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

Experiments were conducted to (1) provide further evidence of the selectivity of [D-Ala2,Leu5,Cys6]enkephalin (DALCE) as an antagonist of delta (delta) receptor ligands and (2) use DALCE as a tool to explore the possible role of delta receptors in restraint stress. Dose- and time-response curves were generated for the respective delta- and mu (mu)-selective opioid agonists DPDPE (3-30 micrograms) and DAGO (0.03-0.3 microgram) 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 micrograms) 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 micrograms) but not that induced by an equivalent analgesic dose of DAGO (0.3 microgram). In the last experiment we determined whether 1 h of restraint stress would (a) alter delta 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 micrograms)/no stress; DALCE/stress. Twenty-four hours after treatment, dose- and time-response curves were generated to test the ability of DPDPE (30-120 micrograms) 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.(ABSTRACT TRUNCATED AT 250 WORDS)