Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peptide E is a mu-selective opioid peptide derived from proenkephalin A which contains [Met5]-enkephalin at the amino end and [Leu5]-enkephalin at the carboxyl end. Peptide E is further processed both centrally and peripherally to a [Leu5]-enkephalin-containing fragment which was investigated to determine if processing leads to alterations in receptor selectivity. Peptide E-(15-25) inhibited electrically stimulated contractions in both the mouse vas deferens, longitudinal muscle, myenteric (IC50 = 459 nmol/L), and guinea pig ileum (IC50 = 2630 nmol/L), indicating a sixfold delta-receptor selectivity. When administered intracerebroventricularly to mice, peptide E-(15-25) also produced potent analgesia which was completely antagonized by naloxone pretreatment, but the peptide had no effect on intestinal transit as measured by the radiochromium geometric center method. This is consistent with earlier findings that intracerebroventricular delta-opioid-selective agents are analgesic but do not inhibit intestinal transit. In vitro radioligand binding assays were performed using male Sprague-Dawley rat whole brain homogenates. The IC50 for peptide E against [3H]naloxone was 1.8 nmol/L compared with the delta-opioid ligand, [3H] [D-Pen2, D-Pen5]-enkephalin of 38.8 nmol/L. The IC50 for peptide E-(15-25) against [3H]naloxone was 497 nmol/L, but for [3H] [D-Pen2, D-Pen5]-enkephalin it was 50.6 nmol/L. Therefore, peptide E loses mu-opioid receptor affinity (1.8-497 nmol/L) after proteolytic processing and the loss of the amino terminal tyrosine but maintains a high delta-opioid affinity (38.8-50.6 nmol/L). These studies demonstrate that enzymatic peptide processing of peptide E to peptide E-(15-25) leads to a shift from mu- to delta-receptor selectivity and a different spectrum of biological effects on gut motility.
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PMID:Changes in opioid receptor selectivity following processing of peptide E: effect on gut motility. 185 Mar 73

We studied behavioral effects of the intraventricularly and intrathecally administered guanidinoethylmercaptosuccinic acid (GEMSA) - a potent inhibitor of enkephalin convertase. When given intraventricularly in doses of 3 and 6 micrograms, GEMSA elicited analgesia; after doses of 12.5 and 25 micrograms the explosive motor behavior and convulsions occurred. Following the intrathecal administration of GEMSA (12.5, 25 and 50 micrograms), an increase in the tail-flick latency was observed; moreover that drug potentiated analgesic effects of the intrathecally applied Met5-enkephalin-Arg6-Phe7 and Met5-enkephalin-Arg6-Gly7-Leu8. All the above effects of GEMSA were significantly attenuated by naloxone. The rats subjected to chronic pain showed a weaker analgesic response to the intrathecally injected GEMSA. The 3H-GEMSA binding to enkephalin convertase in the spinal cord of these rats produced only a slight increase in KD; besides, no changes in the enzyme activity were observed. The study shows that GEMSA has a potent pharmacological action in the central nervous system. Furthermore, this effect is partly due to the influence of GEMSA on endogenous opioid peptide systems, possibly on proenkephalin A.
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PMID:Analgesic and convulsant effects of guanidinoethylmercaptosuccinic acid (GEMSA)--a potent enkephalin convertase inhibitor. 310 92

The distribution of methionine-enkephalin-Arg6-Gly7-Leu8, a unique peptide derived from proenkephalin A in the rat brainstem, was studied immunocytochemically by using a highly specific antiserum to this octapeptide sequence. Immunoreactive perikarya with various shapes and sizes were detected in many regions of the rat brainstem. Dense accumulation of immunoreactive perikarya and fibers was seen in the nuclei associated with special sensory and visceral functions, such as the interpeduncular nucleus, the parabrachial nucleus, the nucleus of the solitary tract, and the nucleus of the spinal tract of the trigeminal nerve. Clusters of methionine-enkephalin-Arg6-Gly7-Leu8-like immunoreactive perikarya and fibers were observed in certain areas considered to play a role in nociception and analgesia, such as the central gray of the midbrain central gray and the raphe magnus nucleus. Some methionine-enkephalin-Arg6-Gly7-Leu8-like immunoreactive perikarya were distributed in the lateral reticular nucleus, the nucleus of the solitary tract, and the raphe magnus nucleus, where monoaminergic neurons were also detected. In addition to the previously reported enkephalinergic cells, we found many methionine-enkephalin-Arg6-Gly7-Leu8 containing neurons; the rostral and caudal linear nucleus of raphe, the median raphe nucleus, entire length of the raphe magnus nucleus, the medial longitudinal fasciculus, the cuneate nucleus, the external cuneate nucleus, the gracile nucleus, and the area postrema. The wide distribution of this octapeptide-like immunoreactivity reflected neurons expressing the preproenkephalin A gene distributed more widely than previously reported and that innervated many regions.
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PMID:Immunocytochemical distribution of met-enkephalin-Arg6-Gly7-Leu8 in the rat lower brainstem. 330 99

