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PubMed1988

Immunoreactive dynorphin is regulated by estrogen in the rat anterior pituitary.

The pituitary and hypothalamic content of dynorphin was determined by radioimmunoassay and characterized by high-performance liquid chromatography (HPLC) in adult female Sprague-Dawley rats, intact and ovariectomized with and without estrogen treatment. Animals were given estradiol benzoate, or vehicle (oil) by six daily intramuscular injections. Anterior pituitary content of immunoreactive (ir)-dynorphin in ovariectomized rats was approximately twice that of intact animals, and consisted of a single HPLC peak co-eluting with dynorphin 32. Administration of estradiol benzoate (0.06-6 micrograms/day) caused a marked decrease of ir-dynorphin in the anterior lobe of castrate female rats, with a half-maximal effect at 0.2 microgram/day; levels were restored to those seen in intact animals with 6 micrograms estradiol benzoate per day, an effect which was not influenced by concomitant administration of progesterone (1 mg/day), or bromocriptine (100 micrograms/day). In the hypothalamus and neuro-intermediate lobe multiple peaks of immunoreactive dynorphin were seen, coeluting with dynorphin A 1-8, dynorphin A 1-17 and dynorphin 32. Neither castration nor estrogen treatment altered ir-dynorphin content in these tissues. These findings suggest that the ovary exerts a specific modulating influence on AP ir-dynorphin in the rat, and that in addition this inhibition appears to be mediated by ovarian estrogen.

Animals↗
PubMed2005

Pathobiology of dynorphins in trauma and disease.

Dynorphins, endogenous opioid neuropeptides derived from the prodynorphin gene, are involved in a variety of normative physiologic functions including antinociception and neuroendocrine signaling, and may be protective to neurons and oligodendroglia via their opioid receptor-mediated effects. However, under experimental or pathophysiological conditions in which dynorphin levels are substantially elevated, these peptides are excitotoxic largely through actions at glutamate receptors. Because the excitotoxic actions of dynorphins require supraphysiological concentrations or prolonged tissue exposure, there has likely been little evolutionary pressure to ameliorate the maladaptive, non-opioid receptor mediated consequences of dynorphins. Thus, dynorphins can have protective and/or proapoptotic actions in neurons and glia, and the net effect may depend upon the distribution of receptors in a particular region and the amount of dynorphin released. Increased prodynorphin gene expression is observed in several disease states and disruptions in dynorphin processing can accompany pathophysiological situations. Aberrant processing may contribute to the net negative effects of dysregulated dynorphin production by tilting the balance towards dynorphin derivatives that are toxic to neurons and/or oligodendroglia. Evidence outlined in this review suggests that a variety of CNS pathologies alter dynorphin biogenesis. Such alterations are likely maladaptive and contribute to secondary injury and the pathogenesis of disease.

Animals↗
PubMed1995

Changes in the content of immunoreactive dynorphin in dorsal and ventral spinal cord of the rat in three different conditions.

Previous study in our group demonstrated that dynorphin exerted a significant analgesic effect in spinal cord, and electroacupuncture (EA) of high frequency (100 Hz) produced analgesia which was mediated by dynorphin released in spinal cord. However, no data are up to nowadays available for demonstrating either from anterior horn or from dorsal horn the dynorphin comes. Using radioimmunoassay, we found in the present study that ir-dynorphin content in dorsal horn was 10 times more than in anterior horn, which were 11.24 +/- 0.91 pmol/10 mg protein and 1.08 +/- 0.20 pmol/10 mg protein, respectively. Stimulation of 100 Hz EA for 30 min produced a significant increase of ir-dynorphin content in dorsal horn, in contrast, no change of ir-dynorphin content was found in anterior horn. For the meanwhile, a significant elevation of ir-dynorphin was induced by 100 Hz EA in cerebrospinal fluid. It is concluded according to these data that EA, as a stimulation in physiological condition, elevates the content of ir-dynorphin only in dorsal horn, and induces release of dynorphin in loci. The released dynorphin acts on dorsal horn to mediate the analgesia of EA.

Animals↗
PubMed1999

Effects of systemically administered dynorphin A(1-17) in rhesus monkeys.

