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At least 19 recordsLinked to original sources
PubMed1986

Conversion of leumorphin (dynorphin B-29) to dynorphin B and dynorphin B-14 by thiol protease activity.

Dynorphin B (rimorphin) is formed from leumorphin (dynorphin B-29) by the action of a thiol protease from rat brain membranes, in a single step. This represents a "single-arginine cleavage" between threonine-13 and arginine-14 of the substrate. We have observed that in addition to dynorphin B, dynorphin B-14 is formed from dynorphin B-29. Among the various protease inhibitors tested, none except p-chloromercuribenzensulfonic acid inhibited the formation of the two products. Both temperature and pH had similar effects on the formation of dynorphin B-14 and dynorphin B. The inhibitory potencies of adrenocorticotropic hormone, peptide E, and dynorphin A were virtually identical for the formation of the two products. These results suggest that the same enzyme may be responsible for the formation of dynorphin B-14 and dynorphin B.

Adrenocorticotropic Hormone↗
PubMed1991

Dynorphins other than dynorphin A(1-17) lack spinal antianalgesic activity but do act on dynorphin A(1-17) receptors.

In recent publications we have proposed that dynorphin (Dyn) A(1-17) functions as an antianalgesic modulator to oppose opioid-induced antinociception in mice. In the present experiments using the tail-flick response in mice, other Dyns [Dyn A(1-8), Dyn A(1-13), Dyn A(2-17), Dyn B and alpha- and beta-neoendorphin] when administered intrathecally (i.t.) were shown not to have antianalgesic activity even at high doses (0.5-1 pmol). These Dyns, i.t., did not antagonize the antinociception produced by physostigmine administered i.c.v. or morphine given i.t. These Dyns lacked the intrinsic antianalgesic activity of Dyn A(1-17). However, they had affinity for Dyn A(1-17) receptors as shown in several ways. 1) The antagonism of physostigmine antinociception produced by Dyn A(1-17) given i.t. was reversed by these Dyns given together with Dyn A(1-17). 2) The effect of endogenously released Dyn A(1-17) was reversed. Administered i.c.v., clonidine simultaneously activates antinociceptive and antianalgesic systems [latter mediated spinally by Dyn A(1-17) release]. Thus, these Dyns given i.t. inhibited the action of endogenously released Dyn A(1-17) and allowed the full manifestation of the antinociceptive action of clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Neuropeptide processing by single-step cleavage: conversion of leumorphin (dynorphin B-29) to dynorphin B.

Dynorphin B (rimorphin) is formed from dynorphin B-29 (leumorphin) by the action of a thiol protease from rat brain membranes. This represents a "single-arginine cleavage" between threonine-13 and arginine-14 of the substrate. In isotope dilution experiments we find that the radioactivity from radiolabelled dynorphin B-29, which appears in dynorphin B during incubation with the enzyme preparation, is not diminished by addition of a high concentration of dynorphin B-Arg14. Moreover, in pulse-chase experiments, radioactivity that appeared in dynorphin B-Arg14 did not decrease, nor did the radioactivity in dynorphin B increase, after chasing with a high concentration of non-radioactive dynorphin B-29. These results indicate that although some dynorphin B-Arg14 is formed by the impure enzyme preparation, it is not an intermediate in the conversion of dynorphin B-29 to dynorphin B. Thus the formation of dynorphin B does not involve the action of a trypsin-like enzyme followed by removal of arginine-14 by a carboxypeptidase B-like enzyme. It appears that a single enzyme converts dynorphin B-29 to dynorphin B in a single step.

Animals↗
PubMed1990

Rostral and caudal ventricular infusion of antibodies to dynorphin A(1-17) and dynorphin A(1-8): effects on electrically-elicited feeding in the rat.

Lateral ventricular injection of antibodies to dynorphin A(1-13) was previously shown to elevate lateral hypothalamic stimulation frequency threshold for eliciting feeding behavior. The antibodies utilized in that study cross-react completely with dynorphin A(1-17) and, to a lesser extent, dynorphin A(1-8). In the present study, highly specific antibodies to dynorphin A(1-17) and dynorphin A(1-8) were infused into the lateral ventricle and mesopontine aqueduct to determine which biologically active dynorphin A fragment mediates feeding and at what level of the CNS this activity is likely to occur. Both antibodies were found to elevate the feeding threshold. Dynorphin A(1-8) antibodies were effective at both injection sites while dynorphin A(1-17) antibodies were only effective at the lateral ventricular site. These findings suggest that feeding-related dynorphin A(1-17) activity may occur predominantly within the forebrain, while dynorphin A(1-8) activity occurs within the brainstem. Only the dynorphin A(1-8) antibodies, infused into the aqueduct, produced a naloxone-like pattern of progressive elevation in serially determined thresholds; this pattern was previously interpreted to reflect a reduction in consummatory reward. Dynorphin A(1-8) activity within some brainstem structure(s) may therefore contribute prominently to the opioid mechanism whose mediation of the hedonic response to food was previously inferred from naloxone antagonism.