BAM-18, a proenkephalin A-derived opioid peptide, is widely distributed throughout rat CNS and displays high affinity for both mu and kappa opioid receptors. In the present study, BAM-18 was tested in two analgesia paradigms, tail-flick and hot-plate. Injections were centrally administered through a chronically implanted unilateral cannula in the lateral ventricle. In the tail-flick, low doses of BAM-18 (5 micrograms) produced a hyperalgesia while high doses of BAM-18 (50 micrograms) produced an analgesic response. Naloxone (10 mg/kg, s.c.) reversed the BAM-18-induced analgesia and unmasked a persistent hyperalgesia. Morphine-induced (1 microgram) analgesia was completely reversed by 5 micrograms BAM-18. In the hot-plate test, high doses of BAM-18 produced analgesia, with no hyperalgesia observed at any dose. Naloxone reversed the BAM-18-induced analgesia. The locomotor effects of BAM-18 did not differ from those of morphine except in effective dose (50 micrograms vs. 5 micrograms, respectively). Opioid and non-opioid effects of BAM-18 are discussed and compared with other endogenous peptides.
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PMID:BAM-18: analgesia, hyperalgesia and locomotor effects. 341 57

To determine whether opioid peptide-receptor pharmacological association found in vitro (e.g., enkephalin-delta, dynorphin-kappa) predict anatomical relationships in situ, immunocytochemical and receptor autoradiographic studies were carried out on adjacent sections from the same brains of formaldehyde-perfused rhesus monkeys. Apparent mu and kappa opioid receptors (labeled, respectively, by [3H] naloxone and [3H]bremazocine under different incubation conditions), but not delta opioid receptors (labeled by [3H]D-Ala2, D-Leu5-enkephalin), survived the fixation procedure, and were found to be colocalized throughout the brain. We have observed complex associations between these binding sites and one, two, or all three opioid peptide systems (i.e., proopiomelanocortin, proenkephalin, and prodynorphin) in different brain regions. These multiple opioid peptide-receptor subtype associations are apparent, for example, in neural systems involved in the processing of pain stimuli, and may be important for mediating different types of analgesia. Since differential processing of proenkephalin and prodynorphin can give rise to opioids of varying receptor selectivities, the colocalization of opioid receptor subtypes may signify that such processing is a key regulatory event in determining which receptor subtype is activated and, thus, the physiological consequences of opioid neurotransmission.
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PMID:Anatomical relationship between opioid peptides and receptors in rhesus monkey brain. 615 4

Using antibodies against the synthetic opioid peptides BAM-22P and peptide F, immunoreactive (ir-) peptides were measured in bovine brain and adrenal medulla. In addition to the high levels in the adrenal medulla, both ir- peptides were measurable in various areas of the brain with highest concentrations in the anterior hypothalamus. Analysis of the ir- components by gel filtration revealed molecular heterogeneity. Besides peptides with the size of BAM-22P or peptide F, various higher molecular weight species were found. These forms were found in the adrenal medulla in much higher concentrations than in the brain indicating a different processing mechanism for proenkephalin. Synthetic BAM-22P injected intracerebroventricularly into mice produces a substantial analgesia (ED50 6.4 nmole) which is almost as high as that of morphine (ED50 2.8 nmole). This finding and the presence of BAM-22P-like compounds in the brain suggests a role of the enkephalinergic system in pain transmission.
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PMID:Pro-enkephalin intermediates in bovine brain and adrenal medulla: characterization of immunoreactive peptides related to BAM-22P and peptide F. 715 41

A large number of neurotransmitters and neuropeptides are concentrated in the dorsal horn of the spinal cord, where they interact in a complex manner and modulate sensory mechanisms. Most studies are carried out in the rat, and little is known of other species. It is relevant to study mammals with a more complex central nervous system, because pain mechanisms are central in both human and veterinary medicine. Immunoreactivity for neuropeptide FF, an amidated octapeptide originally isolated from bovine brain, was found immunocytochemically at all levels of porcine spinal cord. In contrast to other species studied so far, the peptide immunoreactivity in porcine spinal cord was confined to the intermediolateral gray matter, especially to the intermediolateral cell column and lamina X of the gray matter. This distribution was remarkably different from that of substance P, proenkephalin A-derived peptides, thyrotropin-releasing hormone, serotonin, and neuropeptide Y. Pharmacologic administration of neuropeptide FF alters behavior in assays for analgesia. The distribution of neuropeptide FF immunoreactivity as revealed by this study suggests that there may be marked species differences in the distribution and function of the peptide.
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PMID:Distribution of neuropeptide FF in porcine spinal cord in comparison with other neuropeptides and serotonin. 752 61

