One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla.
An enkephalin analog that selectively binds to the MU OPIOID RECEPTOR. It is used as a model for drug permeability experiments.
One of the endogenous pentapeptides with morphine-like activity. It differs from MET-ENKEPHALIN in the LEUCINE at position 5. Its first four amino acid sequence is identical to the tetrapeptide sequence at the N-terminal of BETA-ENDORPHIN.
One of the endogenous pentapeptides with morphine-like activity. It differs from LEU-ENKEPHALIN by the amino acid METHIONINE in position 5. Its first four amino acid sequence is identical to the tetrapeptide sequence at the N-terminal of BETA-ENDORPHIN.
A disulfide opioid pentapeptide that selectively binds to the DELTA OPIOID RECEPTOR. It possesses antinociceptive activity.
A delta-selective opioid (ANALGESICS, OPIOID). It can cause transient depression of mean arterial blood pressure and heart rate.
One of the three major groups of endogenous opioid peptides. They are large peptides derived from the PRO-OPIOMELANOCORTIN precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; OPIOID PEPTIDES is used for the broader group.
Cell membrane proteins that bind opioids and trigger intracellular changes which influence the behavior of cells. The endogenous ligands for opioid receptors in mammals include three families of peptides, the enkephalins, endorphins, and dynorphins. The receptor classes include mu, delta, and kappa receptors. Sigma receptors bind several psychoactive substances, including certain opioids, but their endogenous ligands are not known.
A class of opioid receptors recognized by its pharmacological profile. Mu opioid receptors bind, in decreasing order of affinity, endorphins, dynorphins, met-enkephalin, and leu-enkephalin. They have also been shown to be molecular receptors for morphine.
A class of cell surface receptors for tachykinins that prefers neurokinin B (neurokinin beta, neuromedin K) over other tachykinins. Neurokinin-3 (NK-3) receptors have been cloned and are members of the G-protein coupled receptor superfamily. They have been found in the central nervous system and in peripheral tissues.
A class of opioid receptors recognized by its pharmacological profile. Delta opioid receptors bind endorphins and enkephalins with approximately equal affinity and have less affinity for dynorphins.
A mammalian neuropeptide of 10 amino acids that belongs to the tachykinin family. It is similar in structure and action to SUBSTANCE P and NEUROKININ A with the ability to excite neurons, dilate blood vessels, and contract smooth muscles, such as those in the URINARY BLADDER and UTERUS.
A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors.
A kappa opioid receptor agonist. The compound has analgesic action and shows positive inotropic effects on the electrically stimulated left atrium. It also affects various types of behavior in mammals such as locomotion, rearing, and grooming.
A family of biologically active peptides sharing a common conserved C-terminal sequence, -Phe-X-Gly-Leu-Met-NH2, where X is either an aromatic or a branched aliphatic amino acid. Members of this family have been found in mammals, amphibians, and mollusks. Tachykinins have diverse pharmacological actions in the central nervous system and the cardiovascular, genitourinary, respiratory, and gastrointestinal systems, as well as in glandular tissues. This diversity of activity is due to the existence of three or more subtypes of tachykinin receptors.
Cell surface proteins that bind TACHYKININS with high affinity and trigger intracellular changes influencing the behavior of cells. Three classes of tachykinin receptors have been characterized, the NK-1; NK-2; and NK-3; which prefer, respectively, SUBSTANCE P; NEUROKININ A; and NEUROKININ B.
An analgesic with mixed narcotic agonist-antagonist properties.
A stable synthetic analog of methionine enkephalin (ENKEPHALIN, METHIONINE). Actions are similar to those of methionine enkephalin. Its effects can be reversed by narcotic antagonists such as naloxone.
A class of opioid receptors recognized by its pharmacological profile. Kappa opioid receptors bind dynorphins with a higher affinity than endorphins which are themselves preferred to enkephalins.
An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of PAIN, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses.
A mammalian neuropeptide of 10 amino acids that belongs to the tachykinin family. It is similar in structure and action to SUBSTANCE P and NEUROKININ B with the ability to excite neurons, dilate blood vessels, and contract smooth muscles, such as those in the BRONCHI.
Agents inhibiting the effect of narcotics on the central nervous system.
The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle.
A class of cell surface receptors for tachykinins that prefers neurokinin A; (NKA, substance K, neurokinin alpha, neuromedin L), neuropeptide K; (NPK); or neuropeptide gamma over other tachykinins. Neurokinin-2 (NK-2) receptors have been cloned and are similar to other G-protein coupled receptors.
A class of opioid peptides including dynorphin A, dynorphin B, and smaller fragments of these peptides. Dynorphins prefer kappa-opioid receptors (RECEPTORS, OPIOID, KAPPA) and have been shown to play a role as central nervous system transmitters.
Compounds with activity like OPIATE ALKALOIDS, acting at OPIOID RECEPTORS. Properties include induction of ANALGESIA or NARCOSIS.
A transfer RNA which is specific for carrying glycine to sites on the ribosomes in preparation for protein synthesis.
A ZINC-containing exopeptidase primarily found in SECRETORY VESICLES of endocrine and neuroendocrine cells. It catalyzes the cleavage of C-terminal ARGININE or LYSINE residues from polypeptides and is active in processing precursors of PEPTIDE HORMONES and other bioactive peptides.
Morphine derivatives of the methanobenzazocine family that act as potent analgesics.
Compounds based on benzeneacetamide, that are similar in structure to ACETANILIDES.
Derivative of noroxymorphone that is the N-cyclopropylmethyl congener of NALOXONE. It is a narcotic antagonist that is effective orally, longer lasting and more potent than naloxone, and has been proposed for the treatment of heroin addiction. The FDA has approved naltrexone for the treatment of alcohol dependence.
