Alternated delta and mu receptor activation: a stratagem for limiting opioid tolerance

The development of tolerance to the antinociceptive effects of chronically administered delta (δ) and mu (μ) agonists was examined in vivo in rats using a protocol of alternated preferential activations of δ and μ receptors. This was accomplished by alternated chronic administrations of the relatively δ- and μ-selective agonists DADLE ([d-Ala2, d-Leu5]-enkephalin [15] and morphine sulfate (MSO4) [4], respectively. Specifically, the agonists were given as 3 sequential 6 day cycles: (1) osmotic pump infusions of DADLE into the lumbar intrathecal space; (2) followed by intraperitoneal injections of MSO4; (3) followed again by intrathecal DADLE infusions. Following each cycle, the agonists' antinociceptive activities were measured using the tail-flick test of nociception. These were compared to their baseline (i.e., drug-naive) activities as a measure of tolerances. In a separate experiment the same total intrathecal dose of DADLE was infused chronically over twelve days without an interposed dose of MSO4. In the alternated agonist experiment, DADLE's antinociceptive ED50 value was increased by 10.4-fold, then reverted to only a 1.5-fold change from baseline and was subsequently shifted to a 13.7-fold increase over baseline. After cycle 2 with MSO4 a significant recovery from DADLE tolerance was noted as compared to that following cycle 1: 1.5- versus 10.4-fold, respectively. Furthermore, the interposition of a cycle of MSO4 between two cycles of DADLE resulted in a much lesser degree of tolerance for DADLE following cycle 3 (12 days of non-continuous DADLE infusion) than was noted after the 12 day continuous DADLE intrathecal infusion (13.7- versus 25.0-fold tolerance, respectively). DADLE was not restricted to δ receptor-specific activity in this experiment as thoroughly as μ selectivity was achieved with MSO4. Because of cross-reactivity to μ receptors, DADLE produced significant cross-tolerance to MSO4. The ED50 value of MSO4 was shifted to the right from baseline by 5.1-fold after the cycle 1 DADLE infusion. The ED50 value of MSO4 was further shifted to the right to 31.6-fold over baseline after cycle 2 with MSO4. Despite DADLE's cross-reactivity to μ receptors, the tolerance to MSO4 regressed from 31.6- to 9.0-fold after the DADLE infusion of cycle 3. This study demonstrated the feasibility of modifying degrees of opioid antinociceptive tolerances in vivo by alternating δ and μ receptor activations.