Profound spinal tolerance after repeated exposure to a highly selective μ-opioid peptide agonist:: Role of δ-opioid receptors

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-NH2 ([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 ED50; s. c.) for 7 days increased ED50 3.6-fold from 0.16 to 0.58 mumol/kg. A higher dose of [Dmt(1)]DALDA (10 times ED50, every 12 h) for 2.5 days resulted in a 11.7 times increase in the ED50 (1.9 mumol/kg). Complete cross-tolerance to morphine was observed, with a 3.4- and 15.1-fold shift in the morphine ED50, 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 ED50, every 12 h) resulted in a 3.4 times shift in the i.c.v. ED50 (15.4 versus 4.6 pmol/mouse) but a 44 times shift in the i.t. ED50 (52.9 versus 1.2 pmol/mouse). Tolerance to [Dmt(1)]DALDA was associated with 30 to 35% reduction in [H-3][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[CH2NH] 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.