A 31-amino acid peptide that is the C-terminal fragment of BETA-LIPOTROPIN. It acts on OPIOID RECEPTORS and is an analgesic. Its first four amino acids at the N-terminal are identical to the tetrapeptide sequence of METHIONINE ENKEPHALIN and LEUCINE ENKEPHALIN.
A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research.
The endogenous peptides with opiate-like activity. The three major classes currently recognized are the ENKEPHALINS, the DYNORPHINS, and the ENDORPHINS. Each of these families derives from different precursors, proenkephalin, prodynorphin, and PRO-OPIOMELANOCORTIN, respectively. There are also at least three classes of OPIOID RECEPTORS, but the peptide families do not map to the receptors in a simple way.
A narcotic antagonist similar in action to NALOXONE. It is used to remobilize animals after ETORPHINE neuroleptanalgesia and is considered a specific antagonist to etorphine.
Compounds that inhibit or block the activity of NEUROKININ-1 RECEPTORS.
Agents that induce NARCOSIS. Narcotics include agents that cause somnolence or induced sleep (STUPOR); natural or synthetic derivatives of OPIUM or MORPHINE or any substance that has such effects. They are potent inducers of ANALGESIA and OPIOID-RELATED DISORDERS.
A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter.
Peptides composed of between two and twelve amino acids.
A narcotic analgesic morphinan used as a sedative in veterinary practice.
A potent inhibitor of membrane metalloendopeptidase (ENKEPHALINASE). Thiorphan potentiates morphine-induced ANALGESIA and attenuates naloxone-precipitated withdrawal symptoms.
A class of cell surface receptors for TACHYKININS with a preference for SUBSTANCE P. Neurokinin-1 (NK-1) receptors have been cloned and are members of the G protein coupled receptor superfamily. They are found on many cell types including central and peripheral neurons, smooth muscle cells, acinar cells, endothelial cells, fibroblasts, and immune cells.
The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.
Compounds capable of relieving pain without the loss of CONSCIOUSNESS.
Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.
The relationship between the dose of an administered drug and the response of the organism to the drug.
Compounds based on a partially saturated iminoethanophenanthrene, which can be described as ethylimino-bridged benzo-decahydronaphthalenes. They include some of the OPIOIDS found in PAPAVER that are used as ANALGESICS.
Sulfhydryl acylated derivative of GLYCINE.
Enzyme that is a major constituent of kidney brush-border membranes and is also present to a lesser degree in the brain and other tissues. It preferentially catalyzes cleavage at the amino group of hydrophobic residues of the B-chain of insulin as well as opioid peptides and other biologically active peptides. The enzyme is inhibited primarily by EDTA, phosphoramidon, and thiorphan and is reactivated by zinc. Neprilysin is identical to common acute lymphoblastic leukemia antigen (CALLA Antigen), an important marker in the diagnosis of human acute lymphocytic leukemia. There is no relationship with CALLA PLANT.
Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques.
The inner portion of the adrenal gland. Derived from ECTODERM, adrenal medulla consists mainly of CHROMAFFIN CELLS that produces and stores a number of NEUROTRANSMITTERS, mainly adrenaline (EPINEPHRINE) and NOREPINEPHRINE. The activity of the adrenal medulla is regulated by the SYMPATHETIC NERVOUS SYSTEM.
A family of hexahydropyridines.
The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium.
A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases IMMUNITY, and provides energy for muscle tissue, BRAIN, and the CENTRAL NERVOUS SYSTEM.
The rate dynamics in chemical or physical systems.
Organelles in CHROMAFFIN CELLS located in the adrenal glands and various other organs. These granules are the site of the synthesis, storage, metabolism, and secretion of EPINEPHRINE and NOREPINEPHRINE.
The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.
The distal and narrowest portion of the SMALL INTESTINE, between the JEJUNUM and the ILEOCECAL VALVE of the LARGE INTESTINE.
A compound produced from succinyl-CoA and GLYCINE as an intermediate in heme synthesis. It is used as a PHOTOCHEMOTHERAPY for actinic KERATOSIS.
A 14-amino acid peptide named for its ability to inhibit pituitary GROWTH HORMONE release, also called somatotropin release-inhibiting factor. It is expressed in the central and peripheral nervous systems, the gut, and other organs. SRIF can also inhibit the release of THYROID-STIMULATING HORMONE; PROLACTIN; INSULIN; and GLUCAGON besides acting as a neurotransmitter and neuromodulator. In a number of species including humans, there is an additional form of somatostatin, SRIF-28 with a 14-amino acid extension at the N-terminal.
The representation of the phylogenetically oldest part of the corpus striatum called the paleostriatum. It forms the smaller, more medial part of the lentiform nucleus.
Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.
Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from DRUG RESISTANCE wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from MAXIMUM TOLERATED DOSE and NO-OBSERVED-ADVERSE-EFFECT LEVEL.
A semisynthetic analgesic used in the study of narcotic receptors.
The naturally occurring or experimentally induced replacement of one or more AMINO ACIDS in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish, enhance, or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties.
The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.
The excretory duct of the testes that carries SPERMATOZOA. It rises from the SCROTUM and joins the SEMINAL VESICLES to form the ejaculatory duct.
Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are linear polypeptides that are normally synthesized on RIBOSOMES.
Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations or by parent x offspring matings carried out with certain restrictions. This also includes animals with a long history of closed colony breeding.
Enzymes that act at a free C-terminus of a polypeptide to liberate a single amino acid residue.
