Enkephalin-Induced Depression of Single Neurons in Brain Areas with Opiate Receptors—Antagonism by Naloxone

Frederickson, Robert C.A.; Norris, Franklin H.

doi:10.1126/science.10625

Cited by 150 publications

(18 citation statements)

References 33 publications

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“…A similar result has been obtained with neurones in several areas of the central nervous system including brain stem (Bradley, Briggs, Gayton & Lambert, 1976), thalamus (Hill, Pepper & Mitchell, 1976), cerebral cortex (Zieglgansberger, fry, Herz, Moroder & Wunsch, 1976) and periaqueductal grey matter (Frederickson & Norris, 1976) of the rat, and the brain stem of the cat (Gent & Wolstencroft, 1976). This depressant action does not occur with all neurones since cells of the posterior cerebral cortex of the rat were not affected by enkephalin (Frederickson & Norris, 1976) and Renshaw cells of cat and rat were excited by this substance (Davies & Dray, 1976). Of these investigators only Hill et al (1976) tested enkephalin for effects on excitation of neurones by noxious stimuli.…”

Section: Discussionsupporting

confidence: 57%

Enkephalins and Dorsal Horn Neurones of the Cat: Effects on Responses to Noxious and Innocuous Skin Stimuli

Duggan

Headley

1977

British J Pharmacology

140

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1In spinal cats anaesthetized with a-chloralose, a study was made of the effects of methionine enkephalin and methionine enkephalin amide on the responses of neurones of spinal laminae IV and V to noxious and innocuous skin stimuli. The enkephalins were ejected from micropipettes either in the region of cell bodies or in the substantia gelatinosa. 2 Administered near cell bodies the enkephalins reduced spontaneous firing and cell responses to both types of skin stimuli. These effects were antagonized by naloxone when administered near cell bodies but not when given intravenously in doses (0.3-0.6 mg/kg) more than adequate to antagonize analgesic doses of morphine. 3 Administered in the substantia gelatinosa the enkephalins were more selective in their action. The predominant effect was a reduction in nociceptive responses with little effect on non-nociceptive responses although spontaneous firing was commonly reduced. Naloxone administered either in the substantia gelatinosa or intravenously (0.1-0.3 mg/kg) reversed these effects of the enkephalins.

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Section: Discussionsupporting

confidence: 57%

Enkephalins and Dorsal Horn Neurones of the Cat: Effects on Responses to Noxious and Innocuous Skin Stimuli

Duggan

Headley

1977

British J Pharmacology

140

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“…Ligand L-2a thus behaves in a manner analogous to μ-and δ-opioid GPCR antagonists such as naloxone. 37,38 Conclusions.…”

Section: Function Of the Receptor Mimic In Solutionmentioning

confidence: 99%

Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor

et al. 2017

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. Ligandmodulated conformational switching in a fully synthetic membrane-bound receptor. Nature Chemistry, 9(5), [420][421][422][423][424][425] University of Bristol -Explore Bristol Research General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. AbstractSignal transduction through G protein-coupled receptors (GPCRs) involves binding to signalling molecules at the cell surface, which leads to global changes in molecular conformation that are communicated through the membrane. Artificial mechanisms for communication involving ligand binding and global conformational switching have been demonstrated so far only in the solution phase. Here we report a membrane-bound synthetic receptor that responds to binding of a ligand by undergoing a conformational change that is propagated over several nanometres, deep into the phospholipid bilayer. Our design uses a helical foldamer core, with structural features borrowed from a class of membrane-active fungal antibiotics, ligated to a water-compatible, metal-centred binding site and a conformationally-responsive fluorophore. Using the fluorophore as a remote reporter of conformational change, we find that binding of specific carboxylate ligands to a Cu(II) cofactor at the binding site perturbs the foldamer's global conformation, mimicking the conformational response of a GPCR to ligand binding.