Animals↗
PubMed1985

Kappa-binding and degradation of [3H]dynorphin A (1-8) and [3H]dynorphin A (1-9) in suspensions of guinea pig brain membranes.

Following incubation of [3H]dynorphin A (1-8) and [3H]dynorphin A (1-9) with suspensions of guinea pig brain membranes, analysis of the supernatants by HPLC has shown that both peptides are degraded at 25 degrees C and at 0 degrees C. Bestatin and captopril reduce degradation at 0 degrees C but for a similar degree of protection at 25 degrees C arginine-containing dipeptides are also required. The effects of these peptidase inhibitors on the degradation profiles indicate that [3H]dynorphin A (1-8) has three main sites of cleavage: the Tyr1-Gly2, Arg6-Arg7, and Leu5-Arg6 bonds. With [3H]dynorphin A (1-9) as substrate the Arg7-Ile8 and Ile8-Arg9 bonds are also liable to cleavage. In binding assays, in contrast to the effects of peptidase inhibitors on the degradation of unbound [3H]dynorphin A (1-8) and [3H]dynorphin A (1-9), bestatin and captopril have little effect on the binding characteristics of the tritiated dynorphin A fragments at the kappa-site at 0 degrees C. However, at 25 degrees C binding is low in the absence of peptidase inhibitors. When binding at mu- and delta-sites is prevented, the maximal binding capacities of [3H]dynorphin A (1-8), [3H]dynorphin A (1-9), and [3H](-)-bremazocine at the kappa-site are similar; [3H]dynorphin A (1-9) has 5-10 times higher affinity for the kappa-site than [3H]dynorphin A (1-8). Comparison of the effects of peptidase inhibitors on unbound dynorphin A fragments with their effects in binding assays suggests that the bound peptides are protected from the action of peptidases.

Animals↗
PubMed1989

Prodynorphin peptide distribution in the forebrain of the Syrian hamster and rat: a comparative study with antisera against dynorphin A, dynorphin B, and the C-terminus of the prodynorphin precursor molecule.

The neuroanatomical distribution of the prodynorphin precursor molecule in the forebrain of the male Syrian hamster (Mesocricetus auratus) has been studied with a novel antiserum directed against the C-terminus of the leumorphin [dynorphin B (1-29)] peptide product. C-peptide staining in sections from colchicine-treated hamsters is compared to staining in sections from untreated animals. In addition, the pattern of C-peptide immunostaining in hamster brain is compared to that in the rat brain. Finally, the C-peptide immunolabeling patterns in hamsters and rats are compared to those obtained with antisera to dynorphin A (1-17) and dynorphin B (1-13). Areas of heaviest prodynorphin immunoreactivity in the hamster include the hippocampal formation, lateral septum, bed nucleus of the stria terminalis, medial preoptic area, medial and central amygdaloid nuclei, ventral pallidum, substantia nigra, and numerous hypothalamic nuclei. Although this C-peptide staining pattern is similar to dynorphin staining reported previously in the rat, several species differences are apparent. Whereas moderate dentate gyrus granule cell staining and no CA4 cell staining have been reported in the rat hippocampal formation, intense immunostaining in the dentate gyrus and CA4 cell labeling are observed in the hamster. In addition, the medial preoptic area, bed nucleus of the stria terminalis, and medial nucleus of the amygdala stain lightly for prodynorphin-containing fibers and cells in the rat, compared to heavy cell and fiber staining in the hamster in all three of these regions. In the rat there is no differential staining between tissues processed with the C-peptide, dynorphin A, and dynorphin B antisera, but numerous areas of the hamster brain show striking differences. In most hamster brain areas containing prodynorphin peptides, the C-peptide antiserum immunolabels more cells and fibers than the dynorphin B antiserum, which in turn labels more cells and fibers than dynorphin A antiserum. However, exceptions to this hierarchy of staining intensity are found in the lateral hypothalamus, substantia nigra, arcuate nucleus, and habenula. The differences in staining patterns between rat and hamster are greatest when C-peptide antiserum is used; apparent species differences are present, though less pronounced, in dynorphin B- and dynorphin A-immunostained material.