The effects of i.v. dynorphin A(1-17) and its main nonopioid biotransformation fragment, dynorphin A(2-17), were compared in rhesus monkeys with those of the selective kappa-opioid agonist, U69, 593, in assays of operant behavior, thermal antinociception, and neuroendocrine function (prolactin release). Dynorphin A(1-17) (0. 1-3.2 mg/kg i.v.) and U69,593 (0.001-0.032 mg/kg s.c.) decreased rates of schedule-controlled (fixed ratio 20) food-reinforced responding, whereas dynorphin A(2-17) (1-3.2 mg/kg i.v.) was ineffective. Pretreatment studies with the opioid antagonist quadazocine (0.32 mg/kg s.c.) revealed that the operant effects of dynorphin A(1-17) were not mediated by kappa- or micro-opioid receptors. A different profile was observed in the warm water tail withdrawal assay of thermal antinociception, where both dynorphin A(1-17) and A(2-17) (0.032-3.2 mg/kg i.v., n = 4) were modestly effective in 50 degrees C water, and both were ineffective in 55 degrees C water. By comparison, U69,593 (0.032-0.18 mg/kg s.c.) was maximally effective in 50 degrees C water and partially effective in 55 degrees C. kappa-opioid agonists increase serum levels of prolactin in animals and humans. Dynorphin A(1-17) (ED(50) = 0.0011 mg/kg i.v.), similar to U69,593 (ED(50) = 0.0030 mg/kg i.v.), was very potent in increasing serum prolactin levels in follicular phase female rhesus monkeys, whereas dynorphin A(2-17) (0.32 mg/kg i.v.) was ineffective. The effects of dynorphin A(1-17) and U69,593 on serum prolactin were both antagonized by quadazocine (0.32 mg/kg s.c.) in a surmountable manner, consistent with opioid receptor mediation. The present studies show that serum prolactin levels are a sensitive quantitative endpoint to study the systemic effects of the endogenous opioid peptide, dynorphin A(1-17), in primates.

Analgesics, Opioid↗
PubMed2001

Femtomolar concentrations of dynorphins protect rat mesencephalic dopaminergic neurons against inflammatory damage.

The hallmark of Parkinson's disease is the death of nigral dopaminergic neurons, and inflammation in the brain has been increasingly associated with the pathogenesis of this neurological disorder. Dynorphins are among the major opioid peptides in the striato-nigral pathway and are important in regulating dopaminergic neuronal activities. However, it is not clear whether dynorphins play a role in the survival of nigral dopaminergic neurons. We have recently demonstrated that lipopolysaccharide (LPS) activates the brain immune cells microglia, in vitro and in vivo, to release neurotoxic factors to degenerate dopaminergic neurons. The purpose of this study was to explore the neuroprotective effect of dynorphins in the inflammation-mediated degeneration of dopaminergic neurons in rat midbrain neuron-glia cultures. LPS-induced neurotoxicity was significantly reduced by treatment with ultra low concentrations (10(-13)--10(-15) M) of the kappa-opioid receptor agonist dynorphin A (1--17) or the receptor binding ineffective [des-Tyr(1)]dynorphin A (2--17), but not by U50488, a synthetic kappa-receptor agonist. The glia-mediated neuroprotective effect of dynorphins was further supported by the finding that femtomolar concentrations of dynorphins did not prevent the killing of dopaminergic neurons by 6-hydroxydopamine. However, ultra low concentrations of dynorphins inhibited LPS-induced production of superoxide. These results suggest a glia-mediated and conventional opioid receptor-unrelated mechanism of action for the neuroprotective effect of ultra low concentrations of dynorphins. Understanding the underlying mechanisms of action should further define the roles of dynorphins in the regulation of dopaminergic neurons and help devise novel strategies to combat neurodegenerative diseases.

Animals↗
PubMed1985

Antinociception and paralysis induced by intrathecal dynorphin A.

