Disease relevance of Endomorphin 2

• 1. Extracellular application of the novel brain peptides endomorphin 1 (EM1) and endomorphin 2 (EM2) inhibited high-threshold Ca2+ channel currents in NGMO-251 cells, a daughter clone of NG108-15 mouse neuroblastoma x rat glioma hybrid cells, in which mu-opioid receptors are overexpressed [1].
• The nucleus ambiguus has been shown to contain mu-opioid receptors and endomorphin-1 and endomorphin-2, the endogenous peptide ligands for the mu-receptor, whilst microinjections of opioids in the ambiguus area evoke bradycardia [2].
• Paradoxical hyperalgesia induced by mu-opioid receptor agonist endomorphin-2, but not endomorphin-1, microinjected into the centromedial amygdala of the rat [3].
• The human neuroblastoma cell line, SH-SY5Y, was used to examine the effects of morphine and the endogenous opioid peptides, endomorphin-1 (EM-1) and endomorphin-2 (EM-2), on mu opioid receptor (MOR) internalization and down-regulation [4].
• Binding of endomorphin-2 to mu-opioid receptors in experimental mouse mammary adenocarcinoma [5].

Psychiatry related information on Endomorphin 2

• A rather nonselective higher dose (50 mg/kg, s.c.) of naloxonazine almost completely antagonized the endomorphin-1 (10 microg)- and endomorphin-2 (10 microg)-induced impairment of passive avoidance learning [6].
• Effects of endomorphin-2 on arterial blood pressure and pain threshold in spontaneously hypertensive rats and modification of these effects by beta-funaltrexamine and nor-binaltorphimine [7].

High impact information on Endomorphin 2

• We have synthesized and pharmacologically characterized a chimeric peptide containing overlapping NH(2)- and COOH-terminal functional domains of the endogenous opioid endomorphin-2 (EM-2) and the tachykinin SP, respectively [8].
• We recently reported the use of an exhaustively stereodiversified library based on endomorphin-2 (1) to discover mu opioid receptor (MOR) ligands of type 2-4 [9].
• After injection of Fluoro-Gold into the medial zone of hypothalamic tuberal region and the lateral hypothalamic area, respectively, endomorphin 1/Fluoro-Gold or endomorphin 2/Fluoro-Gold double-labeled neuronal cell bodies were found chiefly in the medial, commissural, lateral and gelatinous parts of the nucleus tractus solitarii [10].
• These results suggest that the spinal antinociception induced by endomorphin-2 is mediated through the stimulation of a distinct subtype of mu(1)-opioid receptor that induces the release of the endogenous kappa-opioid peptide dynorphin A-(1-17) in the spinal cord [11].
• Inhibition by endomorphin-1 and endomorphin-2 of excitatory transmission in adult rat substantia gelatinosa neurons [12].

Biological context of Endomorphin 2

• These results indicate that endomorphin-2 elicits depressor and bradycardic responses and inhibits baroreflex function when injected into the RVLM [13].
• Pharmacological characterization of the [125I]endomorphin-2 binding sites was made using endomorphin-2 and two other micro selective ligands, morphiceptin, and [D-1-Nal3]morphiceptin on MCF7 cell membrane preparations and whole MCF7 cells [14].
• We propose that different degrees of receptor endocytosis for receptor inactivation after stimulation of mu-opioid receptors by endomorphin-1 and endomorphin-2 and/or two separate subtypes of mu-opioid receptors are involved in the antinociception induced by endomorphin-1 and endomorphin-2 [15].
• Structure-activity relationships of novel endomorphin-2 analogues with N-O turns induced by alpha-aminoxy acids [16].
• The two most potent analogs were [D-1-Nal(4)]- and [D-2-Nal4]endomorphin-2, with IC50 values 14 +/- 1.25 and 19 +/- 2.1 nM, respectively, compared with 1.9 +/- 0.21 nM for endomorphin-2 [17].

