Acute antinociceptive tolerance and partial cross-tolerance to endomorphin-1 and endomorphin-2 given intrathecally in the mouse

Abstract

The effect of pretreatment with endomorphin-1 (EM-1) or endomorphin-2 (EM-2) given intrathecally (i.t.) on the tail-flick inhibition induced by subsequent i.t. injection of EM-1 or EM-2 was studied in CD-1 mice. Pretreatment with EM-1 (32.7 nmol) for 1–3 h, but not 4 h, attenuated the tail-flick inhibition induced by i.t. EM-1 (16.3 nmol), while pretreatment with EM-2 (70 nmol) for 0.5–1.5 h, but not 2 h, attenuated tail-flick inhibition induced by i.t. EM-2 (35 nmol). EM-1 (32.7 nmol) pretreatment for 1.5 h produced 5.3- and only 2.4-folds shift to the right of the dose-response curves for EM-1- and EM-2-induced tail-flick inhibition, respectively, while EM-2 (70 nmol) pretreatment for 1 h caused 4.3- and 4.5-folds shift to the right for EM-2- and EM-1-induced tail-flick inhibition, respectively. Thus, mice made antinociceptive tolerant to EM-1 were partially cross-tolerant to EM-2 and mice made antinociceptive tolerant to EM-2 were completely cross-tolerant to EM-1. It is proposed that EM-1- and EM-2-induced antinociception are mediated by the stimulation of two different subtypes of μ-opioid receptors in mouse spinal cord; one subtype is stimulated by both EM-1 and EM-2, and another subtype is stimulated by EM-2.