Intrathecal administration of dynorphin A in rats produced dose-dependent antinociceptive effects in the tail-flick test to radiant heat and on a limb-flexion test to pressure. The potency of dynorphin A as an analgesic agent on the tail-flick test was dependent upon the duration of cannula implantation. When a short-term procedure was used (drug injected 1 day after catheter implantation) dynorphin A was approximately equipotent to morphine, whereas in animals with long-term implants (drug injected 7 or more days after catheter implantation) dynorphin A was an order of magnitude less potent than morphine. [D-Ala2,D-Leu5]enkephalin was the most potent opioid tested, and in the tail-flick test (long-term procedure) it was about 2 orders of magnitude more potent than dynorphin A and 7 times more potent than morphine. [Leu]enkephalin had no detectable antinociceptive effects. Low doses of naloxone (1 and 2 mg/kg s.c.) completely blocked the antinociceptive effects of morphine and [D-Ala2,D-Leu5]enkephalin, but neither low nor high (40 mg/kg s.c.) doses clearly blocked the antinociceptive effects of dynorphin A. Thus, dynorphin A has an antinociceptive action at the level of the spinal cord, and mu opioid receptors do not mediate these effects. In addition, high doses of dynorphin A (20 nmol or greater) produced long-lasting hindlimb paralysis, which suggests that dynorphin peptides may play a role in motor function in the spinal cord. This paralytic action of dynorphin A was not antagonized by naloxone in doses up to 32 mg/kg s.c.

Animals↗
PubMed1983

Regional distribution of dynorphin and neo-endorphin peptides in rat brain, spinal cord, and pituitary.

Five products of the dynorphin gene--alpha-neo-endorphin, beta-neo-endorphin, dynorphin A, dynorphin A-(1-8), and dynorphin B--were measured in various regions of rat brain and in rat spinal cord and pituitary. Specific antisera were used, supplemented by gel permeation analysis and high performance liquid chromatography, confirming the presence of dynorphin-32, dynorphin A, and dynorphin B in rat brain. In whole brain, alpha-neo-endorphin, dynorphin A-(1-8), and dynorphin B are present in much greater amounts than beta-neo-endorphin or dynorphin A. Although a general parallelism was found in the distribution of the five peptides, there were also noteworthy exceptions, suggesting that differential processing may occur.

Animals↗
PubMed1994

Dynorphin opioids present in dentate granule cells may function as retrograde inhibitory neurotransmitters.

The granule cell population response to perforant path stimulation decreased significantly within seconds following release of endogenous dynorphin from dentate granule cells. The depression was blocked by the opioid receptor antagonists naloxone and norbinaltorphimine, suggesting that the effect was mediated by dynorphin activation of kappa 1 type opioid receptors. Pharmacological application of dynorphin B in the molecular layer was effective at reducing excitatory synaptic transmission from the perforant path, but application in the hilus had no significant effect. These results suggest that endogenous dynorphin peptides may be released from a local source within the dentate molecular layer. By light microscopy, dynorphin-like immunoreactivity (dynorphin-LI) was primarily found in granule cell axons in the hilus and stratum lucidum with only a few scattered fibers evident in the molecular layer. At the extreme ventral pole of the hippocampus, a diffuse band of varicose processes was also seen in the molecular layer, but this band was not present in more dorsal sections similar to those used for the electrophysiological studies. Electron microscopic analysis of the molecular layer midway along the septotemporal axis revealed that dynorphin-LI was present in dense-core vesicles in both spiny dendrites and unmyelinated axons with the majority (74%) of the dynorphin-LI-containing dense-core vesicles found in dendrites. Neuronal processes containing dynorphin-LI were observed throughout the molecular layer. The results suggest that dynorphin release from granule cell processes in the molecular layer regulates excitatory inputs entering the hippocampus from cerebral cortex, thus potentially counteracting such excitation-induced phenomena as epileptogenesis or long-term potentiation.

Animals↗
PubMed1996

Differential sensitivity of recombinant N-methyl-D-aspartate receptor subunits to inhibition by dynorphin.

