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Spinal interaction between μ and δ opioid receptors in naive and morphine-tolerant rats


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.

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Correspondence to Pál Riba.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Riba, P., Király, K.P., Friedmann, T. et al. Spinal interaction between μ and δ opioid receptors in naive and morphine-tolerant rats. BMC Pharmacol 9 (Suppl 2), A48 (2009).

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