Valproic acid (VPA) induces abstinence behavior and analgesia and displays an anticonvulsant effect, but its exact mechanism of action is not yet clear. In order to view whether proenkephalin derived-peptides are involved in the mechanism of VPA-induced behavior, we analyzed immunoreactive-met-enkephalin (IR-ME) in rat striatum, midbrain, and amygdala 10, 20, and 45 min after i.p. injection of 200 mg/kg of VPA. VPA induced body shakes that peaked within 5 to 10 min. IR-ME increased in the striatum and decreased in the midbrain at 10, 20, and 45 min, reaching the highest and lowest levels at 10 and 20 min, respectively. No changes occurred in the amygdala. Gel filtration chromatography followed by HPLC of striatum extracts showed that the increased IR-ME levels corresponded to low molecular weight peptides, including ME. These results indicate that VPA produced rapid changes of IR-ME levels in rat brain and suggest peptide participation in the mechanisms of VPA-induced behavior. The anticonvulsant effect of VPA was tested in rats treated with pentylenetetrazol (70 mg/kg) 30 min after VPA (400 mg/kg) administration, and IR-ME was analyzed in striatum 15 min later. No changes in striatal IR-ME levels occurred in protected rats (no behavioral convulsions), compared with those treated only with VPA, but a significant decrease appeared in unprotected animals (clonic convulsions). These results suggest that striatal ME may participate in the mechanism of VPA-induced abstinence behavior and in the anticonvulsant effect. Otherwise, midbrain ME might be involved in other VPA behaviors such as analgesia.
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PMID:Valproic acid-induced rapid changes of met-enkephalin levels in rat brain. Probable association with abstinence behavior and anticonvulsant activity. 781 91

The role of the opioid receptor-endogenous opioid peptide system in mediating analgesia induced by nitrous oxide has been a controversial subject. Most previous studies provided only indirect evidence either to support or refute the involvement of opioid receptors and/or endogenous opioid peptides. To provide more direct evidence, we measured concentrations of five naturally occurring endogenous opioid peptides in third ventricular cerebrospinal fluid from eight acclimated dogs with chronically implanted ventricular catheters. Paired samples of cerebrospinal fluid were obtained from each animal when breathing room air or 66-75 vol% nitrous oxide in oxygen through a face mask. Endogenous opioid peptides were physically separated using reversed phase high-performance liquid chromatography and quantified using radioimmunoassays. Nitrous oxide inhalation increased cerebrospinal fluid concentrations of met5-enkephalin from a control value of 0.30 +/- 0.07 (mean +/- SEM, n = 8) to 42.4 +/- 8.1 pmol/mL (P = 0.0006). Increases ranged from 28 to more than 400 times the control value. Met5-enkephalin-arg6-phe7 concentrations also increased from 14.5 +/- 2.5 to 57.6 +/- 17.8 pmol/mL (P = 0.018). No significant changes were noted in concentrations of dynorphin A, dynorphin B, or beta-endorphin. These results directly support the hypothesis that nitrous-oxide-induced analgesia involves the proenkephalin-derived family of endogenous opioid peptides.
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PMID:Nitrous oxide selectively releases Met5-enkephalin and Met5-enkephalin-Arg6-Phe7 into canine third ventricular cerebrospinal fluid. 789 15

The opioid peptide system in the brain is probably the most extensive and diverse peptidergic transmission system. Three peptide precursors, pro-opiomelanocortin, proenkephalin and prodynorphin produce over 20 opioid peptides collectively known as the endorphins, enkephalins and dynorphins. Their effects are mediated by three receptors mu, delta and kappa, and the opioid system has control over several physiological functions including pain, locomotion, mood, diuresis, thermoregulation, stress, respiratory, gastrointestinal and cardiovascular function. Lead treatment (primarily using rat models) has shown that exposure to this metal in the perinatal period alters the development of endorphins and enkephalins, toxic effects which for the pro-opiomelanocortin products may be manifested at the gene level. Lead also alters the development of mu and delta receptors and biological responses to opioids such as analgesia, locomotion and stress responses. There are indications that the dynorphin/kappa opioid system is less affected than the mu and delta systems and this may suggest vulnerability to toxicity in the postnatal period as kappa systems are fully developed at birth whilst mu and delta systems are immature. In addition, hypothalamic and pituitary disruption of opioid peptides, plus alteration of stress-mediated activity by lead point to toxicity upon opioid controlled hormonal function. Comparative studies with other CNS neurochemicals and measures of blood lead levels suggest that opioid peptides are among the most sensitive neurotransmitter/neurohormonal systems to toxic insult by lead.
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PMID:Lead toxicity and alterations in opioid systems. 824 86


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