Naloxone produces protracted tolerance in mice treated with a single dose of morphine

Previously we have shown that naloxone (NLX)-induced withdrawal in acutely dependent mice [a single dose of 100 mg/kg of morphine sulfate (MS) s.c.] leads to an increase in the degree and duration of the dependent state. In this study we investigated the modulation of opioid tolerance by NLX in acutely tolerant mice (a single dose of 100 mg/kg of MS s.c.). When acutely tolerant mice were injected 3 hr later with 32 mg/kg of NLX, tolerance to the antinociceptive effect of MS could be observed for at least 12 days after MS injection. The same dose of NLX given 3 days after MS injection also led to the prolongation of MS tolerance whereas 4 mg/kg of NLX had no effect. By using the latter protocol, if the ineffective 4-mg/kg dose of NLX was preceded 2 hr before with 10 mg/kg of MS, tolerance to MS could be detected for at least 6 days. When this protracted tolerance (100 mg/kg of MS followed 3 hr later by 32 mg/kg of NLX) was studied at spinal and supraspinal sites, tolerance to MS at supraspinal sites was greater and more prolonged than at spinal sites. [D-Pen2,D-Pen5]enkephalin did not show cross-tolerance at either site. U50,488H [trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)-cyclohexyl]benzeneacetamide) showed a slowly developing cross-tolerance only at the supraspinal sites. In acutely tolerant animals, the tolerance that developed at supraspinal and spinal sites was of equal magnitude and contributed additively to the total tolerance observed in the animals.(ABSTRACT TRUNCATED AT 250 WORDS)