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[D-Ala2,Leu5,Cys6]enkephalin: Short-term agonist effects and long-term antagonism at delta opioid receptors

1989; Elsevier BV; Volume: 10; Issue: 2 Linguagem: Inglês

10.1016/0196-9781(89)90037-5

1873-5169

Daniel J. Calcagnetti, Michael S. Fanselow, Fred J. Helmstetter, Wayne D. Bowen,

Receptor Mechanisms and Signaling

Four experiments were conducted. Two examined the in vivo short-term effects ( 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°C). In the second experiment, we determined that immobility was attenuated by pretreatment with naltrexone methobromide (QNTX, 0.1 μg), and the δ selective antagonist, 16-methyl cyprenorphine (M80, 5 μg). 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 μ and δ 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 δ receptor. Rats were injected ICV with 6.7 μg 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). At the doses tested, these agonists produced an equivalent level of analgesia as indicated by reduction in formalin-induced behavior. DPDPE-induced analgesia was completely blocked by pretreatment with DALCE but analgesia produced by DAGO and U50488H was not affected. These data suggest that in vivo, DALCE acts like a long-term (irreversible) antagonist selective for δ receptors. The fourth experiment tested DALCE's ability to reverse conditional fear-induced analgesia that has previously been shown to involve δ receptors. Rats received footshocks in an observation chamber and were injected ICV with DALCE (6.7 μg) or saline either 24,48 or 72 hr prior to testing. DALCE was equally effective at increasing formalin-induced behavior in rats treated at each interval. DALCE's reversal of conditional analgesia 72 hr after injection suggests that this peptide acts like an irreversible antagonist. Our results support a role for δ receptor involvement in the expression of conditional analgesia.