Stress-induced tolerance to delta receptor agonist DPDPE and selectivity of the irreversible δ-ligand, DALCE

Abstract

Experiments were conducted to (1) provide further evidence of the selectivity of [ d-Ala 2,Leu 5,Cys 6]enkephalin (DALCE) as an antagonist of delta (δ) receptor ligands and (2) use DALCE as a tool to explore the possible role of δ receptors in restraint stress. Dose- and time-response curves were generated for the respective δ- and mu (μ)-selective opioid agonists DPDPE (3–30 μg) and DAGO (0.03–0.3 μg) to increase the latency to paw-lick in the hot-plate test in rats. Both agonists produced robust analgesia lasting at least 20 min when injected intracerebroventricularly (i.c.v.). DALCE (0.4–10 μg) administered i.c.v. 24 h earlier failed to affect baseline pain sensitivity. DALCE pretreatment dose-dependently blocked the increase in paw-lick latency produced by DPDPE (30 μg) but not that induced by an equivalent analgesic dose of DAGO (0.3 μg). In the last experiment we determined whether 1 h of restraint stress would (a) alter δ receptor sensitivity as indexed by DPDPE-induced analgesia and (b) attenuate the ability of DALCE to functionally antagonize DPDPE-induced analgesia. Rats were assigned to one of four treatment groups: i.c.v. vehicle injection/no stress; vehicle/stress; i.c.v. DALCE (10 μg)/no stress; DALCE/stress. Twenty-four hours after treatment, dose- and time-response curves were generated to test the ability of DPDPE (30–120 μg) to increase paw-lick latency. Prior exposure to stress alone produced tolerance to DPDPE-induced analgesia. DALCE pretreatment antagonized DPDPE similarly regardless of stress condition. The effects of both stress and DALCE were surmounted by the highest dose of DPDPE. It is possible that DPDPE produced analgesia by acting at sites other than δ receptors. We conclude that DALCE is a selective δ antagonist and that stress can induce tolerance to the analgesic effect of DPDPE.