TY - JOUR
T1 - Opioid agonist and antagonist antinociceptive properties of [D-Ala2,Leu5,Cys6]enkephalin
T2 - Selective actions at the delta(noncomplexed) site
AU - Jiang, Q.
AU - Bowen, W. D.
AU - Mosberg, H. I.
AU - Rothman, R. B.
AU - Porreca, F.
PY - 1990
Y1 - 1990
N2 - The present study used the irreversibly binding enkephalin analog, [D-Ala2,Leu5,Cys6]enkephalin (DALCE) in an effort to determine whether selective agonist and antagonist properties could be demonstrated at hypothesized types of opioid delta receptors previously termed the delta(noncomplexed) and the delta(complexed) sites. These putative subtypes of delta receptors have been functionally distinguished on the basis of involvement (i.e., delta(complexed)) in the modulation of mu-mediated effects such as antinociception. Intracerebroventricular administration of DALCE or the reference delta and mu agonists, [D-Pen2,D-Pen5]enkephalin (DPDPE) and morphine, to mice all produced antinociception in the warm-water tail-flick test in a dose- and time-related manner. Maximal effects with DALCE were seen at +10 min and significant antinociception could be detected for approximately 1 hr; DALCE was 3- and 90-fold more potent than i.c.v. morphine and DPDPE, respectively. The antinociceptive effects of i.c.v. DALCE and DPDPE, but not those of morphine, were antagonized by the selective delta antagonist, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH, suggesting that the antinociception associated with the peptides was mediated through a delta receptor. DALCE pre-treatment up to 24 hr before testing, a time at which this compound did not produce antinociception, significantly blocked the i.c.v. DPDPE antinociceptive effect as well as that of DALCE itself, but not that of morphine, suggesting long-lasting DALCE antagonism at a delta receptor. Modulation of morphine antinociception was demonstrated with subeffective doses of i.c.v. DPDPE or [Met5]enkephalin, but not with subeffective doses of i.c.v. DALCE. In addition to a lack of modulation of morphine antinociception after acute administration, i.c.v. DALCE (at -24 hr) did not directly antagonize the antinociceptive actions of morphine or block the modulation of morphine by DPDPE or [Met5]enkephalin. These data suggest that i.c.v. DALCE given acutely produces direct antinociceptive actions through a supraspinal delta receptor, and additionally, DALCE subsequently acts as a long-lasting delta antagonist. However, unlike the actions of DPDPE or [Met5]enkephalin, neither the direct delta agonist or antagonist actions of DALCE are associated with indirect modulation of morphine antinociception. These findings provide further support for the concept of a functional opioid mu-delta receptor complex and support the existence of subtypes of opioid delta receptors that may be distinguished on the basis of their modulation of mu agonist actions (i.e., delta(complexed) and delta(noncomplexed) receptors); thus, DALCE appears to selectively interact with the delta(noncomplexed) receptor.
AB - The present study used the irreversibly binding enkephalin analog, [D-Ala2,Leu5,Cys6]enkephalin (DALCE) in an effort to determine whether selective agonist and antagonist properties could be demonstrated at hypothesized types of opioid delta receptors previously termed the delta(noncomplexed) and the delta(complexed) sites. These putative subtypes of delta receptors have been functionally distinguished on the basis of involvement (i.e., delta(complexed)) in the modulation of mu-mediated effects such as antinociception. Intracerebroventricular administration of DALCE or the reference delta and mu agonists, [D-Pen2,D-Pen5]enkephalin (DPDPE) and morphine, to mice all produced antinociception in the warm-water tail-flick test in a dose- and time-related manner. Maximal effects with DALCE were seen at +10 min and significant antinociception could be detected for approximately 1 hr; DALCE was 3- and 90-fold more potent than i.c.v. morphine and DPDPE, respectively. The antinociceptive effects of i.c.v. DALCE and DPDPE, but not those of morphine, were antagonized by the selective delta antagonist, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH, suggesting that the antinociception associated with the peptides was mediated through a delta receptor. DALCE pre-treatment up to 24 hr before testing, a time at which this compound did not produce antinociception, significantly blocked the i.c.v. DPDPE antinociceptive effect as well as that of DALCE itself, but not that of morphine, suggesting long-lasting DALCE antagonism at a delta receptor. Modulation of morphine antinociception was demonstrated with subeffective doses of i.c.v. DPDPE or [Met5]enkephalin, but not with subeffective doses of i.c.v. DALCE. In addition to a lack of modulation of morphine antinociception after acute administration, i.c.v. DALCE (at -24 hr) did not directly antagonize the antinociceptive actions of morphine or block the modulation of morphine by DPDPE or [Met5]enkephalin. These data suggest that i.c.v. DALCE given acutely produces direct antinociceptive actions through a supraspinal delta receptor, and additionally, DALCE subsequently acts as a long-lasting delta antagonist. However, unlike the actions of DPDPE or [Met5]enkephalin, neither the direct delta agonist or antagonist actions of DALCE are associated with indirect modulation of morphine antinociception. These findings provide further support for the concept of a functional opioid mu-delta receptor complex and support the existence of subtypes of opioid delta receptors that may be distinguished on the basis of their modulation of mu agonist actions (i.e., delta(complexed) and delta(noncomplexed) receptors); thus, DALCE appears to selectively interact with the delta(noncomplexed) receptor.
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M3 - Article
C2 - 2173752
AN - SCOPUS:0025200799
SN - 0022-3565
VL - 255
SP - 636
EP - 641
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -