Profound Spinal Tolerance after Repeated Exposure to a Highly Selective μ-Opioid Peptide Agonist: Role of δ-Opioid Receptors

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Abstract
Recent studies suggest that δ-opioid receptors play a role in the development of opioid tolerance and led us to hypothesize that highly selective μ-opioid agonists may produce less tolerance. H-2′,6′-dimethyltyrosine-d-Arg-Phe-Lys-NH2([Dmt1]DALDA) has extraordinary selectivity for μ-receptors (Kiδ/Kiμ> 14,000). Daily administration of [Dmt1]DALDA (5 times ED50; s.c.) for 7 days increased ED50 3.6-fold from 0.16 to 0.58 μmol/kg. A higher dose of [Dmt1]DALDA (10 times ED50, every 12 h) for 2.5 days resulted in a 11.7 times increase in the ED50 (1.9 μmol/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. [Dmt1]DALDA administration. Five doses of [Dmt1]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 [Dmt1]DALDA was associated with 30 to 35% reduction in [3H][Dmt1]DALDA binding in brain and spinal cord. Coadministration of [Dmt1]DALDA with δ-antagonist naltriben (NTB) reduced spinal tolerance by 50%. Even after spinal tolerance had been established, addition of a δ-antagonist (NTB or H-Tyr-TicΨ[CH2NH]Phe-Phe-OH) significantly enhanced the potency of i.t. [Dmt1]DALDA 2- to 4-fold. These results suggest that agonist activation of δ-receptors is not necessary for the development of opioid tolerance; however, δ-receptors play a modulatory role in the maintenance of the tolerant state.