Probing the opioid receptor complex with (+)-trans-superfit. I. Evidence that [D-Pen2,D-Pen5]enkephalin interacts with high affinity at the δcx binding site

Rothman, Richard B.; Mahboubi, Artin; Bykov, Victor; Kim, Chong-Ho; Jacobson, Arthur E.; Rice, Kenner C.

doi:10.1016/0196-9781(91)90026-l

Cited by 21 publications

(4 citation statements)

References 21 publications

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“…The lat ter evidence is particularly intriguing, as the p-selectivity of sufentanil is very high (> 100-fold) [21,22], One likely explanation for these data is that the responses are me diated by a population of interacting p-and 8-receptors. The existence of such receptors is suggested both by radioligand-binding studies, and inhibition of adenylate cyclase [41][42][43][44][45][46] as well as physiologic experiments show ing delta receptor effects on p-mediated antinociception [34,47] as well as morphine tolerance and dependence [48,49], Several characteristics of the present findings support this possibility. These actions of naltrindole are consistent with reports that the p/8-selectivity of coopera tive p/8-receptors is much lower than that for unasso ciated receptors [46], In addition, P-FNA is postulated to block a specific population of p-receptors which interact with 8-receptors [42], Surprisingly, these receptors occur in low density in the hypothalamus [41], the postulated site of opiate-induced GH secretion [50], However, recent studies of p/8-interactions in analgesia have shown that the relevant p-and 8-receptor populations might be at dif ferent sites [38].…”

Section: Discussionsupporting

confidence: 77%

μ-Opioid Agonists Stimulate Growth Hormone Secretion in Immature Rats

Eason¹,

Francis²,

Kuhn³

1996

Neuroendocrinology

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The purpose of the present study was to evaluate the opioid receptor subtype mediating opioid modulation of growth hormone (GH) secretion during ontogeny. The µ-agonist morphine and the Kagonist U50,488 caused a stimulation and inhibition of GH secretion, respectively, on postnatal day 10. Studies on postnatal days 2, 5, 10, 15 and 20 showed that ĸ-inhibition could be observed as early as day 2, but substantial µ-stimulation was not observed until postnatal day 10. Intracerebroventricular (i.c.v.) administration of the µ-selective peptide [D-Ala²-NMe-Phe⁴-Gly-ol]-enkephalin (DAMGO) elicited a marked rise in GH secretion, while administration of the δ-agonists [D-pen²D)-pen⁵]-enkephalin (DPDPE) or deltorphin II caused only a minor and non-dose-related rise in GH secretion in neonatal rats. The relative importance of µ- and δ-receptors in stimulating GH secretion was also studied in older pups (day 20). i.c.v. administration of DAMGO stimulated GH secretion, while neither DPDPE nor deltorphin II consistently increased GH secretion. Furthermore, peripheral administration of either morphine or the highly selective µ-agonist sufentanil elicited marked GH secretion on postnatal day 20, but only combined administration of the µ-antagonist β-funaltrexamine (β-FNA) and the δ-antagonist naltrindole substantially diminished these responses. These results suggest that both µ- and ĸ-opioid receptors are involved in the regulation of GH secretion in neonatal rats. While δ-receptors do not play a prominent independent role in this response, they may act synergistically with µ-receptors in producing stimulation.

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Section: Discussionsupporting

confidence: 77%

μ-Opioid Agonists Stimulate Growth Hormone Secretion in Immature Rats

Eason¹,

Francis²,

Kuhn³

1996

Neuroendocrinology

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“…A second explanation might be that DPDPE and [Met'lenkephalin are acting through a nontraditional opioid binding site such as the reported p-8 receptor complex mentioned above. It is of interest that a recent report indicated that DPDPE has a high affinity interaction with a receptor complex such as the p-6 complex in vitro (Rothman et al, 1991). Further evidence that 6 opioid receptors per se are not involved in the opioid-dependent growth effects found in this study is the fact that 6 opioid receptors are not reported to be present during early postnatal development in rodents (however, see Zagon et al, 1990a).…”

Section: Discussionmentioning

confidence: 72%

“…Studies on the selectivity of DPDPE for the 6 opioid site have shown DAGO, morphine, and normorphine to have high affinity for a portion of the 6 opioid receptor (Cotton et a]., 1985). To add to the complexity, in some systems 6 and p opioid receptor types do not function independently; these two receptor types are reported to interact to generate novel effects (Rothman and Westfall, 1983;Schoffelmeer et al, 1986;Heyman et al, 1989;Rothman et al, 1991) and may, in fact, be products of the same gene (Cabon et al, 1988). Thus, because DAGO had no noticeable effect on glial growth, morphine's ability to inhibit glial growth is likely to be mediated by a non-p opioid receptor type.…”

