The role of δ opioid receptors in opioid antinociception and tolerance development is still unclear. In the spinal cord of morphine-tolerant mice δ receptor ligands given intrathecally (i.t.) differently influenced the antinociceptive effect of the μ agonist D-Ala2-methyl-glycinol (DAMGO). The δ1 agonist D-Pen2,5-enkephalin (DPDPE) inhibited, the δ2 agonist deltorphin II did not alter, and the δ antagonist cha-TIPPψ potentiated the effect of DAMGO. We hypothesized that during the development of morphine tolerance the formation of μ-δ heterodimers may contribute to the spinal μ opioid tolerance. Delta ligands may affect the dimer formation differently. Those, like DPDPE may facilitate the dimer formation, hence inhibit the antinociceptive effect of DAMGO by causing virtual μ receptor down-regulation. Ligands that do not affect the dimer formation do not influence antinociception but ligands with the presumed capability of disconnecting the dimers may decrease the spinal tolerance to DAMGO. The δ ligand profile in morphine-tolerant rats, were also studied.
Male Wistar rats (150-200 g) were treated with subcutaneous (s.c) morphine twice daily for four days with increasing doses (50, 100, 200, 200 μmol/kg). On the fifth day the antinociceptive effect (rat tail flick test) of DAMGO was measured alone and combined with a fixed dose of δ ligands given i.t.: DPDPE, Ile3,5-deltorphin II, cha-TIPPψ and naltrindole, respectively.
The repeated treatment with morphine resulted in approximately three to six-fold shift of the ED50 value of DAMGO compared to that of naive rats. Both in naive control and morphine-tolerant rats all ligands except naltrindole potentiated the antinociceptive effect of i.t. DAMGO (two to five-fold). In the tolerant rats the potentiation restored the potency of DAMGO to the control level.
Delta ligands behave differently in rats than in mice. One possible explanation could be a higher basal density of the μ-δ heterodimers in rats. The inhibitory action of naltrindole on the antinociceptive effect of DAMGO could be explained by its relatively low μ/δ selectivity as well as by the different effect on the μ-δ heterodimer. The difference in the DPDPE effect in morphine-tolerant rats and mice requires further clarification.
This work was supported by the Hungarian grants OTKA K-60999 and ETT-441/2006, and a Bolyai Fellowship of the Hungarian Academy of Sciences and Faculty of General Medicine, Semmelweis University.