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)
Calcagnetti
D J
DJ
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322.
Bowen
W D
WD
Holtzman
S G
SG
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D020881:Enkephalin, D-Penicillamine (2,5)-; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine / Q000031:analogs & derivatives*; D004745:Enkephalins / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000187:drug effects; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D017465:Receptors, Opioid, delta; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000378:metabolism*
D000700:Analgesics; D004745:Enkephalins; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; C053821:enkephalin-Leu, Ala(2)-Cys(6)-; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; D020881:Enkephalin, D-Penicillamine (2,5)-