Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endogenous opioid peptides - enkephalins, beta-endorphin and dynorphins - are located in specific sites of the brain, the spinal cord, the autonomic ganglia and the enteric nervous system. Endogenous opioids participate in the regulation of nervous visceral afference and sensitivity as well as of several visceral motor function induced by the central nervous system and through the enteroenteric and the myoenteric reflexes. Their final effect on gut physiology is the net and harmonically balanced result of their binding to mu, delta and kappa opioid receptor subtypes. Exogenous opioid receptor ligands with different affinities for the opioid receptor subtypes have been effectively used to modify and normalize altered gut functions. The mu receptor agonists - morphine and, to a greater extent, the meperidine congeners diphenoxylate and loperamide - have been shown to slow gastrointestinal transit by their effects on the circular and longitudinal muscle of the intestine. Diphenoxylate and, more efficiently, loperamide, for the lack of any effect on the central nervous system, have been usefully employed in the treatment of diarrhea in irritable bowel syndrome (IBS) patients. Unlike the mu receptor agonists morphine and loperamide, which invariably stimulate colonic motility, trimebutine, which has almost equal affinity for mu, delta and kappa receptors, has no effect on normal colonic activity but reduces the abnormal increase in postprandial motor activity in IBS patients and accelerates slow large bowel transit in constipated patients. Opioid ligands can be usefully employed to normalize altered visceral sensitivity in IBS patients. The kappa receptor agonist fedotozine exerts its antinociceptive effect by acting on peripheral nerve endings of sensory vagal and nonvagal afferent pathways. Fedotozine has been shown to increase the threshold of perception to colonic distension in experimental conditions and to affect favourably symptoms of IBS in clinical trials.
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PMID:Role of opioid ligands in the irritable bowel syndrome. 1020 12

The role of endogenous opioid systems in the analgesic response to exogenous opiates remains controversial. We previously reported that mice lacking the peptide neurotransmitter beta-endorphin, although unable to produce opioid-mediated stress-induced antinociception, nevertheless displayed intact antinociception after systemic administration of the exogenous opiate morphine. Morphine administered by a peripheral route can activate opioid receptors in both the spinal cord and brain. However, beta-endorphin neuronal projections are confined predominantly to supraspinal nociceptive nuclei. Therefore, we questioned whether the absence of beta-endorphin would differentially affect antinociceptive responses depending on the route of opiate administration. Time- and dose-response curves were obtained in beta-endorphin-deficient and matched wild-type C57BL/6 congenic control mice using the tail-immersion/withdrawal assay. Null mutant mice were found to be more sensitive to supraspinal (i.c.v.) injection of the micro-opioid receptor-selective agonists, morphine and D-Ala(2)-MePhe(4)-Gly-ol(5) enkephalin. In contrast, the mutant mice were less sensitive to spinal (i.t.) injection of these same drugs. Quantitative receptor autoradiography revealed no differences between genotypes in the density of mu, delta, or kappa opioid receptor binding sites in either the spinal cord or pain-relevant supraspinal areas. Thus we report that the absence of a putative endogenous ligand for the mu-opioid receptor results in opposite changes in morphine sensitivity between discrete areas of the nervous system, which are not simply caused by changes in opioid receptor expression.
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PMID:Disparate spinal and supraspinal opioid antinociceptive responses in beta-endorphin-deficient mutant mice. 1111 19

