Pharmacological properties of a proenkephalin A-derived opioid peptide: BAM 18 (original) (raw)
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Peptides, 1998
peptide receptor studies. 9. Identification of a novel non--non-␦-like opioid peptide binding site in rat brain. PEPTIDES 19(6) 1079 -1090, 1998. Quantitative binding studies resolved two high-affinity [ 3 H][D-Ala 2 ,D-Leu 5 ]enkephalin binding sites in rat brain membranes depleted of binding sites by pretreatment with the irreversible agent BIT. -The two binding sites had lower (␦ ncx-2 , Ki ϭ 96.6 nM) and higher (␦ ncx-1 , Ki ϭ 1.55 nM) affinity for DPDPE. The ligand-selectivity profile of the ␦ ncx-1 site was that of a classic ␦ binding site. The ligand-selectivity profile of the ␦ ncx-2 site was neitheror ␦-like. The Ki values of selected agents for the ␦ ncx-2 site were: [pCl]DPDPE (3.9 nM), DPLPE (140 nM), and DAMGO (2.6 nM). Under these assay conditions, [ 3 H][D-Ala 2 ,D-Leu 5 ]enkephalin binding to the cells expressing the cloned receptor is very low and pretreatment of cell membranes with BIT almost completely inhibits [ 3 H]DAMGO and [ 3 H][D-Ala 2 ,D-Leu 5 ]enkephalin binding. Intracerebroventricular administration of antisense DNA to the cloned delta receptor selectively decreased [ 3 H][D-Ala 2 ,D-Leu 5 ]enkephalin binding to the ␦ ncx-1 site. Administration of buprenorphine to rats 24 h prior to preparation of membranes differentially affected , ␦ ncx-1 , and ␦ ncx-2 binding sites. Viewed collectively, these studies have identified a novel non--non-␦-like binding site in rat brain.
Opioid peptides, opioid receptors and mechanism of down regulation
Indian journal of experimental biology, 2003
Biogenesis of various endogenous opioid peptides, anatomical distribution and the characteristics of multiple receptors with which they interact provides an opportunity for understanding the role of opioid systems and mechanism of opioid tolerance. Cellular and anatomical distribution of opioid receptor and their function is important for identification of neuronal systems and local network involved in initiation of drug action and subsequent development of adaptations resulting from repeated drug use. The details concerning discovery and progress in endogenous opioid peptide research and their distribution in brain have been described in this review. This review also describes opioid receptors, their distribution and mechanism of down regulation, which may be one of the causes for tolerance to opioids. Agonist induced down regulation and recent evidence for involvement of ubiquitin/proteasome system in this process has been discussed.
Life Sciences, 2000
This study was undertaken to examine the receptor selectivity of Met-enkephalin-Arg 6-Phe 7 (MERF) employing radioreceptor binding assays in human cerebral cortex membranes, and to elucidate the responsible receptors that mediate the regulatory action of MERF on high (20 mM) K ϩ-stimulated release of [ 3 H]norepinephrine ([ 3 H]-NE) in rat cortex slices. SpeciÞc binding of [ 3 H]MERF was inhibited by DAMGO, Tyr-D-Arg-Phe-Sar(TAPS), bremazocine and ethylketocyclazocine (EKC), but not by U69,593 (U69) and DPDPE. MERF showed high afÞnity for speciÞc binding sites of [ 3 H]DAMGO. However, MERF had little inßuence on the speciÞc binding of [ 3 H]DPDPE, [ 3 H]U69 and [ 3 H]diprenorphine ([ 3 H]DIP) in the presence of 1 M each of DAMGO, DPDPE and U69. In [ 3 H]NE release experiments using rat cortex slices, DAMGO, MERF and EKC, in order of their potency, inhibited K ϩ-stimulated release of [ 3 H]NE. The inhibitory effects of MERF and DAMGO were more sensitive than that of EKC to antagonism by CTAP, nor-binaltorphimine (nor-BNI) and naloxone. These results suggested that MERF possesses high afÞnity for-receptors, but not for ␦-, 1-, and very low afÞnity for 2-receptors in human cerebral cortex membranes. Also, the inhibitory effect of MERF on the K ϩ-stimulated release of [ 3 H]NE appears to be mediated by-receptors in rat cerebral cortex slices.