Dynorphin is an endogenous ligand for kappa-opioid receptors. We investigated the effect of dynorphin 1-13 on different heteromeric subunits of recombinant mouse N-methyl-D-aspartate (NMDA) receptors expressed in Xenopus oocytes by using voltage-clamp recording methods. Dynorphin inhibited the NMDA-activated currents of all heteromeric NMDA receptor subunits tested. The different NMDA receptor subunits, however, exhibited a differential sensitivity to dynorphin. For the epsilon-1/zeta-1 subunit combination the EC50 was 19 microM; the other NMDA receptor subunit combinations were less sensitive to dynorphin and had the following order of sensitivity: epsilon-2/zeta-1 > epsilon-4/zeta-1 > epsilon-3/zeta-1. Inhibition of NMDA-activated currents by dynorphin was not competitive with NMDA, and was voltage-independent. NMDA-activated currents were not affected by the synthetic kappa-opioid receptor agonist U50488 ¿trans-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzene-acetamide¿, the specific kappa-opioid receptor antagonist nor-binaltorphimine1 or the nonspecific opioid receptor antagonist naloxone. In addition, nor-binaltorphimine1 or naloxone did not attenuate dynorphin inhibition of NMDA-activated current. The observations suggest that dynorphin inhibition of NMDA receptor function is mediated by an interaction of dynorphin with NMDA receptors, rather than an action involving kappa-opioid receptors. The data also show that different heteromeric NMDA receptor subunits exhibit a differential sensitivity to dynorphin.

Animals↗
PubMed1999

Dynorphin A1-13 causes elevation of serum levels of prolactin through an opioid receptor mechanism in humans: gender differences and implications for modulation of dopaminergic tone in the treatment of addictions.

Dynorphin peptides act preferentially at kappa- as well as mu- and delta-opioid receptors. This study was conducted to determine whether dynorphin peptides act to lower dopaminergic tone in the tuberoinfundibular system, resulting in elevated serum prolactin levels and, if so, whether such an effect is mediated by the opioid receptors. Dose-related increases in serum prolactin levels were observed after dynorphin A1-13 was administered i.v. in doses of 120 and 500 micrograms/kg to healthy human volunteers with no history of drug or alcohol abuse. Studies were then conducted to determine whether this effect is opioid receptor mediated and, if so, whether at kappa- or mu types. Pretreatment with the opioid antagonist nalmefene (30 mg i.v.), which has high affinity at both mu- and kappa-opioid receptors, caused a greater attenuation in dynorphin A1-13-stimulated increases in serum prolactin levels than pretreatment with similarly high doses of naloxone, an antagonist with lower affinity for both mu- and kappa-opioid receptors. These results suggest dynorphin A1-13 lowers tuberoinfundibular dopaminergic tone through action at kappa- and possibly mu-opioid receptors. Female subjects were significantly more responsive to the prolactin effects of dynorphin than were male subjects. Dynorphin gene expression, dynorphin peptides, and kappa-opioid receptor gene expression and binding have been shown to be altered in response to cocaine administration. Also, both dynorphin peptides and synthetic kappa-opioid agonists have been shown to lower dopamine levels in the nucleus accumbens and to attenuate cocaine-induced surges in dopamine levels. Thus, a dynorphin-like compound capable of reaching critical mesolimbic-mesocortical and nigrostriatal dopaminergic systems may be effective in the management of cocaine addiction.

Adult↗
PubMed2002

Nitric oxide synthase inhibitors influence dynorphin A (1-17) immunoreactivity in the rat brain following hyperthermia.