The interaction of two or more substrates or ligands with the same binding site. The displacement of one by the other is used in quantitative and selective affinity measurements.
Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.
A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.
The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain).
Injections into the cerebral ventricles.
Introduction of therapeutic agents into the spinal region using a needle and syringe.
Striped GRAY MATTER and WHITE MATTER consisting of the NEOSTRIATUM and paleostriatum (GLOBUS PALLIDUS). It is located in front of and lateral to the THALAMUS in each cerebral hemisphere. The gray substance is made up of the CAUDATE NUCLEUS and the lentiform nucleus (the latter consisting of the GLOBUS PALLIDUS and PUTAMEN). The WHITE MATTER is the INTERNAL CAPSULE.
Compounds containing the PhCH= radical.
One of two ganglionated neural networks which together form the ENTERIC NERVOUS SYSTEM. The myenteric (Auerbach's) plexus is located between the longitudinal and circular muscle layers of the gut. Its neurons project to the circular muscle, to other myenteric ganglia, to submucosal ganglia, or directly to the epithelium, and play an important role in regulating and patterning gut motility. (From FASEB J 1989;3:127-38)
Bluish-colored region in the superior angle of the FOURTH VENTRICLE floor, corresponding to melanin-like pigmented nerve cells which lie lateral to the PERIAQUEDUCTAL GRAY.
The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.
The parts of a macromolecule that directly participate in its specific combination with another molecule.
Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES).
Substances used for their pharmacological actions on any aspect of neurotransmitter systems. Neurotransmitter agents include agonists, antagonists, degradation inhibitors, uptake inhibitors, depleters, precursors, and modulators of receptor function.
Analogs or derivatives of morphine.
A common neoplasm of early childhood arising from neural crest cells in the sympathetic nervous system, and characterized by diverse clinical behavior, ranging from spontaneous remission to rapid metastatic progression and death. This tumor is the most common intraabdominal malignancy of childhood, but it may also arise from thorax, neck, or rarely occur in the central nervous system. Histologic features include uniform round cells with hyperchromatic nuclei arranged in nests and separated by fibrovascular septa. Neuroblastomas may be associated with the opsoclonus-myoclonus syndrome. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2099-2101; Curr Opin Oncol 1998 Jan;10(1):43-51)
Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor.
Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.
Quantitative determination of receptor (binding) proteins in body fluids or tissue using radioactively labeled binding reagents (e.g., antibodies, intracellular receptors, plasma binders).
A cylindrical column of tissue that lies within the vertebral canal. It is composed of WHITE MATTER and GRAY MATTER.
A neuropeptide of 29-30 amino acids depending on the species. Galanin is widely distributed throughout the BRAIN; SPINAL CORD; and INTESTINES. There are various subtypes of GALANIN RECEPTORS implicating roles of galanin in regulating FOOD INTAKE; pain perception; memory; and other neuroendocrine functions.
... enkephalins MeSH D12.776.641.650.575.281.075 - enkephalin, ala(2)-mephe(4)-gly(5)- MeSH D12.776.641.650.575.281.231 - ... enkephalin, leucine MeSH D12.776.641.650.575.281.381 - enkephalin, methionine MeSH D12.776.641.650.575.281.600 - enkephalin, d- ... 5)- MeSH D12.776.641.650.800.354 - eledoisin MeSH D12.776.641.650.800.475 - kassinin MeSH D12.776.641.650.800.500 - neurokinin ...
... enkephalins MeSH D12.644.468.281.075 - enkephalin, ala(2)-mephe(4)-gly(5)- MeSH D12.644.468.281.231 - enkephalin, leucine MeSH ... mephe(4),met(0)-ol-enkephalin MeSH D12.644.468.281.600 - enkephalin, d-penicillamine (2,5)- MeSH D12.644.548.009 - activins ... gly(5)- MeSH D12.644.400.575.281.231 - enkephalin, leucine MeSH D12.644.400.575.281.381 - enkephalin, methionine MeSH D12.644. ... enkephalins MeSH D12.644.400.575.281.075 - enkephalin, ala(2)-mephe(4)- ...
Its structure is H-Tyr-D-Ala-Gly-N-MePhe-Gly-ol. DAMGO has been used in experimental settings for the possibility of ... DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin) is a synthetic opioid peptide with high μ-opioid receptor specificity. It was ... Koehl A, Hu H, Maeda S, Zhang Y, Qu Q, Paggi JM, et al. (June 2018). "Structure of the µ-opioid receptor-Gi". Nature. 558 (7711 ... 32 (5): 829-839. doi:10.1016/S0896-6273(01)00517-7. PMID 11738029. S2CID 16396686. He L, Fong J, von Zastrow M, Whistler JL ( ...
... enkephalins MeSH D12.776.641.650.575.281.075 - enkephalin, ala(2)-mephe(4)-gly(5)- MeSH D12.776.641.650.575.281.231 - ... enkephalin, leucine MeSH D12.776.641.650.575.281.381 - enkephalin, methionine MeSH D12.776.641.650.575.281.600 - enkephalin, d- ... 5)- MeSH D12.776.641.650.800.354 - eledoisin MeSH D12.776.641.650.800.475 - kassinin MeSH D12.776.641.650.800.500 - neurokinin ...
... enkephalins MeSH D12.644.468.281.075 - enkephalin, ala(2)-mephe(4)-gly(5)- MeSH D12.644.468.281.231 - enkephalin, leucine MeSH ... mephe(4),met(0)-ol-enkephalin MeSH D12.644.468.281.600 - enkephalin, d-penicillamine (2,5)- MeSH D12.644.548.009 - activins ... gly(5)- MeSH D12.644.400.575.281.231 - enkephalin, leucine MeSH D12.644.400.575.281.381 - enkephalin, methionine MeSH D12.644. ... enkephalins MeSH D12.644.400.575.281.075 - enkephalin, ala(2)-mephe(4)- ...