Animals↗
PubMed1985

Colocalization of dynorphin-A(1-17) and dynorphin-A(1-8) within some perikarya of rat duodenum: immunohistochemical evidence for the presence of two separate dynorphinergic systems.

Adjacent serial sections through the rat duodenum were alternately stained for immunofluorescence microscopic studies with specific anti-sera directed to the opioid peptides dynorphin-A(1-17) and dynorphin-A(1-8), respectively. This resulted in the evidence that two separate dynorphinergic neuron populations are present there: intramural neurons, revealing a colocalization of dynorphin-A(1-17) and dynorphin-A(1-8), were round, contained a large and round nucleus and were lying sporadically in the longitudinal muscle layer as well as bulb-shaped neurons expressing only a dynorphin-A(1-8) immunoreactivity. The latter were recognized abundantly in the myenteric plexus. Myenteric plexus nerve fibres and terminals were immunoreactive for dynorphin-A(1-8), but not for dynorphin-A(1-17). Dynorphin-A(1-8) immunostained nerve terminals formed close contacts with large non-dynorphinergic myenteric plexus perikarya. These findings might indicate that dynorphin-A(1-8) is processed directly from its prodynorphin ('preproenkephalin B') precursor within myenteric plexus perikarya and indirectly via dynorphin-A(1-17) within intramural perikarya, indicating the presence of two separate dynorphinergic systems in the rat duodenum.

Animals↗
PubMed1989

Induction of the gene encoding pro-dynorphin by experimentally induced arthritis enhances staining for dynorphin in the spinal cord of rats.

The response of dynorphinergic neurons in the lumbosacral spinal cord of the rat to chronic arthritic inflammation was studied by the combined use of biochemical and immunohistochemical procedures. In polyarthritic rats, in which all four limbs showed a swelling, inflammation and hyperalgesia, a pronounced elevation was seen in the level of messenger ribonucleic acid encoding prodynorphin (pro-enkephalin B) in the lumbosacral spinal cord. In addition, the levels of immunoreactive dynorphin A1-17, a primary gene product of this precursor, were greatly increased. This activation was reflected in a striking intensification of the immunohistochemical staining of both dynorphin and alpha/beta-neo-endorphin, a further major product of pro-dynorphin. In control animals perikarya were stained exceedingly rarely and encountered only in laminae I and II. Stained fibres and varicosities were seen throughout the dorsal and ventral gray matter, being most concentrated in laminae I, II, IV and V of the dorsal horn and dorsolateral to the central canal. In polyarthritic rats, fibres and varicosities were much more intensely stained throughout the cord, particularly in laminae I/II, IV and V and dorsolateral to the central canal. Many strongly-stained perikarya could be seen: these comprised many small diameter cells in laminae I and II, and some large diameter marginal neurons and large diameter cells, heterogenous in appearance, in the deeper laminae IV and V. Monolaterally inflamed rats injected in the right hind-paw showed pathological changes only in this limb. Correspondingly, in unilateral inflammation, an elevation in immunoreactive dynorphin was seen exclusively in the right dorsal horn and the above-described intensification of staining for dynorphin and neo-endorphin was seen only in this quadrant. This reveals the neuroanatomical specificity of the response. Thus, in the lumbosacral cord of the rat, pro-dynorphin neurons are most preponderant in laminae I, II, IV and V. A pronounced intensification of the immunohistochemical staining of these neurons is seen in chronic arthritis. Furthermore, there is a parallel elevation in the levels of messenger ribonucleic acid encoding pro-dynorphin and of its primary products dynorphin and neo-endorphin. These findings demonstrate an enhancement in the functional activity of spinal cord localized dynorphin neurons in the response to chronic arthritic inflammation.

Animals↗
PubMed1986

Degradation of dynorphin-(1-13) and dynorphin-(1-17) by the neuroblastoma cell membrane. Evidence for the involvement of a cysteine protease.

The membrane of mouse neuroblastoma N-18 cells degraded dynorphin-(1-13), dynorphin-(1-17), and Leu-enkephalin. The degradation of the former two peptides was inhibited strongly by N-ethylmaleimide, moderately by diisopropylphosphorofluoridate and phosphoramidon, and slightly by bestatin. When Leu-enkephalin was the substrate, however, the effects of phosphoramidon and bestatin were marked and those of N-ethylmaleimide and diisopropylphosphorofluoridate were negligibly small. Captopril did not affect the degradation of the two dynorphins and Leu-enkephalin, but inhibited the further cleavage of N-terminal fragments generated from dynorphin-(1-13) by the N-ethylmaleimide-sensitive protease. Thus, a cysteine protease and, probably, a serine protease are responsible to the initial fragmentation of the dynorphins.