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“…There are discrepancies in the correlation between opiate receptor and enkephalin localizations. (a) Though the caudate-putamen displays high levels of opiate receptor binding in biochemical (14,15) and autoradiographic (9) experiments as well as substantial endogenous levels of enkephalin in both radioreceptor assays (5,6) (14,15), demonstrates specific electrophysiological responses to opiates and enkephalin (16)(17)(18), and possesses moderate levels of enkephalin by radio-receptor and radioimmunoassay (5,6,12 "enkephalinergic" neurons that pass through these areas and synapse on opiate receptors elsewhere. Similar to the distribution of opiate receptors (8)(9)(10), the distribution of immunoreactive enkephalin corresponds to regions that mediate functions that are influenced by opiates.…”

mentioning

confidence: 99%

Opioid peptide enkephalin: immunohistochemical mapping in rat central nervous system.

Simantov¹,

Kuhar²,

Uhl³

et al. 1977

Proc. Natl. Acad. Sci. U.S.A.

450

105

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Using specific antisera to methionine-enkephalin and leucine-enkephalin, we have visualized apparent enkephalin-containing neuronal fibers and terminals throughout the central nervous system of the rat. Immunoreactive enkephalin displays sharply defined localizations. Regions of highest immunofluorescent density include the laminae I and II of the spinal cord, the substantia gelatinosa of the caudal nucleus of nerve V, the vagal nuclei of the medulla, the periventricular and periaqueductal areas of the upper medulla and midbrain, dorsomedial thalamic regions, specific hypothalamic nuclei, the basal ganglia, particularly the globus pallidus and the central nucleus of the amygdala, and the lateral septum. In certain regions enkephalin immunofluorescence corresponds closely with the distribution of autoradiographic opiate receptor grains.The opiate-like pentapeptides methionine-enkephalin (Metenk) and leucine-enkephalin (Leu-enk) (1, 2) appear to be endogenous ligands for the opiate receptor. The regional localization of enkephalin in mammalian brain, determined biochemically, resembles that of opiate receptor binding (3-6). In subcellular fractionation studies, enkephalin is localized to synaptosomal fractions that contain nerve terminals (7). Autoradiographic studies of the opiate receptor reveal sharply defined localizations to structures mediating functions affected by opiates, such as pain perception (8)(9)(10). If the enkephalins are neurotransmitters or neuromodulators associated with opiate receptors, one might expect enkephalin to be localized microscopically to neuronal systems impinging on opiate receptors. Preliminary immunohistochemical studies show immunoreactive enkephalin fluorescence in nerve fibers and terminals with highest densities in areas enriched in opiate receptors (11). We now report a detailed mapping of the rat central nervous system for immunoreactive enkephalin.MATERIALS AND METHODS Antisera Preparation. Met-enk or Leu-enk (20 mg) was coupled to keyhole limpet hemocyanin (10 mg) by incubation for 30 min in distilled water at room temperature with 150 mg of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. The material was dialyzed extensively against distilled water, lyophilized, suspended in 3 ml of distilled water, and stored. Guinea pigs were immunized with 1 mg of the hemocyanincoupled enkephalin diluted 1:10 in saline and mixed 1:1 with Freund's complete adjuvant. Rabbits were injected with 1.6 mg of this conjugate. The immunization was repeated three to four times at 3 to 4 week intervals using incomplete Freund's adjuvant. The guinea pigs and rabbits were bled 7-10 days after the third and subsequent immunizations and the sera were tested for enkephalin binding in radioimmunoassays (ref. 12; Abbreviations: Met-enk, methionine-enkephalin; Leu-enk, leucineenkephalin.* To whom reprint requests should be addressed.Simantov, Childers, and Snyder, unpublished data). Enkephalin binding by these antisera was not displaced by high concentrations of substance P, glucagon, insulin...

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Enkephalin-Induced Depression of Single Neurons in Brain Areas with Opiate Receptors—Antagonism by Naloxone

Cited by 150 publications

References 33 publications

Enkephalins and Dorsal Horn Neurones of the Cat: Effects on Responses to Noxious and Innocuous Skin Stimuli

Enkephalins and Dorsal Horn Neurones of the Cat: Effects on Responses to Noxious and Innocuous Skin Stimuli

Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor

Opioid peptide enkephalin: immunohistochemical mapping in rat central nervous system.

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