The endogenous opioid system and the hypothalamic-pituitary-adrenal (HPA) axis have been implicated in many of the neurobiological effects of cocaine. Previous studies in our laboratory showed that "binge" pattern cocaine administration increases preprodynorphin (ppDyn) mRNA levels in the caudate putamen and circulating levels of corticosterone in the rat. The present study extended these findings to guinea pigs, a species known to have a kappa opioid receptor profile similar to that of humans. Male guinea pigs were treated with: (a) "binge" pattern cocaine for 7 days (subchronic) (3 x 15 mg/kg/day, hourly, intraperitoneal); (b) "binge" pattern saline for 5 days followed by "binge" pattern cocaine for 2 days (subacute); or (c) "binge" pattern saline for 7 days. Thirty minutes after the final injection, levels of ppDyn mRNA were quantitated in the nucleus accumbens, caudate putamen, frontal cortex, amygdala, hippocampus, and hypothalamus using a solution hybridization RNase protection assay. Regional distribution of ppDyn mRNA levels in the guinea pig brain was similar to that found in rat, with highest levels in the nucleus accumbens and caudate putamen. In the caudate putamen, ppDyn mRNA was significantly increased following either 2 days (38% increase) or 7 days (32% increase) of "binge" pattern cocaine administration as compared to saline-treated controls. No significant changes in ppDyn mRNA levels were found in any other brain region. Both subacute and subchronic "binge" cocaine administration significantly elevated plasma levels of adrenocorticotropin hormone (ACTH) and cortisol. However, the ACTH and cortisol increases were significantly blunted following 7 days of "binge" cocaine administration as compared to 2 days of drug treatment, reflecting the development of HPA tolerance or adaptation to repeated cocaine administration. Thus, the ppDyn mRNA and HPA responses to cocaine in guinea pigs are similar to those observed in rats.
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PMID:Elevation of guinea pig brain preprodynorphin mRNA expression and hypothalamic-pituitary-adrenal axis activity by "binge" pattern cocaine administration. 1142 39

The response to centrally administered beta-endorphin has been characterized by decreasing sympathetic nervous activity and decreased cardiovascular tone. We investigated the effect of the central administration of both mu and kappa opioid receptor agonist and antagonists on cardiovascular responses. The administration of the mu agonist, DAMGO (0.2nmol) increased the mean arterial pressure (MAP) and stimulated iliac vasoconstriction while higher doses (2 and 20nmol) decreased MAP and stimulated iliac vasodilation. The administration of the kappa receptor agonist, Dynorphin decreased the MAP and stimulated superior mesenteric vasodilation. beta-Funaltrexamine reduced MAP and superior mesenteric vasodilation while nor-binaltorphimine increased MAP and iliac and superior mesenteric vasoconstriction. We conclude that mu receptor activation decrease or increase MAP depending on the mu agonist concentration. However, kappa receptor activation is consistently associated with a decrease in MAP.
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PMID:Cardiovascular responses to central administration of mu and kappa opioid receptor agonist and antagonist in normal rats. 1289 62

The intracerebroventricular (i.c.v.) infusion of beta-endorphin can cause either a decrease in blood pressure in normal rats or an increase in obese rats. Diet-induced obesity is associated with an increase of hypothalamic mu opioid receptors. Since beta-endorphins act by opioid receptors, we investigated the effect of CNS mu as well as kappa opioid receptor agonist and antagonist on mean blood pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) in male Wistar rats fed either a high fat (HF) (40% fat by weight) or a regular low fat (control) (4% fat by weight) diet. After a 12-week-feeding period the animals were implanted with i.c.v. cannulas and 3-5 days later they were anesthetized and instrumented to record MAP, HR and RSNA. HF rats have higher MAP and the i.c.v. injection of a mu opioid agonist (DAMGO) initially decreased the MAP and then increased MAP, HR and RSNA in the normal animals. The increase was greater in HF animals. The i.c.v. injection of the mu antagonist (beta-FNA) resulted in a significantly greater decrease in MAP in HF animals. beta-FNA increased the RSNA in the HF rats but decreased it in the normal rats. The kappa agonist (dynorphin) decreased MAP in normal rats followed by a return to baseline, but not in HF rats. The kappa antagonist, nor-binaltorphimine (N-BP), increased MAP and RSNA in normal rats and to a lesser extent in HF rats. These findings suggest that rats given a high fat diet have higher blood pressures and a greater mu opioid-mediated responsiveness with a greater mu opioid-mediated autonomic tone. Additionally there is a decreased kappa responsiveness and tone in the HF rats. Both these changes, increased mu and decreased kappa responsiveness could strongly contribute to the increased blood pressure in obese animals.
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PMID:The effect of CNS opioid on autonomic nervous and cardiovascular responses in diet-induced obese rats. 1500 58

