dynorphins and spiradoline

Striatal dynorphin system function may be altered in Parkinson's disease. To evaluate whether treatment with a selective dynorphin agonist improves motor symptoms, four parkinsonian patients received single daily injections of spiradoline under controlled conditions. Doses ranging from 1 to 4 micrograms/kg had no discernible effect on motor performance when given alone or in combination with levodopa-carbidopa. Three patients developed dose-limiting adverse effects, especially behavioral alterations. These results suggest that dynorphin replacement strategies, using spiradoline-like kappa-1 agonists, may have limited value in the therapy of patients with Parkinson's disease.

Topics: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Dynorphins; Humans; Levodopa; Middle Aged; Motor Activity; Parkinson Disease; Pyrrolidines

Nociceptin/orphanin FQ (N/OFQ), a 17-amino-acid peptide, is an endogenous agonist whose receptor is similar in sequence to mu, delta and kappa opioid receptors. It has been reported that N/OFQ can block antinociceptive effects induced by opioid receptor agonists in the radiant heat tail-flick test and warm water tail-withdrawal test. The present study was designed to see the effect of N/OFQ on antinociception induced by opioid receptor agonists in the cold water tail-flick (CWT) test, which measures a different type of pain. In adult male Sprague-Dawley (S-D) rats given subcutaneous (s.c.) injections of saline or morphine (8 mg/kg), intracerebroventricular (i.c.v.) injection of N/OFQ (18 microg) 15 min later produced a significant reversal of morphine antinociception (P<0.01, ANOVA followed by Duncan's test), compared to the corresponding saline control group. Saline (t=+15 min, i.c.v.) had no effect on s.c. morphine antinociception (P>0.01), compared to the corresponding saline control group. When the kappa opioid receptor agonist spiradoline (80 mg/kg, s.c.) was used instead of morphine, similar results were observed. In another series of experiments, it was found that i.c.v. injection of N/OFQ (18 microg) reversed the antinociception induced by i.c.v. injection of the selective mu opioid agonist PL017 (2 microg), delta opioid agonist DPDPE (50 ng) and kappa opioid agonist dynorphin (21.5 microg), respectively. These results indicate that N/OFQ may be an endogenous anti-opioid peptide in the brain of rats in the CWT test.

Topics: Analgesics, Opioid; Animals; Cold Temperature; Dynorphins; Endorphins; Enkephalin, D-Penicillamine (2,5)-; Male; Morphine; Nociceptin; Opioid Peptides; Pain; Pain Measurement; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Tail; Water

Isolation of young male Sprague Dawley rats for 7 days provoked hypertension which was exacerbated by hippocampal administration of an antisense oligodeoxynucleotide targeted to the kappa-opioid receptor (1 microg/0.5 microL bilaterally, twice daily, during the isolation or grouping period). Systolic blood pressure rose from a mean of 134 to 162 mmHg in isolated rats treated with antisense and only 139 to 151 mmHg in grouped rats treated with antisense. In grouped rats treated with either vehicle or missense, isolation caused a mean increase in systolic blood pressure of only 16 and 14 mmHg respectively. Neither the missense oligodeoxynucleotide nor the vehicle had any significant effects upon systolic pressure in grouped rats, which had not been isolated. Pharmacological studies indicated that rats previously treated with the antisense had no significant depressor response to U62, 066E (a non-peptide kappa agonist known to reduce blood pressure acutely when administered into the hippocampus), however rats previously treated with vehicle or missense exhibited a significant hypotensive response to the drug. This implies that the antisense had reduced the density or activity of the kappa receptors within the hippocampal formation. These data are in accordance with our previous studies, i.e. in several rat models of hypertension, the increase in blood pressure may be modulated via hippocampal kappa opioid receptors.

Topics: Animals; Blood Pressure; Dynorphins; Heart Rate; Hippocampus; Hypertension; Injections; Male; Microinjections; Mutation, Missense; Oligodeoxyribonucleotides, Antisense; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; RNA, Messenger; Social Isolation; Stress, Psychological

The effects of the extremely selective mu-opioid receptor agonist, [D-Arg2,Lys4]-dermorphin-(1-4)-amide (DALDA), the mu-opioid receptor agonist morphine, the mu/delta agonist D-Ala2, Leu5, Arg6-enkephalin (dalargin), the kappa-opioid receptor agonist spiradoline, and the sigma1-receptor antagonist DuP 734 on ventricular fibrillation threshold (VFT) was investigated in an experimental post-infarction cardiosclerosis model and an immobilization stress-induced model in rats. Both models produced a significant decrease in VFT. The postinfarction cardiosclerosis-induced decrease in VFT was significantly reversed by intravenous administration of dalargin (0.1 mg/kg), DALDA (0.1 mg/kg), or morphine HCl (1.5 mg/kg). Pretreatment with naloxone (0.2 mg/kg) completely eliminated the increase in cardiac electrical stability produced by DALDA. Both spiradoline (8 mg/kg, i.p.) and DuP 734 (1 mg/kg, i.p.) produced a significant increase in VFT in rats with post-infarction cardiosclerosis. This effect of spiradoline was blocked by nor-binaltorphimine. The immobilization stress-induced decrease in VFT was significantly reversed by administration of either DALDA, spiradoline or DuP 734. In conclusion, activation of either mu- or kappa1-opioid receptors or blockade of sigma1-receptors reversed the decrease in VFT in both cardiac compromised models. Since DALDA and dalargin essentially do not cross blood brain barriers, their effects on VFT may be mediated through peripheral mu-opioid receptors.