Amino Acids↗
PubMedDate not supplied

[D-Ala2, (F5) Phe4]-dynorphin 1-13-NH2 (DAFPHEDYN): a potent analog of dynorphin 1-13.

Intracerebroventricular administration of the dynorphin analog, [D-Ala2,(F5)Phe4]-dynorphin 1-13-NH2 (DAFPHEDYN) in rats produced diuresis and profound analgesia. Both effects were antagonized by central administration of naltrexone or naloxone. Intravenous administration of 10, 25, and 50 mg/kg of DAFPHEDYN failed to induce diuresis. The increased potency of DAFPHEDYN was apparent from the failure of an equal dose of the parent compound (dynorphin 1-13) to produce diuresis and the failure of [D-Ala2]-dynorphin 1-13-NH2 to produce analgesia. Radioligand binding studies indicated the DAFPHEDYN retains the same degree of kappa selectivity as the parent compound (dynorphin 1-13) though a drop in affinity occurred. DAFPHEDYN may be of significant interest because it retains the essential pharmacology of the parent compound and exhibits marked in vivo potency.

Analgesia↗
PubMed1988

[125I]dynorphin(1-8) produces a similar pattern of kappa-opioid receptor labelling to [3H]dynorphin(1-8) and [3H]etorphine in guinea pig brain: a quantitative autoradiographic study.

kappa-Opioid receptors were radiolabelled with the peptides [125I]dynorphin(1-8) and [3H]dynorphin(1-8) or with [3H]etorphine on guinea pig forebrain and cerebellar sections and visualized by quantitative autoradiography. All three radioligands yielded similar patterns of kappa-receptor localization. However, quantitative analysis showed that using saturating concentrations of the tritiated radioligands the apparent density of specific [3H]etorphine-labelled kappa-sites was 1.5-5.4 times greater than that achieved with [3H]dynorphin(-8). The apparent rank order of regional density of kappa-sites on a quantitative basis with all 3 radioligands was similar. A high density of kappa-receptors was found in the nucleus accumbens, striatum, globus pallidus, cerebral cortex (layers V-VI), hippocampal and cerebellar molecular layers, substantia nigra and substantia gelatinosa of the spinal cord. A lower density of these sites was associated with the thalamus, hypothalamus and the amygdaloid complex. Thus, in view of the advantages of using iodinated ligands in autoradiography this study has shown that [125I]dynorphin(1-8) is an acceptable ligand for labelling kappa-receptors in the brain.

Animals↗
PubMed1987

Intrathecal dynorphin A1-13 and dynorphin A3-13 reduce rat spinal cord blood flow by non-opioid mechanisms.

Radiolabeled microspheres were used to examine the effects of paralytic intrathecal doses of dynorphin A (Dyn A1-13) and Dyn A3-13 on rat brain and spinal cord blood flows and cardiac output. Dyn A1-13 produced significant dose-related reductions in blood flow to lumbosacral and thoracic spinal cord without altering cardiac output and blood flow to brain and cervical spinal cord. Naloxone failed to block these effects. Dyn A3-13, which lacks opioid activity, also significantly reduced blood flow in lumbosacral spinal cord. Thus, the paralytic effects of Dyn A in the rat may involve reductions in spinal cord resulting from non-opioid actions of Dyn A.

Animals↗
PubMed1992

Dynorphin A-(1-17) and dynorphin B are released from in vitro superfused rat hypothalami. Effects of depolarizing agents and ovariectomy.

We measured the release of immunoreactive (ir) dynorphin (dyn) A-(1-17) and dyn B from the rat hypothalamus by an in vitro superfusion technique. The system was validated on the basis of the recovery and stability of radiolabeled peptides added to the superfused hypothalami. These were detected as authentic peptides by reverse-phase high-performance liquid chromatography (rp-HPLC) only in the presence of a cocktail of peptidase inhibitors added to the superfusion medium. We observed spontaneous release of ir-dyn B, evaluated by a validated radioimmunoassay in the superfusates, that was increased by potassium and veratridine depolarization. It was calcium-dependent and tetrodotoxin-sensitive. We could not evaluate ir-dyn A-(1-17) directly in the superfusates, because the peptidase inhibitors added to the medium significantly altered the tracer-antibody reaction. To obviate this problem, pooled superfusate samples were purified on C18 cartridges and assayed by rp-HPLC. Rp-HPLC analysis of superfusates revealed two molecular forms with the same retention time as authentic dyn A-(1-17) and dyn B which were four times higher in K(+)-stimulated fractions. We could not detect dyn A-(1-32), comprising dyn A-(1-17) and dyn B, even though this peptide is recognized by the antibodies used in this study and is detected in acetic acid extracts of the rat hypothalamus. The spontaneous and K(+)-evoked release of ir-dyn A-(1-17) and ir-dyn B were significantly higher in 2-week ovariectomized rats, in parallel with the increase of their content in the anterior hypothalamus preoptic area.

