[D-Ala2,Leu5,Cys6]enkephalin: short-term agonist effects and long-term antagonism at delta opioid receptors.
Four experiments were conducted. Two examined the in vivo short-term effects (less than 35 min) and two examined the in vivo long-term effects (greater than 2 days) of the synthetic enkephalin analogue, [D-Ala2,Leu5,Cys6]enkephalin (DALCE). In the short term, DALCE was found to produce analgesia and transient immobility after intracerebroventricular (ICV) administration. We found a dose-related increase in paw-lick latency for rats placed on a hotplate (52 degrees C). In the second experiment, we determined that immobility was attenuated by pretreatment with naltrexone methobromide (QNTX, 0.1 microgram), and the delta selective antagonist, 16-methyl cyprenorphine (M80, 5 micrograms). QNTX and M80 significantly attenuated DALCE-induced immobility by more than 50% of control. Paw-lick latency was then measured on the hotplate to assess analgesia. Pretreatment with M80 reliably attenuated the DALCE-induced analgesia. Whereas QNTX failed to reliably attenuate paw-lick latency on the first trial, it was as effective as M80 on the second trial. We suggest that the short-term agonist effects of DALCE are produced by actions at mu and delta opioid receptors as would be predicted from prior in vitro studies showing moderate to high affinity, respectively, at these receptors. In the third experiment, DALCE was shown to display long-term behavioral antagonism that was selective for the delta receptor. Rats were injected ICV with 6.7 micrograms of DALCE and tested 48 hr later. Analgesia was measured by injecting 15% formalin subcutaneously followed 20 min later by an ICV injection of one of three selective opioid agonists (DAGO, DPDPE or U50488H).(ABSTRACT TRUNCATED AT 250 WORDS)
Calcagnetti
D J
DJ
Department of Psychology, Dartmouth College, Hanover, NH 03755.
Fanselow
M S
MS
Helmstetter
F J
FJ
Bowen
W D
WD
D000698:Analgesia; D000818:Animals; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D004334:Drug Administration Schedule; D004743:Enkephalin, Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine / Q000031:analogs & derivatives*; D004745:Enkephalins / Q000494:pharmacology; D005260:Female; D007276:Injections, Intraventricular; D010146:Pain / Q000503:physiopathology; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D017465:Receptors, Opioid, delta; D012016:Reference Values; D013329:Structure-Activity Relationship
D004745:Enkephalins; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; C053821:enkephalin-Leu, Ala(2)-Cys(6)-; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine