Spinal interaction between the highly selective mu agonist DAMGO and several delta opioid receptor ligands in naive and morphine-tolerant mice

Szentirmay, A. K. and Király, K. P. and Lenkey, N. and Lackó, E. and Al-Khrasani, M. and Friedmann, T. and Timár, Júlia and Gyarmati, S. and Tóth, Géza and Fürst, Zsuzsanna and Riba, Pál (2013) Spinal interaction between the highly selective mu agonist DAMGO and several delta opioid receptor ligands in naive and morphine-tolerant mice. BRAIN RESEARCH BULLETIN, 90. pp. 66-71. ISSN 0361-9230

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Abstract

Since the discovery of opioid receptor dimers their possible roles in opioid actions were intensively investigated. Here we suggest a mechanism that may involve the mu-delta opioid heterodimers. The exact role of delta opioid receptors in antinociception and in the development of opioid tolerance is still unclear. While receptor up-regulation can be observed during the development of opioid tolerance no mu receptor down-regulation could be detected within five days. In our present work we investigated how the selective delta opioid receptor agonists and antagonists influence the antinociceptive effect of the selective mu receptor agonist DAMGO in naive and morphine-tolerant mice. We treated male NMRI mice with 200 mu mol/kg subcutaneous (s.c.) morphine twice daily for three days. On the fourth day we measured the antinociceptive effect of DAMGO alone and combined with delta ligands: DPDPE, deltorphin II (agonists), TIPP and TICP psi (antagonists), respectively, administered intrathecally (i.t) in mouse tail-flick test. In naive control mice none of the 8 ligands caused significant changes in the antinociceptive action of DAMGO. The treatment with s.c. morphine resulted in approximately four-fold tolerance to i.t. DAMGO, i.e. the ED50 value of DAMGO was four times as high as in naive mice. 500 and 1000 pmol/mouse of the delta(1) selective agonist DPDPE enhanced the tolerance to DAMGO while 1000 pmol/mouse of the delta(2) selective agonist deltorphin II did not influence the degree of tolerance. However, both B antagonists TIPP and TICP psi potentiated the antinociceptive effect of i.t. DAMGO, thus they restored the potency of DAMGO to the control level. The inhibitory action of DPDPE against the antinociceptive effect of DAMGO could be antagonized by TIPP and TICP psi. We hypothesize that during the development of morphine tolerance the formation of mu delta heterodimers may contribute to the spinal 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 mu receptor down-regulation. Ligands that do not affect the dimer formation do not influence antinociception either but ligands with the presumed capability of disconnecting the dimers may decrease the spinal tolerance to DAMGO. (C) 2012 Elsevier Inc. All rights reserved.

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