The effect of the pretreatment with endomorphin-1 or endomorphin-2 given into anterior 4th ventricle (i.vt.) on the antinociception with the tail-flick test induced by subsequent intraventricular (i.vt.) injection of endomorphin-1 or endomorphin-2 were studied in rats. The i.vt. pretreatment with 30 nmol of endomorphin-1 or 60 nmol of endomorphin-2 developed an antinociceptive tolerance to the subsequently challenging dose of i.vt.-administered endomorphin-1 or endomorphin-2, respectively, with different time courses. The endomorphin-1-induced antinociceptive tolerance reached a maximal level at 2 h, recovered slowly in 24 h after the pretreatment with endomorphin-1, whereas endomorphin-2-induced antinociceptive tolerance developed in 1 h and recovered in 4 h. Rats made tolerant to endomorphin-1 by i.vt. pretreatment with endomorphin-1 exhibited nearly no cross-tolerance to endomorphin-2 to produce antinociception. On the other hand, rats made tolerant to endomorphin-2 exhibited a complete cross-tolerance to endomorphin-1 to produce antinociception. We propose that different degrees of receptor endocytosis for receptor inactivation after stimulation of mu-opioid receptors by endomorphin-1 and endomorphin-2 and/or two separate subtypes of mu-opioid receptors are involved in the antinociception induced by endomorphin-1 and endomorphin-2.
Copyright 2002 Elsevier Science B.V.