Profound spinal tolerance after repeated exposure to a highly selective mu-opioid peptide agonist: role of delta-opioid receptors

• Published in: The Journal of pharmacology and experimental therapeutics 2002-07, Vol.302 (1), p.188-196
• Main Authors: Zhao, Guo-Min, Wu, Dunli, Soong, Yi, Shimoyama, Megumi, Berezowska, Irena, Schiller, Peter W, Szeto, Hazel H
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - pharmacology; Animals; Drug Tolerance; Injections, Spinal; Injections, Subcutaneous; Kinetics; Male; Mice; Morphine - pharmacology; Oligopeptides - pharmacology; Pain Measurement - drug effects; Radioligand Assay; Rats; Receptors, Opioid, delta - antagonists & inhibitors; Receptors, Opioid, delta - drug effects; Receptors, Opioid, mu - agonists; Spinal Cord - drug effects
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.302.1.188

Recent studies suggest that delta-opioid receptors play a role in the development of opioid tolerance and led us to hypothesize that highly selective mu-opioid agonists may produce less tolerance. H-2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH(2) ([Dmt(1)]DALDA) has extraordinary selectivity for mu-receptors (K(i)(delta)/K(i)(mu) > 14,000). Daily administration of [Dmt(1)]DALDA (5 times ED(50); s.c.) for 7 days increased ED(50) 3.6-fold from 0.16 to 0.58 micromol/kg. A higher dose of [Dmt(1)]DALDA (10 times ED(50), every 12 h) for 2.5 days resulted in a 11.7 times increase in the ED(50) (1.9 micromol/kg). Complete cross-tolerance to morphine was observed, with a 3.4- and 15.1-fold shift in the morphine ED(50), respectively. We also compared the extent of spinal versus supraspinal tolerance after repeated s.c. [Dmt(1)]DALDA administration. Five doses of [Dmt(1)]DALDA (10 times ED(50), every 12 h) resulted in a 3.4 times shift in the i.c.v. ED(50) (15.4 versus 4.6 pmol/mouse) but a 44 times shift in the i.t. ED(50) (52.9 versus 1.2 pmol/mouse). Tolerance to [Dmt(1)]DALDA was associated with 30 to 35% reduction in [(3)H][Dmt(1)]DALDA binding in brain and spinal cord. Coadministration of [Dmt(1)]DALDA with delta-antagonist naltriben (NTB) reduced spinal tolerance by 50%. Even after spinal tolerance had been established, addition of a delta-antagonist (NTB or H-Tyr-TicPsi[CH(2)NH]Phe-Phe-OH) significantly enhanced the potency of i.t. [Dmt(1)]DALDA 2- to 4-fold. These results suggest that agonist activation of delta-receptors is not necessary for the development of opioid tolerance; however, delta-receptors play a modulatory role in the maintenance of the tolerant state.