The possibility that nitric oxide synthase (NOS) inhibitors influence dynorphin immunoreactivity following hyperthermia was examined in a rat model using a pharmacological approach. Previous reports from our laboratory show that hyperthermia induces an upregulation of NOS in several brain regions that seems to be instrumental in causing cell injury. Recent reports suggest that nitric oxide (NO) can influence dynorphin neurotransmission in the normal brain as well as in several pathological states. Since dynorphin is neurotoxic in different animal models of brain or spinal cord injury, it may be that the peptide will contribute to the cell injury in hyperthermia. The present investigation was carried out to determine whether hyperthermia can influence dynorphin immunoreactivity in the brain, and if so, whether inhibition of NOS will influence the peptide distribution in the brain following heat stress. Rats subjected to hyperthermia at 38 degrees C for 4 h in a biological oxygen demand incubator (BOD) resulted in a marked upregulation of dynorphin immunoreactivity in several brain regions e.g., cerebral cortex, hippocampus, cerebellum and brain stem. Pretreatment of rats with two potent NOS inhibitors, L-NAME (30 mg/kg/day, i.p. for 7 days) or L-NMMA (35 mg/kg/day, i.p. for 7 days) significantly attenuated the dynorphin immunoreactivity in the brain. These drugs were also able to reduce hyperthermia induced blood-brain barrier (BBB) permeability, brain edema formation and cell injury. Taken together, our results suggest that (i). hyperthermia has the capacity to upregulate dynorphin immunoreactivity in the brain, (ii). inhibition of NOS considerably attenuates the dynorphin immunoreaction following heat stress and (iii). upregulation of dynorphin is somehow contributing to hyperthermia induced brain damage, not reported earlier.

Animals↗
PubMed2002

Topical application of dynorphin A (1-17) antiserum attenuates trauma induced alterations in spinal cord evoked potentials, microvascular permeability disturbances, edema formation and cell injury: an experimental study in the rat using electrophysiological and morphological approaches.

Dynorphin is a neuropeptide that is present in high quantities in the dorsal horn of the spinal cord. The peptide is actively involved in pain processing pathways. However, its involvement in spinal cord injury is not well known. Alteration in dynorphin immunoreactivity occurs following a focal trauma to the rat spinal cord. Infusion of dynorphin into the intrathecal space of the cord results in ischemia, cell damage and abnormal motor function. Antibodies to dynorphin when injected into the intrathecal space of the spinal cord following trauma improve motor recovery, reduce edema and cell changes. However, influence of dynorphin on trauma induced alteration in spinal cord bioelectrical activity is still not known. Spinal cord evoked potentials (SCEP) are good indicator of spinal cord pathology following trauma. Therefore, in present investigation, influence of dynorphin antibodies on trauma induced changes in SCEP were examined in our rat model. In addition, spinal cord edema formation, microvascular permeability disturbances and cell injury were also investigated. Our results show that topical application of dynorphin antiserum (1 : 200) two min before injury markedly attenuated the SCEP changes immediately after injury. In the antiserum treated animals, a significant reduction in the microvascular permeability, edema formation and cell injury was observed in the traumatised spinal cord. These observations suggest that (i). dynorphin is involved in the altered bioelectrical activity of the spinal cord following trauma, (ii). the peptide actively participates in the pathophysiological processes of cell injury in the spinal cord trauma, and (iii). the dynorphin antiserum has potential therapeutic value for the treatment of spinal cord injuries.

Animals↗
PubMed1989

Corticotropin-releasing factor stimulates the release of methionine-enkephalin and dynorphin from the neostriatum and globus pallidus of the rat: in vitro and in vivo studies.

This study examined the changes in the in vitro and in vivo release of methionine-enkephalin (Met-enkephalin), and dynorphin from the rat neostriatum in response to corticotropin-releasing factor (CRF). The levels of each opioid peptide were measured in the same sample collected at each time interval by specific radioimmunoassay methods. The in vitro release experiments were conducted using neostriatal slices (250 microns) obtained from adult male Wistar rats whereas in the in vivo studies, the release of both Met-enkephalin and dynorphin were assessed in push-pull perfusates of the caudate nucleus (containing both Met-enkephalin and dynorphin cell bodies/fibres) and the globus pallidus (containing Met-enkephalin and dynorphin terminals) of chloral hydrate-anaesthetised adult male Wistar rats. In the in vitro studies, CRF (10(-12), 10(-10) and 10(-8) M) (applied in pulses of 75 min) stimulated both Met-enkephalin and dynorphin release from the neostriatal slices in a dose-related manner; in the presence of the CRF receptor antagonist, alpha-helical CRF9-41 (10(-6) M) the release of both Met-enkephalin and dynorphin in response to CRF (10(-8) M) were completely blocked. Push-pull perfusion experiments conducted in both the caudate nucleus and the globus pallidus, also demonstrated a dose-related increase in the release of both Met-enkephalin and dynorphin in response to CRF (10(-12), 10(-10) and 10(-8) M) applied in 60-min pulses. In addition, in each of the two brain sites, the release of both Met-enkephalin and dynorphin in response to CRF (10(-8) M) was completely blocked by alpha-helical CRF9-41 (10(-6) M). Both the in vitro and in vivo studies thus demonstrate that CRF can exert potent effects on Met-enkephalin and dynorphin release within the neostriatum-pallidum of the rat and that such effects are mediated via receptors specific for CRF, probably located on both the cell bodies and terminals of these opioid-containing neurones. The data obtained in this study thus substantiate the view that CRF, in addition to its regulation of pituitary opioid peptides, can communicate to opioid-containing neurones within the central nervous system and that many of the effects elicited by CRF may be ascribed to the opioid peptide released by CRF.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Modulation of central nervous system actions of corticotropin-releasing factor by dynorphin-related peptides.

