg/kg b.i.d. s.c.) and were tested 36 hr later for morphine or sufentanil antinociception in the hot-plate paw-lift test, or withdrawal was precipitated with 5 mg/kg of naloxone 12 hr after the last chronic morphine dose. Twenty-seven-, 20- and 15-day-old rats all developed tolerance as indicated by a rightward shift of the dose-response curve after chronic morphine. Animals treated on days 4 to 8 and tested on day 10 did not develop tolerance to the same chronic dose regimen used in older animals. In contrast to the observed developmental difference in tolerance, both neonatal and weanling rats developed physical dependence after morphine treatment, as evidenced by the presence of withdrawal symptoms after naloxone administration. Withdrawal in weanling rats was characterized by ptosis, piloerection, abnormal posture, forepaw treading, vocalization on touch and mastication. In addition, both serum corticosterone and adrenocorticotropic hormone secretion were increased during passive withdrawal. The behaviors constituting the withdrawal syndrome precipitated in neonates were distinct from those in weanling rats. Spontaneous vocalization, wall climbing, tremor, mouthing and increased locomotion were all observed. As in the older animals, both serum corticosterone and adrenocorticotropic hormone secretion were elevated during passive withdrawal. Tremor also was induced in opiate naive neonates when naloxone (5 mg/kg) was administered 2 hr after a single 25-mg/kg morphine injection. Brain and serum morphine levels and the time course of antinociception were not altered by chronic morphine treatment at any age. Saturation binding assays in brain homogenates indicated that chronic morphine did not produce changes in receptor number or affinity for the antagonist. The shift induced by the guanine nucleotide Gpp(NH)p (10 microM) from high to low affinity on days 27 and 10, respectively, was not altered by chronic morphine treatment. These data indicate that 10-day-old rats are refractory to developing tolerance relative to older animals, and that changes in receptor number or coupling to guanine nucleotide proteins do not accompany tolerance to this regimen.
Windh, RT; Little, PJ; Kuhn, CM
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