Male ICR mice were rendered tolerant by intrathecal (IT) injection once a day with either mu-agonist, D-Ala2-NMePhe4-Gly-ol-enkephalin (DAMGO) or delta-agonist, D-Pen2-D-Pen5-enkephalin (DPDPE) (toleragen) by doubling the dose each day starting from 0.125 and 1 microgram for DAMGO and DPDPE, respectively, for 6 days. On day 6, the magnitude of tolerance was assessed by establishing IT dose-response lines for the effect of the chronic drug given as bolus injections (probe). The antinociception was assessed by the tail-flick and hot-plate test. Repeated IT injections of DPDPE reduced inhibition of the tail-flick and hot-plate response induced by DPDPE (ED50 values for DPDPE increase 10-fold) but not DAMGO. Repeated IT injections of DAMGO reduced inhibition of the tail-flick and hot-plate response induced by DAMGO (ED50 value for DAMGO increase 7- to 10-fold) but not DPDPE. The effects of the tolerance to mu- and delta-opioid receptor activity in the spinal cord on inhibition of the tail-flick and hot-plate response induced by intracerebroventricularly (ICV) administered beta-endorphin and morphine were then studied. beta-Endorphin or morphine at different doses were injected ICV 4 hr after the last IT injection of DPDPE or DAMGO. Repeated IT bolus injections of DPDPE reduced inhibition of the tail-flick response but not the hot-plate response induced by beta-endorphin. On the other hand, repeated IT bolus injections of DAMGO did not affect inhibition of the tail-flick and hot-plate response induced by beta-endorphin.(ABSTRACT TRUNCATED AT 250 WORDS)