The present studies were undertaken to examine the influence of mu (beta-endorphin, DAMGO, FK 33-824), delta (met-enkephalin, leu-enkephalin, DPLPE) and kappa opioid receptor agonists (dynorphin A, dynorphin B, U 50488) used at different doses (1-1000 nM) alone and in combination with LH (100 ng/ml) on steroidogenesis in porcine granulosa cells derived from large follicles. The effects of mu, delta and kappa receptor agonists on both basal and LH-induced progesterone (P4) secretion were negligible. Agonists of mu opioid receptors reduced basal androstenedione (A4), testosterone (T) and oestradiol (E2) release. Co-treatment with LH entirely abolished the inhibitory effect of these agonists on A4 and E2 secretion and resulted in an increase in T release. The addition of delta receptor agonists was followed by a decrease in basal A4, T and E2 secretion. The cells incubated in the presence of LH increased the androgen production and abrogated the inhibitory effect of delta agonists on E2 output. Basal A4, T and E2 release was also suppressed by kappa receptor agonists. The presence of LH in culture media extended the inhibitory effect of these opioids on E2 output and caused either abolition of the inhibitory influence of kappa agonists or even augmentation of both androgen release in response to the opioids. In conclusion, these data support the involvement of three major types of opioid receptors in the regulation of porcine granulosa cell steroidogenesis.
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PMID:The influence of opioid peptides on steroidogenesis in porcine granulosa cells. 1512 17

Here we report the new drug design and synthesis of a series of 6,14-endoethenomorphinan-7-carboxamide derivatives as a putative epsilon opioid receptor agonist. One of these compounds, 17-(cyclopropylmethyl)-4,5alpha-epoxy-3,6beta-dihydroxy-6,14-endoethenomorphinan-7alpha-(N-methyl-N-phenethyl)carboxamide (TAN-821), showed agonistic activity for a putative epsilon opioid receptor (IC(50) = 71.71nM) in the rat vas deferens (RVD) preparations. TAN-821 stimulated the binding of the nonhydrolyzable guanosine 5'-triphosphate analog, guanosine 5'-(gamma-thio)-triphosphate (GTPgammaS), to the mouse pons/medulla membrane via the activation of putative epsilon opioid receptor. Moreover, TAN-821 given intracerebroventricularly (i.c.v.) produced a marked antinociception in the tail-flick test (ED(50) = 1.73 microg) and the hot-plate test (ED(50) = 2.05 microg) in a dose-dependent manner. The antinociception induced by TAN-821 administered i.c.v. was blocked by the i.c.v.-pretreatment with a putative epsilon opioid receptor partial agonist beta-endorphin [1-27], but not a mu opioid receptor antagonist beta-FNA, a delta opioid receptor antagonist NTI, or a kappa opioid receptor antagonist nor-BNI. The present results suggest that TAN-821 may be a useful tool for the investigation on the pharmacological properties of the putative epsilon opioid receptor.
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PMID:Drug design and synthesis of epsilon opioid receptor agonist: 17-(cyclopropylmethyl)-4,5alpha-epoxy-3,6beta-dihydroxy-6,14-endoethenomorphinan-7alpha-(N-methyl-N-phenethyl)carboxamide (TAN-821) inducing antinociception mediated by putative epsilon opioid receptor. 1524 90

The aversive response to naloxone administration observed in human and animal studies suggests the presence of an endogenous opioid tone regulating hedonic state but the class(es) of opioid peptides mediating such opioid hedonic tone is uncertain. We sought to address this question using mice deficient in either beta-endorphin or pro-enkephalin in a naloxone-conditioned place aversion paradigm. Mice received saline in the morning in one chamber and either saline or naloxone (0.1, 1 or 10 mg/kg, s.c.) in the afternoon in another chamber, each day for 3 days. On the test day they were given free access to the testing chambers in the afternoon and the time spent in each chamber was recorded. Whereas wild-type and beta-endorphin-deficient mice exhibited a robust conditioned place aversion to naloxone, pro-enkephalin knockout mice failed to show aversion to naloxone at any dose tested. In contrast, these mice showed a normal conditioned aversion to the kappa opioid receptor agonist, U50,488 (5 mg/kg), and to LiCl (100 mg/kg) indicating that these mice are capable of associative learning. In a separate experiment, pro-enkephalin knockout mice, similar to wild-type and beta-endorphin-deficient mice, demonstrated a significant conditioned place preference to morphine (2.5, 5 and 10 mg/kg s.c.). These data suggest that enkephalins, but not endorphins, may mediate an endogenous opioid component of basal affective state and also indicate that release of neither endogenous enkephalins nor endorphins is critical for the acquisition or expression of the association between contextual cues and the rewarding effect of exogenously administered opiates.
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PMID:Endogenous enkephalins, not endorphins, modulate basal hedonic state in mice. 1581 47