Guthrie, B., Payne, K., Alderson, P., McMurdo, M. E. T. & Mercer, S. W., 4 Oct 2012, In: British Medical Journal. 345, p. - 5 p ... Hoyte, T. A., Ali, A. & Bearn, D. R., Aug 2020, In: Pediatric Dental Journal. 30, 2, p. 86-91 6 p.. Research output: ... Guo, K., Greenstein, A., Mahmood, S. & Lowe, T., Jun 2020, In: BMJ Case Reports. 13, 6, 2 p., e233893.. Research output: ... Ocak Karabay, S., Asi, D. S. & Swennen, A., Feb 2015, In: Creative Education . 6, 2, p. 181-185 5 p.. Research output: ...
The μ-opioid receptor-selective agonist, [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO), reduced the hyperalgesia in heterozygous ... enkephalin (DPDPE) and deltorphin ([D- Ala2]deltrophin-II), produced significantly greater antihyperalgesia in knockout mice (P ... MePhe4,Gly-ol5]enkephalin (DAMGO), reduced the hyperalgesia in heterozygous and wild-type but not in μ-opioid receptor knockout ... The μ-opioid receptor-selective agonist, [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO), reduced the hyperalgesia in heterozygous ...
Enkephalin, Ala(2)-MePhe(4)-Gly(5)-, Female, Fentanyl, Gene Knock-In Techniques, Male, Membrane Potentials, Mice, Nociception, ... Gly-ol]-enkephalin (DAMGO) or fentanyl dose-dependently inhibited depolarization-induced CGRP release from rat sciatic nerve ... N-MePhe(4), ... In vitro, using β-arrestin-2/MOP double-transfected human ... DAMGO as well as fentanyl lead to a recruitment of β-arrestin-2 to the membrane followed by a β-arrestin-2 reappearance in the ...
Adenylyl Cyclase Inhibitors Amino Acid Sequence Cyclic AMP Down-Regulation Drug Tolerance Enkephalin, Ala(2)-MePhe(4)-Gly(5)- ... Enkephalins GTP Phosphohydrolases Humans Levorphanol Molecular Sequence Data Naltrexone Narcotics Neuroblastoma Neurons ... Please consider white-listing Labnodes since 1) ad-blockers like uBlock break Labnodes functionality and 2) Labnodes does not ...
  • In cultured mouse dorsal root ganglion neurons, two mechanistically different forms of desensitization were observed after acute or chronic treatment with the micro agonist [D-Ala2, N-MePhe4, Gly-ol5]-enkephalin (DAMGO). (
  • Although the mu selective agonist [ d -Ala 2 -MePhe 4 -Gly-ol 5 ]enkephalin (DAMGO) and the delta selective agonist [ d -Pen 2 , d -Pen 5 ]enkephalin (DPDPE) are both antinociceptive when administered directly into the spinal cord of mice, 50% of antinociceptive dose (AD 50 ) of DAMGO is about 2 orders of magnitude lower than the AD 50 of DPDPE. (
  • The pA 2 value of CTAP for DPDPE was virtually identical with that for DAMGO. (
  • In competition studies under equilibrium conditions, NalBzoH and diprenorphine both retained their potency in the presence of the stable GTP analog 5′-guanylylimidophosphate, consistent with their mu antagonist properties, whereas the agonist DAMGO showed more than a 3-fold loss of affinity. (
  • DAMGO ([D-Ala 2 , N-MePhe 4 , Gly-ol]-enkephalin) is a synthetic opioid peptide with high μ-opioid receptor specificity. (
  • After exposure to 5 μM of DAMGO, phosphorylation of the C-terminally truncated receptor and the mutant receptor T394A was reduced to 40 and 10% of that of the wild-type receptor, respectively. (
  • 7,8 However, morphine, a partial agonist of MOR, differs profoundly from full opioid agonists such as [D-Ala, 2 MePhe, 4 Gly-ol 5 ]enkephalin (DAMGO): The opiate binds to MOR without causing rapid internalization of the receptor in MOR-transfected cells. (
  • METHODS: SH-SY5Y cells (passage 70-80) were used to obtain ketamine dose-response curves for inhibition of 0.4 nM [(3)H][D-Ala(2),MePhe(4),Gly(ol)(5)] enkephalin (DAMGO) binding to mu(2) opioid receptors and of forskolin (1 microM)-stimulated cyclic AMP (cAMP) formation. (
  • We bath-applied [D-Ala 2 ,N-MePhe 4 ,Gly-ol 5 ]-enkephalin (DAMGO), a potent synthetic µ-opioid receptor (µOR) agonist, in conditions of low excitability in vitro when burstlets appeared at times bursts would have been expected or when preBötC rhythmic activity consisted solely of burstlets. (
  • Under constant-flow conditions, injections of the μ-selective agonists, endomorphin 1 and 2, PL017 ([N-MePhe 3 , D-Pro 4 ]-morphiceptin), and DAMGO, and the ORL 1 receptor agonist, nociceptin/OFQ, produced dose-dependent decreases in hindquarters perfusion pressure. (
  • Responses to endomorphin 1 and 2, PL017, DAMGO, and nociceptin/OFQ were not altered by the cyclooxygenase inhibitor sodium meclofenamate or the K + (ATP) channel blocker U-37883A. (
  • The results of these studies indicate that responses to endomorphin 1 and 2, PL017, and DAMGO are mediated in large part by the release of nitric oxide, while responses to nociceptin/OFQ are mediated by an L-NAME-insensitive mechanism. (
  • We found that a selective µ-opioid agonist, [D-Ala², NMe-Phe⁴, Gly-ol]-enkephanlin (DAMGO), induced an outward current mediated by K⁺ channels in GABAergic interneurons. (
  • In this study, we examined whether a µ-opioid agonist, [D-Ala2,N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO), affects the two-pore domain K⁺ channel (K2P) current in rat SG neurons using a slice whole-cell patch clamp technique. (
  • It has been shown that [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO), a potent MOR agonist inducing the internalization, facilitates morphine to internalize MOR, suggesting that MOR agonists with low relative activity versus endocytosis (RAVE) values such as DAMGO can potentiate analgesic effects of morphine through stimulating MOR internalization. (