Corticotropin-releasing factor (CRF) and dynorphin-related peptides are co-localized within a subset of hypothalamic neurons suggesting the possibility of their co-release. Therefore, studies were performed in conscious unrestrained rats to examine whether dynorphin-related peptides modify the central nervous system (CNS) actions of CRF on sympathetic nervous activity and cardiovascular function. Intracerebroventricular (i.c.v.) administration of dynorphin A1-8 (0.1 and 1.0 nmol) did not alter arterial pressure (AP) or heart rate (HR). I.c.v. injection of dynorphin A1-13 (0.1, 0.3 and 1.0 nmol) produced transient elevations of HR but did not significantly affect AP. I.c.v. administration of dynorphin A1-17 (0.1, 0.3 and 1.0 nmol) elicited delayed (10-15 min) and transient elevations of AP and HR. CRF (0.15 nmol, i.c.v.) produced immediate and sustained elevations of AP, HR and plasma catecholamine levels. Upon simultaneous administration, 0.1 nmol of dynorphin A1-17, but not 0.1 nmol of dynorphin A1-8 or dynorphin A1-13, markedly attenuated CRF-induced elevations of AP, HR, and plasma catecholamine levels. The results suggest that selected dynorphin-related peptides may modify the CNS actions of CRF.

Animals↗
PubMed1993

Cardiovascular effects of microinjection of dynorphin fragments into the nucleus of the solitary tract (NTS) are mediated by non-opioid mechanisms.

The nucleus of the solitary tract (NTS) is important for the regulation of cardiovascular homeostasis. In the present study we investigated the effect of dynorphin A-(1-13), dynorphin A-(1-17) and dynorphin A-(2-17) microinjected into the NTS on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV) and left ventricular stroke work (LVSW) following hemorrhage in conscious rats. Following fixed-volume hemorrhage (8 ml/300 g), microinjection of dynorphin A-(2-17) (6 nmol), which is inactive at opioid receptors, into the NTS significantly attenuated the recovery of CO, SV and LVSW following hemorrhage when compared to those animals receiving a microinjection of normal saline (NS) vehicle into the NTS (P < 0.01). NTS microinjection of dynorphin A-(2-17) also increased HR following hemorrhage when compared with the NS group (P < 0.05). No significant effects were observed on CO, SV and LVSW following NTS microinjection of the kappa-opioid agonists, dynorphin A-(1-13) and dynorphin A-(1-17), although dynorphin A-(1-13) microinjection increased HR following hemorrhage when compared with control animals (P < 0.05). Microinjection of all three peptide fragments had no significant effect on MAP when compared with MAP of the control group following hemorrhage. The results of this study suggest that dynorphin A-(2-17) in the NTS can attenuate the compensatory cardiovascular responses to hemorrhage, perhaps via a non-opioid mechanism.

Analysis of Variance↗
PubMed1982

Potency of three opiate antagonists to reverse the inhibitory activity of dynorphin, enkephalins and opioid-like alkaloids on the guinea pig ileum.