Anatomical context of Endomorphin 2

• We conclude that the more potent anti-nociceptive effect induced by 2/100 Hz EAS, as compared with that of (2 + 100) Hz EAS, was due, at least partly, to the synergistic interaction of endomorphin-2 and dynorphin in rat spinal cord [18].
• The endomorphin-2-like immunoreactive axon terminals formed synapses with both immunopositive and immunonegative processes [19].
• Endomorphin-1 (0.1-10 microM), endomorphin-2 (0.1-10 microM) and beta-endorphin (0.1-10 microM) increased guanosine-5'-o-(3-[35S]thio)triphosphate binding to the pons/medulla membranes from C57BL/6 ByJ and CXBK mice in a concentration-dependent manner [20].
• Differential mechanisms of antianalgesia induced by endomorphin-1 and endomorphin-2 in the ventral periaqueductal gray of the rat [21].
• The present study was conducted to examine the metabolism of endomorphin-2 by synaptic membranes prepared from mouse brain [22].

Associations of Endomorphin 2 with other chemical compounds

• The effects of pretreatment with endomorphin-1 (EM-1) and endomorphin-2 (EM-2) given into the ventral periaqueductal gray (vPAG) to induce antianalgesia against the tail-flick (TF) inhibition produced by morphine given into the vPAG were studied in rats [21].
• A functional assay, based on aequorin-derived luminescence triggered by receptor-mediated changes in intracellular calcium levels, was used to examine relative potency and efficacy of the mu-opioid agonists endomorphin-1, endomorphin-2, morphiceptin, and their position 3-substituted analogs, as well as the delta-agonist deltorphin-II [23].
• We confirmed that endomorphin-2 expression starts later in the postnatal period than substance P [24].
• The endomorphin-2 but not endomorphin-1 current amplitude was increased by dipeptidyl peptidase IV inhibitor diprotin A (30 muM) [12].
• Thus, degradation of endomorphin-2 by brain synaptic membranes seems to take place mainly through the cleavage of Pro(2)-Phe(3) bond by dipeptidyl peptidase IV, followed by release of free phenylalanine and PheNH(2) from the liberated fragment, Phe-PheNH(2) by aminopeptidase [22].

Gene context of Endomorphin 2

• Co-localization of endomorphin-2 and substance P in primary afferent nociceptors and effects of injury: a light and electron microscopic study in the rat [25].
• Furthermore, purified dipeptidyl peptidase IV hydrolyzed endomorphin-2 at the cleavage site, Pro(2)-Phe(3) bond [22].
• Endomorphin-1 and endomorphin-2 differentially interact with specific binding sites for substance P (SP) aminoterminal SP1-7 in the rat spinal cord [26].
• Endomorphin-2 inhibited TNF-alpha, IL-10, and IL-12 productions, but potentiated IL-1beta production by macrophages [27].
• While MOR was upregulated on peripheral and central nerve terminals, inflammation did not alter endomorphin-2 expression in nerve fibers either in the dorsal horn of the spinal cord or in subcutaneous tissue [28].

Analytical, diagnostic and therapeutic context of Endomorphin 2

• In this study, we show that the ectopic fibers also express endomorphin-2, and describe the postnatal development of such expression, as detected by immunocytochemistry [24].
• Using immunoelectron microscopy, we examined the ultrastructure of the endomorphin-2-like immunoreactive processes and their synaptic relationships in the spinal cord [19].
• The recently discovered endomorphin 1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin 2 (Tyr-Pro-Phe-Phe-NH2) were investigated with respect to their direct receptor-binding properties, and to their ability to activate G proteins and to inhibit adenylyl cyclase in both cellular and animal models [29].
• Later, endomorphin-1 and endomorphin-2 have been detected in the immune system of rats and humans using radioimmunoassay in combination with reverse-high-phase-liquid chromatography [28].
• A potent, stable and specific inhibitor of this enzyme, Ala-Pyrrolidonyl-2-nitrile, has been described which should potentiate endomorphin-2-induced analgesia [30].

References