  • An example of this is the mu opioid receptor (MOPr), where the agonists morphine and [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO) induce desensitization of the MOPr by different mechanisms, largely protein kinase C (PKC)- or GRK-dependent, respectively. (
  • Trizma hydrochloride, dimethyl sulfoxide, (D-Ala2, N-Me-Phe4, glisinol5)-encephalin or DAMGO and (5,7,8(3)- N- methyl- N - [7-(1-pyrolidinyl)1-oxaspyro [4,5] dek- 8- il] benzenacetamide or U69,593 (Sigma St. (
  • D-Ala2,N-MePhe4,Gly5-ol]-enkephalin (DAMGO, 10 microm)-stimulated [35S]GTPgammaS binding was performed in both tissue sections and isolated membranes. (
  • The action of ME was mimicked by the μ-selective agonist [D-Ala 2 , N-Me-Phe 4 , Gly 5 -ol]-enkephalin (DAMGO), and was partially blocked by the μ-selective antagonists naloxonazine and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP). (
  • The effect of DAMGO at 10 -5 M was significantly higher than at 10 -6 M, whereas the effect of endomorphins did not differ at the two concentration levels. (
  • The purpose of this study was to determine if the highly selective MOR agonist [d-Ala 2 ,N-MePhe 4 ,Gly-ol]-enkephalin (DAMGO) attenuates the exercise pressor reflex and which of these two channels are responsible for this effect. (
  • The mu opioid receptor agonist D-Ala 2 , N-Me-Phe 4 , Gly-ol 5 -enkephalin (DAMGO) produced dose-dependent hyperpolarizations of ARC neurons. (
  • Chronic morphine treatment for 4 days reduced DAMGO potency 2.5-fold with no change in the maximal response. (
  • Possible abnormal pain and spinal antinociceptive tolerance were evaluated after intrathecal administration of [D-Ala 2 , N-Me-Phe 4 , Gly-ol 5 ]enke phalin (DAMGO), an opioid μ agonist. (
  • Pretreatment with the mu-opioid receptor agonist, [D-Ala(2), N-Me-Phe(4),Gly(5)-ol]enkephalin (DAMGO), or the ORL1 receptor agonist, orphanin FQ/nociceptin desensitized both mu-opioid and ORL1 receptor responses. (
  • The 100% methanol, 75% ethanol, and 40% 2-propanol extracts of black cohosh effectively displaced the specific binding of [3H]DAMGO to hMOR. (
  • High-efficacy agonists such as [d-Ala(2)-MePhe(4)-Gly-ol]enkephalin (DAMGO), fentanyl, or etonitazene stimulate the phosphorylation of both C-terminal threonine 370 (T370) and serine 375 (S375). (
  • Studies examining presynaptic regulation of POMC neurons by opioids have used the nonspecific opioid receptor agonist [Met 5 ]-enkephalin, leaving it unclear which opioid receptors are present on terminals presynaptic to POMC neurons. (
  • For example, morphine binding produces a μOR with low affinity for β-arrestin proteins and limited receptor internalization, whereas enkephalin analogs promote robust trafficking of both β-arrestins and the receptors. (
  • It is estimated that over 5% of the human genome encode for these receptors and represents one of the biggest family of ancestrally related proteins. (
  • Both EMs displaced binding of [ 3 H]-[ d -Ala 2 , N -Me-Phe 4 ,Gly 5 -ol]enkephalin to μ-receptors in dorsal root ganglia (DRG). (
  • Exogenous EM-2 in addition to μ-receptors also activates peripheral δ-receptors, which does not involve actions via other opioid peptides. (
  • and some studies suggested that exogenous EM-2-induced antinociception was mediated by the release of dynorphin A(1-17) and methionine (Met)-enkephalin, which activated κ- and δ-receptors, respectively ( Tseng, 2002 ). (
  • The majority acts at sites within the brainstem respiratory network including drugs that act at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (ampakines), 5-hydroxytryptamine receptor agonists, phospodiesterase-4 inhibitors, D 1 -dopamine receptor agonists, the endogenous peptide glycyl-glutamine, and thyrotropin-releasing hormone. (
  • The efficiency of GPCR signaling is tightly regulated and ultimately limited by the coordinated phosphorylation of the receptors by specific GPCR kinases and the subsequent interaction of the phosphorylated receptors with β-arrestin 1 and β-arrestin 2. (
  • Because GPCRs, such as the substance P receptor and the opioid receptors, participate in processing the sensation of pain, we characterized analgesic responses through the μ opioid receptor (μOR) in mice lacking β-arrestin 2. (
  • 4 Exposure of G protein-coupled receptors to their agonists often results in rapid attenuation of receptor responsiveness. (
  • However, because this agent does not produce opioid-like respiratory depression , it might not interact with mu(2) opioid receptors. (
  • Therefore, we have studied the interaction of ketamine with mu(2) opioid receptors expressed in SH-SY5Y cells. (
  • ONCLUSION: The present study indicates that a clinically relevant concentration of ketamine interacts with mu(2) opioid receptors. (
  • The κ and δ receptors represent ~10 ± 3% and ~5 ± 2% of the [ 3 H]diprenorphine binding sites, respectively. (
  • Synthetic opioids are substances created to act as agonists for the opioid receptors (μ, δ, and κ subtypes), mainly found in the brain, spinal cord, and digestive tract ( 2 ). (
  • 3. The method of claim 2, wherein said peptide has a binding affinity for the kappa opioid receptor that is 10 times greater, 100 times greater, 1,000 times greater, or more than its binding affinity for non-kappa opioid receptors. (
