Tolerance to δ-but not μ-opioid receptors in the spinal cord attenuates inhibition of the tail-flick response induced by β-endorphin administered intracerebroventricularly in mice

Abstract

Male ICR mice were rendered tolerant by intrathecal (IT) injection once a day with either μ-agonist, D-Ala 2-NMePhe 4-Gly-ol-enkephalin (DAMGO) or δ-agonist, D-Pen 2-D-Pen 5-enkephalin (DPDPE) (toleragen) by doubling the dose each day starting from 0.125 and 1 μg 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 (ED 50 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 (ED 50 value for DAMGO increase 7- to 10-fold) but not DPDPE. The effects of the tolerance to μ- and δ-opioid receptor activity in the spinal cord on inhibition of the tail-flick and hot-plate response induced by intracerebroventricularly (ICV) administered β-endorphin and morphine were then studied. β-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 β-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 β-endorphin. Repeated IT bolus injections of either DPDPE or DAMGO did not affect inhibition of the tail-flick and hot-plate response induced by morphine. The results suggest that spinal δ- but not μ-opioid receptors are involved in ICV administered β-endorphin-induced inhibition of the tail-flick response. Neither spinal μ- nor δ-receptors are involved in inhibition of the tail-flick and hot-plate response induced by morphine given ICV.