Supraspinal Antinociception

There is considerable evidence that 51- and 52-opioid receptors act at supraspinal sites to modulate nociceptive responses. Direct ICV injection of the putative 5-opioid agonists DPDPE or DPLPE in the mouse produced dose-dependent antinociception that was blocked by ICI 174,864 but not by h-FNA 87,88 . Furthermore, 5-opioid selective doses of DPDPE given ICV blocked nociception, but not gastrointestinal transit, in mice 99 .The ICV administration of DPDPE has been shown to produce...

Stomach

In the rat stomach, opioid agonists have been shown to prevent the formation of gastric ulcers in response to acidified ethanol or other irritants. This action is mediated through delta opioid receptors present in both the ENS and CNS 74,75 and is not due to a reduction in gastric acid output 76 . Agonist stimulation of delta opioid receptors in the brainstem appears to increase vagal outflow to the stomach, resulting in the release of cytopro-tective nitric oxide and prostaglandins from vagal...

Other Effects of Delta Agonists Related to Reinforcement

Two other behavioral procedures have been used extensively to investigate delta agonist effects that may be related to reinforcement. One of these procedures, place conditioning, typically uses an experimental apparatus that consists of two or more compartments separated by removable barriers 35,36 . During the training phase, subjects are confined to one compartment after vehicle administration and are confined to a different compartment after administration of a dose of a test drug. During...

Opioid Peptides And Receptors In The Heart

Opioid receptors involved in regulating cardiovascular function have been localized to various regions of the central nervous system and peripherally to cardiac myoctyes and autonomic nerve endings 3,4 . Myocardial binding studies have shown the presence of delta and kappa opioid receptors on rat ventricular myocytes 5,6 . Ventura et al. 7 demonstrated that kappa and delta receptors are present on the sarcolemmal membranes of rat hearts. These receptors appeared to be involved in the regulation...

Opioidmediated Antinociception 71 Spinal Antinociception

That the 5-opoid receptors exist on the terminals of primary afferents in the spinal cord strongly suggests that agonists acting at these sites would be effective antinociceptive agents 83,84 . Shock titration tests performed in rats and monkeys demonstrated that 5-opioid agonists produce antinociception when given intrathecally (ITH), even in morphine-tolerant animals 85 . Both DPDPE and DPLPE given ITH produced dose-dependent antinociception after ITH injection in the mouse 86 . Furthermore,...

Discovery Of Nonpeptide Delta

RECEPTOR-SELECTIVE LIGANDS NALTRINDOLE, BW373U86, SNC 80, AND TAN 67 Peptides are known to have limited permeability in blood brain barrier and poor oral bioavailability. To study central effects of peptides, they need to be injected centrally either by intracerebralventriculer (ICV) or by intrathecal (IT) spinal injection. For a long period of time, there were only peptides available for delta receptors. It is also unclear whether or not effects produced by central injected peptides differ...

Small and Large Intestine

Although the mu opioid receptor appears to be the most significant receptor type mediating the inhibitory actions of opioids on the electrically evoked contractions of the LMMP preparation from the guinea pig ileum, the delta opioid receptor also plays a significant role in the local modulation of smooth muscle contractility in the small intestines of many mammalian species 68 . In the canine ileal circular smooth muscle, for example, it has been shown that both delta and mu opioid receptors...

Characterization Of Endogenous Opioids In The Immune System

Originally, the endogenous opioids enkephalin, dynorphin, and endorphin were considered to be specific products of the nervous system, but cells of the immune system have recently been shown to express these peptides. These mediators stem from three different prohormones proenkephalin, proopiomelanocortin (POMC), and prodynorphin, encoded by three separate genes. All opioids start with the same sequence, Tyr-Gly-Gly-Phe, followed by methionine or leucine. Transcription of the POMC gene has been...

Bioactive Conformation Of Conformationally Constrained Delta Peptide Ligands

The development of cyclic, conformationally restricted opioid peptide ligands allowed significant advances in the elucidation of the bioactive conformation ) of opioid peptides, since these more rigid analogues are less subject to the dynamic averaging that typifies flexible, linear peptides. As the first of the conformationally constrained, highly delta selective peptides, DPDPE was an especially attractive target for conformational analysis. Several groups, ourselves included, proposed...

Interactions Of Mu And Delta Receptors Within The Pagrvm System

The idea that interactions between mu and delta contribute to behavioral and physiological effects of opioid agonists has been considered for over a decade. Evidence for mu delta cooperativity has been obtained using molecular, cellular, and behavioral approaches 46-52 . However, models of mu delta interaction have not yet been considered in detail from a circuit perspective. Thus, given that both mu and delta agonists can produce antinociception following focal application within the RVM, the...