  • The potential interactions of natively expressed mu-opioid and opioid receptor-like (ORL1) receptors were studied by exposing intact BE(2)-C cells to agonists or antagonists for 1 h. (
  • furthermore, oxytocin-induced synaptic plasticity requires activation of nucleus accumbens 5-ht1b receptors, the blockade of which prevents social reward. (
  • Dopamine D2 receptors (D2Rs) are densely expressed in the striatum and have been linked to neuropsychiatric disorders such as schizophrenia1,2. (
  • Our data support the continued investigation of compounds that target 5-HT2A and σ1 receptors in METH-induced overdose, including their potential to yield emergency reversal agents. (
  • Analgesic Tolerance of Opioid Agonists in Mutant Mu-Opioid Receptors E" by Guangwen Li, Fei Ma et al. (
  • Furthermore, TRPA1 receptors mediate the pruritus induced by activation of PAR-2, but H2S does not interfere with this pathway. (
  • Here, we evaluate μOR trafficking in response to activation by a novel μ-selective agonist derived from the naturally occurring plant product, salvinorin A. It is interesting that this compound, termed herkinorin , does not promote the recruitment of β-arrestin-2 to the μOR and does not lead to receptor internalization. (
  • Evidence for DOR-KOR heteromers in peripheral sensory neurons included coimmunoprecipitation of DOR with KOR, a DOR-KOR heteromer selective antibody augmented the antinociceptive effect of DPDPE in vivo, and the DOR-KOR heteromer agonist 6′-GNTI inhibited adenylyl cyclase activity in vitro as well as PGE 2 -stimulated thermal allodynia in vivo. (
  • Buprenorphine activation of [ 35 S]GTPγS binding would be an example of such a MOP receptor agonist (McPherson et al . (
  • 2. The method of claim 1, wherein said peripherally, selective kappa opioid receptor agonist, a salt thereof or a pro-drug thereof comprises a peptide. (
  • The mu opioid agonists alfentanil and fentanyl, the kappa opioid agonists ethylketocyclazocine (EKC) and U69,593, the delta opioid agonist BW373U86 {(±)-4-((R*)-a-((2S*5R*)-4-allyl-2,5-dimethyl-1- piperazinal)-3-hydroxy-benzyl)-N,N-diethylbenzamide dihydrochloride} and the nonopioid, noncompetitive N-methyl-D-aspartate antagonist ketamine all produced a dose-dependent decrease in rates of responding. (
  • Additionally, antagonist effects of individual doses of quadazocine in combination with each agonist were evaluated by using in vivo apparent pK(B) analysis, and pK(B) values were found to be similar to the more rigorously determined pA 2 values. (
  • The intradermal injection of the PAR-2 peptide agonist SLIGRL-NH2 (8-80nmol) caused a dose-dependent scratching that was unaffected by intraperitoneal pre-treatment with the histamine H1 antagonist pyrilamine (30mg/kg). (
  • Studies in mice have shown that β-arrestin-2 plays an important role in the development of morphine-induced tolerance, constipation, and respiratory depression. (
  • RGS9-2, a brain-specific splice variant of the RGS9 gene, is highly enriched in striatum and also expressed at much lower levels in periaqueductal gray and spinal cord, structures known to mediate various actions of morphine and other opiates. (
  • We show here that acute morphine administration increases expression of RGS9-2 in NAc and the other CNS regions, whereas chronic exposure decreases RGS9-2 levels. (
  • Functional deletion of the β-arrestin 2 gene in mice resulted in remarkable potentiation and prolongation of the analgesic effect of morphine, suggesting that μOR desensitization was impaired. (
  • Moreover, they suggest that inhibition of β-arrestin 2 function might lead to enhanced analgesic effectiveness of morphine and provide potential new avenues for the study and treatment of pain, narcotic tolerance, and dependence. (
  • The antinociceptive (blocking of pain perception) actions of morphine are mediated through stimulation of the μOR, as demonstrated by the lack of morphine analgesia observed in knockout mice deficient in the μOR ( 5 , 6 ). (
  • In Europe and North America, highly potent synthetic opioids, which mimic the effects of heroin and morphine, are a growing health threat ( 1 - 4 ). (
  • The major pharmacologic actions of morphine (e.g., euphoria, analgesia, sedation, respiratory depression, decreased gastrointestinal motility, and physical dependence) are all due to agonistic actions at the μ-opioid receptor (MOR) 4 ( 7 , 8 ). (
  • 5-8 A previous study suggests that there is no significant difference in the μ opioid receptor binding in the whole brain homogenate between normal and diabetic rats and that the decreased potency of systemic morphine may be related to altered distribution and clearance kinetics in diabetic rats. (
  • MrgC11 activation also inhibited the coupling of MOR to β-arrestin-2 and enhanced the morphine-dependent inhibition of cAMP production. (
  • Fifty ng/mL of fentanyl reduced the electroconvulsive activity, and 1 micrometer of DAGO ([D-Ala2, N-Me-Phe4, Gly-ol]-enkephalin) also decreased the electroconvulsive activity. (
  • Although mu opioid peptide (MOP) receptor agonists remain the most effective and widely used analgesics, their abuse liability and possibility of causing respiratory arrest have contributed to escalating medical and economic burdens and fueled the opioid crisis in the global community ( 4 , 5 ). (
  • In addition, mice that are deficient in β-arrestin 1 display increased cardiac contractility in response to β adrenergic receptor agonists ( 4 ). (