Reassessment of opioid binding sites in the rat brain
Neuropeptides, 1986
Opioid binding sites have been characterized pharmacologically in membranes from different areas of the rat brain. Delta,mu and sites belonging to the kappa family (Kl,K2,K3) have been detected.Delta sites were more abundant in cortex and striatum,mu sites in striatum and hypothalamus,while kappa binding site concentration was higher in deeper enkephalic structures (brainstem,cerebellum,hypothalamus) and the pituitary gland. A distinct distribution of each subtype of the kappa site was found: kappa 1 sites were higher in the spinal cord,kappa 2 sites in the brainstem and kappa 3 sites in cerebellum. The distribution of delta and kappa sites in the central nervous system was correlated with the distribution of proenkephalin-A derived peptides and precursors, suggesting that these peptides could be their endogenous ligands.
Non-opioid actions of opioid peptides
Life Sciences, 2004
Beside the well known actions of opioid peptides on A-, y-and n-opioid receptors, increasing amount of pharmacological and biochemical evidence has recently been published about non-opioid actions of various opioid peptides. These effects are not abolished by naloxone treatments. Such non-opioid effects are observed both in nervous tissues and in the cellular elements of the immune system. Peptides exhibiting non-opioid effects include h-endorphin, dynorphin A, nociceptin/OFQ, endomorphins, hemorphins and a number of Proenkephalin A derived peptides, such as Met-enkephalin, Met-enkephalin-Arg-Phe (MERF) and bovine adrenal medullary peptide (BAM22). Non-opioid actions are exerted through different neuronal receptors, e.g., dynorphin hyperalgesia through NMDA receptor, Met-enkephalin induced regulation of cell growth through zeta (~) receptors, pain modulation by nociceptin through ORL-1 or NOP receptors, while BAM22 acts through sensory neuron specific G protein-coupled receptors (SNSR). We have investigated Met-enkephalin-Arg-Phe (MERF) and its analogues by the means of direct and indirect radioligand binding assays. It has been found that in addition to n 2 and y-opioid receptors, MERF can act also through j 2-or probably via FMRF-NH 2 receptors in rat cerebellum. A role of functionally assembling heterodimer receptors in mediating the non-conventional actions of these peptide ligands can not be excluded as well.
Peptides, 1985
Combined autoradiographic-immunocytochemical analysis of opioid receptors and opioid peptide neuronal systems in brain. PEPTIDES 6: Suppl. 1, 37--47, 1985.--Using adjacent section autoradiography-immunocytochemistry, the distribution of [3H]naloxone binding sites was studied in relation to neuronal systems containing [Leu]enkephalin, dynorphin A, or/3-endorphin immunoreactivity in rat brain. Brain sections from formaldehyde-perfused rats show robust specific binding of [3H]naloxone, the pharmacological ~-like) properties of which appear unaltered. In contrast, specific binding of the 8 ligand [3H]D-AlaZ,D-LeuS-enkephalin was virtually totally eliminated as a result of formaldehyde perfusion. Using adjacent section analysis, we have noted associations between [3H]naloxone binding sites and one, two, or all three opioid systems in different brain regions; however, in some areas, no apparent relationship could be observed. Within regions, the relationship was complex; for example, in caudate-putamen, patches ofopioid receptors did not correspond to the distribution of enkephalin immunoreactivity, but there was a correspondence between subeallosal streaks of binding sites and enkephalin. The complexity of the association between [3H]naloxone binding sites and the multiple opioid systems, and previous reports of colocalization of Ix and K receptors in rat brain, are inconsistent with a simple-one-to-one relationship between a given opioid precursor and opioid receptor subtype. Instead, since differential processing of the three precursors gives rise to peptides of varying receptor subtype potencies and selectivities, the multiple peptide-receptor relationships may point to a key role of post-translational processing in determining the physiological consequences of opioid neurotransmission.
Irreversible labelling of rat brain opioid receptors by enkephalin chloromethyl ketones
Neuropeptides, 1986
Chloromethyl ketone derivatives of leucine enkephalin (LE), D-Ala2-Leu5-enkephalin (DALE) and D-Ala2-D-Leu5-enkephalin (DADLE) were synthesized. They all show high affinity for rat brain opioid binding sites. Preincubation of the membrane fraction with enkephalin chloromethyl ketones causes a significant inhibition of /3H/-naloxone binding which cannot be reversed by extensive washing. It was found that the irreversible inhibition is selective for the high affinity (KD less than 1 nM) /3H/-naloxone binding site (putative mu-1 site). The irreversible blockade of opioid binding was partially protected by opiate alkaloids and opioid peptides, suggesting that non-specific labelling also occurs. Affinity of enkephalin chloromethyl ketones toward the mu sites is greater than that of the parent compounds. It was also found that the covalent inhibition of mu sites (/3H/-dihydromorphine and /3H/-DAGO binding) is more effective than that of delta sites (/3H/-DALE binding). We conclude that these chloromethyl ketone derivatives can be used as affinity labels for the opioid receptors, allowing us to study the structure of the mu receptor subtype.