Selective Delta Opioid Receptor Agonists And Their Antinociceptive Actions

Currently, most narcotic analgesics used clinically act through mu opioid receptors, but their use is limited by side effects, such as vomiting, respiratory depression, constipation, and dependence 25 . In contrast, delta opioid receptor agonists can produce antinociception with mild incidence of several somatic signs of withdrawal, indicating that delta opioid receptors remain potentially important therapeutic targets for the development of novel analgesic agents 26 . The ability of delta...

Opioid System And Depression New Therapeutic Target

Most antidepressant therapies concentrate on the enhancement of aminergic neurotransmission. There are a number of other targets that may play a role in this disease, such as GABA, stress hormones, opioids, and others. Changes in opioid signaling have been associated with the antidepressant-like effects of electroconvulsive therapy (ECT) however, opioids are rarely discussed as a potential drug therapy. This chapter discusses the involvement of endogenous opioids in depression and opioid...

Contributors

Josue Alfaro-Lopez University of Arizona, Tucson, Arizona, U.S.A. Michael J. Bishop, Ph.D. GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, U.S.A. Iwona Bonney Department of Anesthesia, Tufts-New England Medical Center, Boston, Massachusetts, U.S.A. David R. Brown, Ph.D. Pharmacology Section, Department of Veterinary PathoBiology and Mucosal and Vaccine Research Center, University of Minnesota, St. Paul, Minnesota, U.S.A. Thomas Burkey University of Arizona,...

Pharmacological Outcome Of Crosstalk Between Delta And Mu Opioid Receptors

The evidence linking the complex interaction between delta and mu opioid receptors now dates back almost a quarter of a century yet the precise molecular mechanism(s) that underlie(s) these effects has not been fully elucidated. The first investigators to report the interaction between opioid receptors were Vaught and Takemori 24 , who demonstrated the enhanced antinociceptive action of morphine following the intracerebroventricular injection of Leu5 enkephalin. Since these landmark studies,...

Development Of Delta Opioid Antagonists

Since 5-selective opioid antagonists are thought to exhibit favorable pharmacological properties, in the past decades considerable effort was undertaken to design potent, selective, and stable delta opioid antagonists. The pseudopeptide ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH) was designed by Cotton et al. 11 , by introducing a synthetic amino acid (Aib a-aminoisobutyric acid) into the prototype delta opioid antagonist, N, N-diallyl-Leu-enkephalin 12 . Later, structure-activity studies...

Discovery Of Benzhydrylpiperazine Opioid Receptor Ligands

In the late 1970s, the molecular biology and pharmacology of opioid receptors were under investigation in the laboratories of Kwen-Jen Chang at Burroughs Wellcome. Early research into delta receptor biology relied on peptidic ligands, such as the enkephalins, as molecular tools. The metabolic instability, formulation difficulties, and in vivo absorption and distribution characteristics made these suboptimal tools for in-depth in vivo studies. The availability of rat brain membranes expressing...

Structureactivity Relationship

Despite a common N-terminal tripeptide (Tyr-D-Xaa-Phe), the two groups of opioid peptides, dermorphins and deltorphins, differ enormously in receptor selectivities but bind to their own receptors with similar affinities. The N-terminal domain contains the minimum sequence essential for binding to opioid receptors whereas the C-terminal domain contains the address requisites for receptor selectivity. The N-terminal tetrapeptides of D-Met-deltorphin and D-Ala-deltor-phins did not show preference...

References

Int J Dev Neurosci 1992 10 3-30. 2. Montecucchi PC, De Castiglione R, Piani S, Gozzini L, Erspamer V. Int J Peptide Prot Res 1981 17 275-279. 3. Broccardo M, Erspamer V, Falconieri-Erspamer G, Improta G, Linari G, Melchiorri P, Montecucchi PC. Br J Pharmacol 1981 73 625-631. 4. Zadina JE, Laszlo H, Ge L-J, Kastin AJ. Nature 1997 386 499-502. 5. Erspamer V. Heatwole H, ed. Amphibian Biology. Surrey Beatty & Sons Publ., 1994 178-350. 6. Erspamer V, Falconieri-Erspamer G, Severini...

Tipp Peptides And Peptidomimetics Highly Potent And Selective 5opioid Antagonists

The results of structure-activity studies on opioid peptides revealed that analogues consisting entirely of aromatic amino acids, such as H-Tyr-D-Phe-Phe-NH2 26 and H-Tyr-D-Phe-Phe-Phe-NH2 27 were quite potent and selective f-agonists. Systematic replacement of the amino acids in these two peptides with conformationally constrained, cyclic L- and D-aromatic amino acids led to the discovery of a new class of 5-opioid antagonists, the so-called TIP(P) peptides, which contain an acid (Tic) residue...