Topics: Animals; Anti-Arrhythmia Agents; beta-Endorphin; Disease Models, Animal; Dynorphins; Enkephalin, Leucine-2-Alanine; Heart; Immobilization; Ligands; Morphine; Myocardial Infarction; Myocardium; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Piperidines; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, delta; Stress, Physiological; Ventricular Fibrillation

1. The kappa 1 and kappa 2 opioid receptor agonists U-62066 (8 mg/kg, i.p.) and (-)-bremazocine (0.7 mg/kg, i.v.), respectively, both exhibit anti-arrhythmic properties against adrenaline-induced dysrhythmias in rats. 2. In contrast, (+)-bremazocine has no effect on adrenaline-induced dysrhythmias. 3. The kappa 1 opioid receptor agonists U-50488 (110 nmol) and [D-Ala2]-dynorphin A (20 nmol) and the kappa 2 opioid receptor agonist (-)-bremazocine (30 nmol) exhibit pro-arrhythmic properties following intracerebroventricular administration. 4. Prior administration of the kappa opioid receptor antagonist nor-binaltorphimine doses i.c.v. (14 nmol), i.p. (10 mg/kg), completely abolishes the pro-arrhythmic (BNI, i.c.v., 14 nmol) as well as anti-arrhythmic (BNI, 10 mg/kg, i.p.) effects of the kappa opioid receptor agonists. 5. Neither hexamethonium (10 mg/kg, i.v.) nor atropine (1 mg/kg, i.v.) have any effect on the anti-arrhythmic actions of the kappa 1 opioid receptor agonist U-62066 following systemic administration. 6. It is suggested that the anti-arrhythmic effects of U-62066 and (-)-bremazocine are associated with the activation of peripheral kappa opioid receptors and do not depend on the activation of kappa opioid receptors in the autonomic nervous system.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Arrhythmias, Cardiac; Benzomorphans; Dynorphins; Male; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, kappa

The dynorphins are endogenous opioid peptides with relative binding selectivity for kappa-receptors. It is unclear whether the dynorphins share the pharmacological profile observed with synthetic kappa-agonists in primates.. The main objective of this study was to compare the effects of s.c. E-2078, a stable dynorphin A(1-8) analog, with two synthetic kappa-opioid ligands, spiradoline (a reference arylacetamide kappa-agonist) and ICI204,448 (a "peripherally selective" kappa-agonist) in behavioral and neuroendocrine endpoints in rhesus monkeys.. Dose-effect curves were determined for s.c. E-2078, spiradoline and ICI204,448 in causing overt sedation and muscle relaxation (as detected in observational rating scales), in increasing latency to retrieve and consume a food pellet and in increasing serum levels of the anterior pituitary hormone, prolactin, in intact female rhesus monkeys.. E-2078 and ICI204,448 (0.1-3.2 mg/kg) caused increases in sedation and muscle relaxation scores, but were less potent and apparently less effective than spiradoline (0.001-0.1 mg/kg) up to the highest doses presently studied. All three agonists were equieffective and approximately equipotent in increasing the latency to retrieve and consume a pellet. Furthermore, E-2078 (0.001-0.032 mg/kg) was equipotent and equieffective with spiradoline in increasing serum prolactin levels, whereas ICI204,448 was less potent, but slightly more effective than the former two agonists. The effects of E-2078 on serum prolactin levels were surmountably antagonized by quadazocine (1 mg/kg) and naltrexone (0.1 mg/kg).. The present studies show that serum prolactin levels are a highly sensitive, quantitative endpoint to study the potency and effectiveness of systemically administered E-2078, and show that the dynorphins may be potent and effective in causing some, but not all, the effects that are observed after the administration of synthetic kappa-agonists.