Glycyl-glutamine (Gly-Gln) is an inhibitory dipeptide synthesized from beta-endorphin(1-31). Previously, we showed that Gly-Gln inhibits morphine conditioned place preference, tolerance, dependence and withdrawal. In this study, we tested whether Gly-Gln's inhibitory activity extends to other rewarding drugs, specifically nicotine. Rats were conditioned with nicotine (0.6 mg/kg, s.c.) for four days and tested on day five. Glycyl-glutamine (100 nmol i.c.v.) inhibited acquisition and expression of a nicotine place preference significantly. Cyclo(Gly-Gln) (100 nmol i.c.v. or 25 mg/kg i.p.), a cyclic Gly-Gln derivative, blocked expression of nicotine place preference but Gly-d-Gln (100 nmol i.c.v.) was ineffective. To study nicotine withdrawal, rats were treated with nicotine (9 mg/kg/day) for seven days and conditioned place aversion was induced with mecamylamine (1 mg/kg, s.c.). Glycyl-glutamine blocked acquisition of place aversion to mecamylamine but not U50,488, a kappa opioid receptor agonist. Glycyl-glutamine thus inhibits the rewarding effects of nicotine and attenuates withdrawal in nicotine dependent rats.
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PMID:Glycyl-glutamine inhibits nicotine conditioned place preference and withdrawal. 1636 88

Beta-endorphin (beta-EP) is generally classified as a mu and delta opioid receptor agonist but is also an agonist of the epsilon opioid receptor. Although several selective agonists and antagonists for mu, delta, and kappa opioid receptors are known, selective epsilon receptor agonists or antagonists have not been reported for some time. Recently, we designed and synthesized the selective epsilon receptor agonist, 17-(cyclopropylmethyl)-4,5alpha-epoxy-3,6beta-dihydroxy-6,14-endoethenomorphinan-7alpha-[N-methyl-N-phenethyl]carboxamide (TAN-821), and the selective epsilon receptor antagonist, 17-(cyclopropylmethyl)-4,5alpha-epoxy-6beta,21-epoxymethano-3-hydroxy-6,14-endoe-thenomorphinan-7alpha-(N-phenethyl)carboxamide (TAN-1014). TAN-821 stimulated binding of the non-hydrolyzable guanosine 5'-triphosphate analogue, guanosine 5'-(gamma-thio)-triphosphate (GTPgammaS), to the mouse pons/medulla membrane via activation of the epsilon receptor. Moreover, TAN-821 given intracerebroventricularly (i.c.v.) produced marked, long-lasting, and dose-dependent antinociception in tail-flick and hot-plate tests. This antinociception induced by i.c.v. administered TAN-821 was blocked by i.c.v. pretreatment with the epsilon opioid receptor partial agonist beta-EP (1-27), but not the mu opioid receptor antagonist beta-FNA, the delta opioid receptor antagonist NTI, or the kappa opioid receptor antagonist nor-BNI. On the other hand, i.c.v. injection of TAN-1014 alone produced no antinociception, and i.c.v. pretreatment with TAN-1014 attenuated the antinociception induced by i.c.v beta-EP. These results suggest that TAN-821 and TAN-1014 are respectively a selective epsilon receptor agonist and antagonist and that they may be useful tools for investigating the pharmacological properties of the epsilon opioid receptor.
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PMID:Rational drug design of selective epsilon opioid receptor agonist TAN-821 and antagonist TAN-1014. 1671 73


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