  • However, [35S]GTPgammaS bindings in the spinal dorsal horn stimulated by other G protein-coupled receptor agonists, including [D-Pen2,D-Pen5]-enkephalin, R(-)N6-(2-phenylisopropyl)-adenosine, and WIN-55212, were not significantly altered in diabetic rats. (
  • 3,4 For instance, many animal and human studies have shown a decreased analgesic potency of μ opioid agonists in diabetic neuropathic pain. (
  • In contrast, the orexigenic opioid agonists [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin and met-enkephalin inhibited both ST-stimulated EPSCs and the frequency of miniature EPSCs. (
  • In vitro, 3 and its analogs were potent agonists in [ 35 S]GTP γ S assays at the mu opioid receptor but failed to recruit β -arrestin-2, which is associated with opioid side effects. (
  • 5 - 9 A more recent approach takes advantage of biased agonism, in which distinct downstream signaling pathways are activated by different agonists working through the same receptor. (
  • Anesthesiology 5 2018, Vol.128, 1027-1037. (
  • Molecular Pharmacology , 51 (4), 666-673. (
  • Journal of Pharmacology and Experimental Therapeutics , 267 (2), 896-903. (
  • Thirty-three new synthetic opioids were detected in Europe between 2009 and 2017 ( 5 ). (
  • In support of this, we found that DPDPE-mediated antinociception was blocked by the mu selective antagonist d -Phe-Cys-Tyr- d -Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP). (
  • In contrast to nor-BNI, the KOR antagonist 5′-guanidinonaltrindole (5′-GNTI) reduced the response of DPDPE both in cultured neurons and in vivo. (
  • The EPSCs were blocked by the glutamate antagonist 2,3- dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline. (
  • The present study assessed whether pretreatment with the 5-HT2A receptor antagonist M100907 or the sigma 1 (σ1) receptor antagonist BD 1047 attenuated METH-induced lethality, hyperthermia, convulsions, and seizures. (
  • In vivo, nor-BNI enhanced the effect of DPDPE and decreased the effect of SNC80 to inhibit PGE 2 -stimulated thermal allodynia. (
  • Antibodies against β-endorphin, methionine-enkephalin, or leucine-enkephalin did not significantly change EM-2-induced antinociception. (
  • Evoked GABAergic inhibitory postsynaptic currents (IPSCs) were reversibly reduced by methionine enkephalin (ME) with an IC 50 value of 1.1 ± 0.3 μM. (
  • These new synthetic opioids are a major public health concern owing to their high potency, ease of accessibility over the internet, and distribution into the regular street heroin supply, where they are often mixed with or substituted for heroin, leading to life-threatening respiratory depression and death ( 1 - 4 ). (
  • This was blocked by locally applied μ-receptor-selective ( d -Phe-Cys-Tyr- d -Trp-Orn-Thr-Pen-Thr-NH 2 ) but not κ-receptor-selective (nor-binaltorphimine) antagonists. (
  • δ-Receptor antagonists (naltrindole and N , N -diallyl-Tyr-Aib-Aib-Phe-Leu) did not influence EM-1-induced but dose-dependently decreased EM-2-induced antinociception. (
  • and if this is the case, 2) does the internalization process have the same kinetics reported from in vitro studies? (
  • We generated β-arrestin 2 knockout (βarr2-KO) mice by inactivation of the gene by homologous recombination ( 7 ). (
  • Mice lacking β-arrestin 2 were identified by Southern (DNA) blot analysis ( Fig. 1 A), and the absence of β-arrestin 2 was confirmed by protein immunoblotting of extracts from brainstem, periaqueductal gray (PAG) tissue, spleen, lung, and skin ( Fig. 1 B) ( 8 ). (
  • Because wild-type, heterozygous (βarr2 +/− ), and homozygous mutant mice had similar amounts of β-arrestin 1 in the brain regions examined ( Fig. 1 B), compensatory up-regulation of β-arrestin 1 in the absence of β-arrestin 2 seems unlikely. (
  • these results demonstrate that the rewarding properties of social interaction in mice require the coordinated activity of oxytocin and 5-ht in the nucleus accumbens, a mechanistic insight with implications for understanding the pathogenesis of social dysfunction in neuropsychiatric disorders such as autism. (
  • Ozgene mice can be found in 31 different countries on 5 continents from small academic institutions to multinational pharmaceutical companies. (
  • Considering that the activation of proteinase-activated receptor 2 (PAR-2) is involved in pruritus both in rodents and humans, in this study we investigated the effect of H2S donors on the acute scratching behavior mediated by PAR-2 activation in mice, as well as some of the possible pharmacological mechanisms involved. (
  • By contrast, RGS9-2 is expressed solely in brain, where it shows a distinctive pattern of expression in brain regions important for the actions of opiate drugs ( 7 , 8 ). (
  • RGS9-2 is highly enriched in striatum (including the ventral striatum or nucleus accumbens, NAc), a region important for opiate reward, but is also present at much lower levels in periaqueductal gray and spinal cord, structures important for opiate analgesia ( 11 ). (
  • These findings, coupled with the presence of RGS9-2 in opiate-responsive CNS regions, led us to hypothesize that RGS9-2 may be a critical negative regulator of opiate action in vivo and may play an important role in cellular adaptations that occur after chronic opiate administration. (
  • According to this theory, a receptor can adopt different active conformations [ 6 ] induced and/or stabilized by ligands, resulting in activation of distinct effectors associated with that receptor [ 5 , 7 - 10 ]. (