Animals↗
PubMed1989

Spinal dynorphin involvement in the analgesia of pregnancy: effects of intrathecal dynorphin antisera.

In both rats and humans there is an analgesia associated with pregnancy. This analgesia is spinally mediated and involves the kappa type of opiate receptor. The current study demonstrates that intrathecal administration of high affinity dynorphin antibodies produces a significant reduction in jump thresholds during pregnancy (day 20). The administration of pre-adsorbed antisera fails to produce this effect. These results support the hypothesis that a spinal dynorphin/kappa opiate receptor system is activated during gestation.

Analgesia↗
PubMed1992

[N-methyl-Tyr1,N-methyl-Arg7-D-Leu8]-dynorphin-A-(1-8)ethylamide, a stable dynorphin analog, produces diuresis by kappa-opiate receptor activation in the rat.

The i.v. administration of E-2078 ([N-methyl-Tyr1-N-methyl-Arg7-D-Leu8]-dynorphin-A-(1-8) ethylamide) to conscious animals in doses of 15, 50 or 200 micrograms/rat caused a dose-related diuretic response associated with a significant in crease in glomerular filtration rate (GFR) and in blood pressure. The overall excretion of Na+ was not modified by the opioid, whereas it reduced K+ output and its fractional excretion. Time course studies demonstrated that the increase in GFR and in blood pressure were transient and did not parallel the changes in urine outflow. Pretreatment of the animal with 1 mg/kg of naltrexone or of naloxone reduced the pressor response but did not reduce the renal action of E-2078. Doses of naltrexone 10 times larger (10 mg/kg) were required to attenuate the diuretic effect and abolish completely the changes in K+ excretion; however, the increase in GFR was not antagonized by 10 mg/kg of naltrexone. Consonant with the studies in conscious rats, perfusion of isolated rat kidneys with 0.2 to 1.8 microM E-2078 increased urine flow in a dose-dependent manner, and this effect was prevented by the simultaneous perfusion of 2 microM naltrexone with the peptide. In pentobarbital-anesthetized animals, E-2078 elicited a diuretic response that was not parallelled by changes in GFR or electrolyte excretion. In addition, E-2078 caused a long lasting decrease in blood pressure which was blocked completely by pretreatment of the animal with 1 mg/kg of naltrexone. The diuretic effect of E-2078 was not modified by pretreatment of the animals with beta-funaltrexamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Synthesis and biological activity of [MeTyr1,MeArg7,D-Leu8]-dynorphin A(1-9)-NHEt and [D-Cys2-Cys5,MeArg7,D-Leu8]-dynorphin A(1-9)-NH2.

The opioid activities of [MeTyr1]-Dyn(1-7)-NH2, [MeTyr1,D-Leu8]-Dyn(1-8)-NH2, [MeTyr1,D-Leu8]-Dyn(1-9)-NH2, [MeTyr1,D-Leu8]-Dyn(1-10)-NH2, [MeTyr1,D-Leu8]-Dyn(1-11)-NH2, and [MeTyr1,D-Leu8,12]-Dyn(1-13)-NH2 were examined in the bioassays (guinea pig ileum, mouse vas deferens and rabbit vas deferens). Because [MeTyr1,D-Leu8]-Dyn(1-9)-NH2 showed the most potent opioid activity of the peptides tested, the biological activities of two kinds of Dyn(1-9) analogues, [MeTyr1,MeArg7,D-Leu8]-Dyn(1-9)-NHEt and [D-Cys2-Cys5,MeArg7,D-Leu8]-Dyn(1-9)-NH2 were determined and compared with those of [MeTyr1,MeArg7,D-Leu8]-Dyn(1-8)-NHEt and [D-Cys2-Cys5,MeArg7,D-Leu8]-Dyn(1-8)-NHEt in the three bioassays, in the receptor binding assays, and in the mouse tail pinch test after subcutaneous administration. The results suggest that the extension of the C-terminal in the peptide chain of [MeArg7,D-Leu8]-Dyn(1-8)-NH2 analogues by Arg is ineffective for increasing the kappa-opioid activities, kappa-receptor selectivity and/or analgesic effects of the peptides.

Amino Acid Sequence↗