Section: Discussionmentioning

confidence: 99%

Glial growth is regulated by agonists selective for multiple opioid receptor types in vitro

Stiene‐Martin

Hauser

1991

J of Neuroscience Research

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To determine whether one or more opioid receptor types might be preferentially involved in gliogenesis, primary mixed glial cultures derived from mouse cerebra were continuously treated with varying concentrations of opioid agonists selective for mu (mu), i.e., DAGO ([D-Ala2, MePhe4, Gly(ol)5]enkephalin), delta (delta), i.e., DPDPE ([D-PEN2,D-PEN5]enkephalin), or kappa (kappa), i.e., U69,593, opioid receptor types. In addition, a group of cultures was treated with [Met5]-enkephalin, an agonist for delta opioid receptors as well as putative zeta (zeta) opioid receptors. Opioid-dependent changes in growth were assessed by examining alterations in (1) the number of cells in mixed glial cultures at 3, 6, and 8 days in vitro (DIV), (2) [3H]thymidine incorporation by glial fibrillary acidic protein (GFAP) immunoreactive, flat (type 1) astrocytes at 6 DIV, and (3) the area and form factor of GFAP-immunoreactive, flat (type 1) astrocytes. DPDPE at 10(-8) or 10(-10) M, as well as [Met5]-enkephalin at 10(-6), 10(-8), or 10(-10) M, significantly reduced the total number of glial cells in culture; but this effect was not observed with DAGO or U69,593 (both at 10(-6), 10(-8), or 10(-10) M). Equimolar concentrations (i.e., 10(-6) M) of [Met5]enkephalin or U69,593, but not DPDPE or DAGO, suppressed the rate of [3H]thymidine incorporation by GFAP-immunoreactive, flat (type 1) astrocytes. DAGO had no effect on growth, although in previous studies morphine was found to inhibit glial numbers and astrocyte DNA synthesis. [Met5]enkephalin (10(-6) M) was the only agonist to significantly influence astrocyte area. Collectively, these results indicate that delta (and perhaps mu) opioid receptor agonists reduce the total number of cells in mixed glial cultures; while [Met5]enkephalin-responsive (and perhaps kappa-responsive) opioid receptors mediate DNA synthesis in astrocytes. This implies that delta opioid receptors, as well as [Met5]enkephalin-sensitive, non-delta opioid receptors, mediate opioid-dependent regulation of astrocyte and astrocyte progenitor growth. These data support the concept that opioid-dependent changes in central nervous system growth are the result of endogenous opioid peptides acting through multiple opioid receptor types.

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“…Some of these studies proposed the existence of an “uncomplexed” DOR and a DOR that was “complexed” with the MOR. These DOR subtypes were labeled DORcx, the DOR in complex with MOR, and DORncx, the non-complexed DOR (Rothman et al 1992a; Rothman et al 1992b; Rothman et al 1991). New DOR selective ligands were also identified and synthesized and several groups classified them into two classes, whereby agonists of one class would not produce cross-tolerance to an agonist of the other class (Mattia et al 1991).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological traits of delta opioid receptors: pitfalls or opportunities?

2013

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Delta opioid receptors (DORs) have been considered as a potential target to relieve pain as well as treat depression and anxiety disorders, and are known to modulate other physiological responses, including ethanol and food consumption. A small number of DOR selective drugs are in clinical trials, but no DOR selective drugs have been approved by the Federal Drug Administration and some candidates have failed in phase II clinical trials, highlighting current difficulties producing effective delta opioid based therapies. Recent studies have provided new insights into the pharmacology of the DOR, which is often complex and at times paradoxical. This review will discuss the existing literature focusing on four aspects: 1) Two DOR subtypes have been postulated based on differences in pharmacological effects of existing DOR-selective ligands 2) DORs are expressed ubiquitously throughout the body and central nervous system and are, thus, positioned to play a role in a multitude of diseases. 3) DOR expression is often dynamic, with many reports of increased expression during exposure to chronic stimuli, such as stress, inflammation, neuropathy, morphine, or changes in endogenous opioid tone. 4) A large structural variety in DOR ligands implies potential different mechanisms of activating the receptor. These combined features of DOR pharmacology illustrate the potential benefit of designing tailored or biased DOR ligands.

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Probing the opioid receptor complex with (+)-trans-superfit. I. Evidence that [D-Pen2,D-Pen5]enkephalin interacts with high affinity at the δcx binding site

Cited by 21 publications

References 21 publications

μ-Opioid Agonists Stimulate Growth Hormone Secretion in Immature Rats

μ-Opioid Agonists Stimulate Growth Hormone Secretion in Immature Rats

Glial growth is regulated by agonists selective for multiple opioid receptor types in vitro

Pharmacological traits of delta opioid receptors: pitfalls or opportunities?

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