To test the hypothesis that dynorphin is a K-opiate agonist acting on the myenteric plexus, the potency of two benzomorphan antagonists (Win 44, 441 and Mr 2266) to block the inhibitory action of dynorphin, enkephalins and opioid alkaloids was determined on the longitudinal muscle preparation of the guinea pig ileum. The effectiveness of these antagonists was compared to that of naloxone. Antagonistic potency was established by calculating the apparent antagonist dissociation constant, Ke, as derived from Schild plots. Win 44, 441 and Mr 2266 were about 7-8 times more potent than naloxone against dynorphin, dynorphin-(1-13) or ethylketocyclazocine. Although the Ke obtained with Win 44, 441 or Mr 2266 against dynorphin or ethylketocyclazocine were significantly lower than those of naloxone, the values obtained for these antagonists did not differ significantly in the case of each of these agonists. With respect to the antagonism of the enkephalins or normorphine, Win 44, 441 was the most potent antagonist. Its Ke value for the enkephalins was 2.5-3 times lower than those for dynorphin or ethylketocyclazocine and in comparison to naloxone, Win 44, 441 was about 5 times more potent. Although Mr 2266 was a potent antagonist of dynorphin, ethylketocyclazocine, the enkephalins or normorphine, it showed no selectivity of action. The fact that the 3 opiate antagonists evidenced similar Ke values for dynorphin and ethylketocyclazocine, but different ones for the enkephalins or normorphine supports the conclusion that dynorphin activates preferentially K- but not mu-opiate receptors in the myenteric plexus.

Animals↗
PubMed1992

Stimulation by corticotropin-releasing factor of the release of immunoreactive dynorphin A from mouse spinal cords in vitro.

Corticotropin-releasing factor (CRF) has been shown to release endogenous opioid peptides from several rat brain regions. Since we have demonstrated previously that the actions produced by intrathecally administered CRF in mice involve spinal kappa opioid receptors, experiments were conducted in this study to test the possibility that CRF may release dynorphin A, a putative endogenous kappa opioid agonist, from the mouse spinal cord. Using a superfusion system in vitro, mouse spinal cords were superfused with aerated (95% O2, 5% CO2) Krebs-Ringer buffer. Fractions of superfusion were collected and dynorphin A levels in each fraction were monitored by radioimmunoassay. The presence of CRF in the perfusion buffer stimulated significantly the release of immunoreactive dynorphin A. The releasing rate of immunoreactive dynorphin A returned to the basal level after withdrawing CRF from the superfusion buffer. The stimulatory effect of CRF on the release of immunoreactive dynorphin A was abolished by alpha-helical CRF-(9-41), a CRF receptor antagonist, indicating that the dynorphin-releasing effect of CRF was mediated by CRF receptors in the spinal cord. Also the dynorphin-releasing effect of CRF was a concentration-related phenomenon, with an estimated EC50 value of 5.3 nM. The results from this study support the hypothesis that intrathecally administered CRF may produce its effects by releasing endogenous dynorphin from the terminals of dynorphin-containing neurons in the spinal cord. This study also provides evidence to support the notion that there is a close communication between CRF- and opioid peptide-containing neuronal pathways in the central nervous system.

Animals↗
PubMed1982

Multiple forms of immunoreactive dynorphin in rat pituitary and brain.

Multiple forms of immunoreactive dynorphin (I-dynorphin) in rat anterior pituitary (AP), intermediate-posterior pituitary (IP) and medial basal hypothalamus (MBH) were examined. Three I-dynorphin peaks were observed on gel filtration. The first peak (big form) was eluted near the position of beta-LPH, and was predominant in AP. The second peak (middle form) was eluted near the position of ACTH. The third peak (small form) was eluted at the position of dynorphin (1-13), ane was predominant in IP and MBH. The heterogeneity of this small form was examined by ion exchange chromatography and reverse phase high performance liquified chromatography (HPLC). I-dynorphin peaks were observed at the positions of dynorphin(1-17), (1-13), (1-11), (1-10) and other peptides. These results strongly suggest (i) the presence of dynorphin(1-17), (1-13), (1-11) and (1-10) in rat IP, (ii) dynorphin(1-11) and (1-10) as the major components in this small form, (iii) the difference of I-dynorphin processing in AP, IP and MBH.

Animals↗