  • 10 , 11 It has been proposed that ligands biased against recruiting β -arrestin-2, or showing preference for activating specific G-protein-mediated signal transduction pathways, will demonstrate diminished side effects. (
  • The ATP-dependent transport of GSH was inhibited by 3-([{3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl}-{(3-dimethylamino-3-oxopropyl)-thio}-methyl]thio)propanoic acid (MK571), with 50% inhibition being obtained with 1.4 μM MK571. (
  • U50,488H, ( trans )-3,4-dichloro- N -methyl- N -[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide. (
  • Rett syndrome is a severe X-linked neurological disorder in which most patients have mutations in the methyl-CpG binding protein 2 (MECP2) gene and suffer from bioaminergic. (
  • The cardiovascular and endocrine activity of three analogs of thyrotropin releasing hor.mone (TRH), 4-nitro-imidazole TRH (4-nitroTRH), 2-trifluoro-methyl-imidazole TRH (2-TFM-TRH) and 4-trifluoromethyl- imidazole TRH (4-TFM-TRH), was compared to TRH in conscious rats. (
  • It was synthesized as a biologically stable analog of δ-opioid receptor -preferring endogenous opioids , leu- and met- enkephalin . (
  • Unlike the effects of AA, the central hypertensive, tachycardic and hyperthennic responses to PGF\(_{2\alpha}\) (0.5-50 l-lg/rat i.c.v .) were significantly attenuated in SHR. (
  • The 4-TFM-TRH was significantly less potent than the 2-TFM-TRH in increasing blood pressure, while the nitro-TRH was more potent than the 2-TFM-TRH in producing tachycardia. (
  • Injection of TRH or the three analogs (1 mg/kg or 5 mg/kg) into the arterial line induced increases in mean arterial pressure, pulse pressure and heart rate and raised plasma prolactin (PRL). (
  • TRH induced a two-fold increase in PRL at the 5 mg/kg dose, while both the fluorinated analogs elici ted a 4 to 5 fold increase in PRL at the higher dose. (
  • 2-4 Although the occurrence of severe respiratory depression and related deaths in the treatment of acute and perioperative pain seems constant over the years (with an incidence of at least 0.5%), 1 , 5 over the last decade there has been a dramatic surge in fatalities from prescription opioids in chronic pain patients due to a dramatic increase in opioid consumption. (
  • From an additional 10 samples found to contain other opioids, 5 were correctly scored positive. (
  • These synthetic opioids were initially explored by research groups or pharmaceutical companies for their potential medicinal use, but they have recently found their way to the illicit drug market ( 1 - 4 ). (
  • Acute cold exposure (-20°C, 4 h) induces a transient decrease in the ventricular fibrillation threshold without morphological and radionuclide signs of irreversible damage to cardiomyocytes. (
  • The acute effect ofT-2 toxemia on local blood flow and vascular resistance in hindquarter. (
  • High-affinity binding of dopamine suggests that D2Rs detect transient reductions in dopamine concentration (the dopamine dip) during punishment learning3-5. (
  • We tested the hypothesis that in isolated rabbit cardiac myocytes, the negative functional effects of cyclic GMP are partly mediated by cyclic GMP-dependent protein kinase activity, and that these effects are altered in thyroxine (T 4 , 0.5 mg/kg/day for 16 days)-induced hypertrophic myocytes. (
  • The lumbar spinal cord was obtained from age-matched normal and diabetic rats 4 weeks after streptozotocin treatment. (
  • Therefore the central effects of AA and PGF \(_{2\alpha}\) on blood pressure, heart rate and body temperature were studied both in SHR and nonootensive Wistar rats (NR) under urethane-anaesthesia. (
  • 5-ht) innervation to the nucleus accumbens, abolishes the reinforcing properties of social interaction. (
  • A cell-based system was set up in which activation of the μ-opioid receptor (MOR) led to recruitment of β-arrestin 2, resulting in functional complementation of a split NanoLuc luciferase and allowing readout via bioluminescence. (
  • Based on these data, we conclude that pruritus secondary to PAR-2 activation can be reduced by H2S, which acts through KATP channel opening and involves NO in a cyclic guanosine monophosphate (cGMP)-independent manner. (
  • The transport of GSH was related to the intracellular GSH concentration up to ∼5 mM and then plateaued. (
  • GPCRs account for up to 50% of currently marketed drugs [ 1 - 4 ] and continue to be the focus of intense research in drug development. (
  • In addition, many of the 25 mammalian RGS proteins known to date contain domains that provide them with additional anchoring or scaffolding properties ( 4 - 6 ). (
  • These proteins differ at their C terminus only, with RGS9-1 containing 18 unique C-terminal amino acids and RGS9-2 containing 209 unique C-terminal amino acids. (
  • These results provide evidence in vivo for the physiological importance of β-arrestin 2 in regulating the function of a specific GPCR, the μOR. (
  • American Journal of Physiology - Regulatory Integrative and Comparative Physiology , 314 (5), R693-R699. (
  • The Nrf2 (nuclear factor E2 p45-related factor 2) transcription factor responds to diverse oxidative and electrophilic environmental stresses by circumventing repression by Keap1, translocating to the nucleus, and activating cytoprotective genes. (