Topics: Animals; Azocines; Dose-Response Relationship, Drug; Dynorphins; Female; Hypnotics and Sedatives; Injections, Subcutaneous; Macaca mulatta; Male; Motor Activity; Muscle Relaxation; Naltrexone; Narcotic Antagonists; Peptide Fragments; Prolactin; Pyrrolidines; Receptors, Opioid, kappa; Time Factors

Neurons in the striatum that project to the substantia nigra contain the opioid peptide dynorphin. Stimulation of D1 dopamine receptors results in increased expression of mRNA encoding dynorphin as well as expression of immediate-early genes such as c-fos in these neurons. Levels of dynorphin vary in different regions of the normal rat striatum, being highest in ventral and medial striatum. In a prior study, we have shown that both regional and temporal patterns of c-fos induction following treatment with the indirect dopamine receptor agonist cocaine are inversely related to those of dynorphin expression. These results suggested that dynorphin is involved in regulating the responsiveness of these neurons to dopamine input. In the present experiments, we examined such a potential role for dynorphin by analyzing the influence of the dynorphin (kappa opioid receptor) agonist spiradoline on immediate-early gene induction by cocaine, and we determined that this immediate-early gene response is mediated by D1 dopamine receptors located in the striatum. As a marker of neuron activation, expression of c-fos and zif 268 immediate-early genes was assessed with quantitative in situ hybridization histochemistry. Results showed that 1) intrastriatal infusion of the D1 dopamine receptor antagonist SCH-23390 (2.5-250 pmol) resulted in a dose-dependent blockade of immediate-early gene induction by cocaine (30 mg/kg); 2 systemic administration of the kappa opioid receptor agonist spiradoline (0.5-10.0 mg/kg) decreased cocaine-induced expression of c-fos and zif 268 mRNAs in striatum in a dose-dependent manner; 3) intrastriatal infusion of spiradoline (1-50 nmol) also suppressed immediate-early gene induction by cocaine, demonstrating that kappa opioid receptors located in the striatum mediate such an effect; and 4) systemic and intrastriatal administration of spiradoline also affected immediate-early gene expression in cortex. These results demonstrate that, in striatum, immediate-early gene induction by cocaine is a D1 dopamine receptor-mediated process that is inhibited by activation of kappa opioid receptors. Therefore, these findings suggest that the striatal dynorphin opioid system acts directly and/or indirectly to inhibit dopamine input to striatonigral neurons through kappa opioid receptor-mediated processes in the striatum.

Topics: Animals; Base Sequence; Benzazepines; Cocaine; Corpus Striatum; Dynorphins; Gene Expression Regulation; Genes, fos; Genes, Immediate-Early; Infusions, Parenteral; Male; Molecular Sequence Data; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Opioid, kappa; Transcriptional Activation

The analgesic and discriminative stimulus properties of U-62,066E, a selective kappa-opioid receptor agonist, were investigated in the rat and compared with those of morphine. In the hot-plate test, U-62,066E produced a potent analgesic effect almost comparable to that of morphine. U-62,066E-induced analgesia was far less sensitive to antagonism by naloxone than was morphine-induced analgesia, but was potently reversed by MR-2266, a kappa-receptor antagonist. Although tolerance occurred to both U-62,066E and morphine analgesia, there was no cross-tolerance between these drugs. U-62,066E did show cross-tolerance to U-50,488H, another selective kappa-receptor agonist. Rats were trained to discriminate either 1.0 mg/kg U-62,066E or 3.2 mg/kg morphine from saline in a two-level food-reinforced procedure. The stimulus effect of U-62,066E was substituted for by U-50,488H and E-2078 a stable dynorphin derivative, but not by morphine. None of the kappa-agonists substituted for the morphine stimulus. Although U-62,066E stimulus by itself was not antagonized by MR-2266 or naloxone up to as high a dose as 10 mg/kg, the U-62,066E-like stimulus effect of U-50,488H was markedly blocked by MR-2266. The dopamine antagonists haloperidol and sulpiride substituted for the U-62,066E stimulus cue that was, however, not attenuated by the dopamine agonist lisuride. Lisuride reversed the U-62,066E-like stimulus induced by U-50,488H.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analgesics; Animals; Benzomorphans; Cues; Discrimination, Psychological; Dopamine; Dopamine Antagonists; Dynorphins; Male; Morphine; Narcotic Antagonists; Peptide Fragments; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

Opioid agonists specific for the mu, delta, and kappa opioid receptor subtypes were tested for their ability to modulate potassium-evoked release of L-glutamate and dynorphin B-like immunoreactivity from guinea pig hippocampal mossy fiber synaptosomes. The kappa opioid agonists U-62,066E and (-) ethylketocyclazocine, but not the mu agonist [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin (DAGO) nor the delta agonist [D-Pen2,5]enkephalin (DPDE), inhibited the potassium-evoked release of L-glutamate and dynorphin B-like immunoreactivity. U-62,066E, but not DAGO or DPDE, also inhibited the potassium-evoked rise in mossy fiber synaptosomal cytosolic Ca2+ levels, indicating a possible mechanism for kappa agonist inhibition of transmitter release. DAGO and DPDE were found to be without any effect on cytosolic Ca2+ levels or transmitter release in this preparation. The U-62,066E inhibition of the potassium-evoked rise in synaptosomal cytosolic Ca2+ levels was partially attenuated by the opioid antagonist quadazocine and insensitive to the delta-opioid specific antagonist ICI 174,864 and the mu opioid-preferring antagonists naloxone and naltrexone. Quadazocine also reversed U-62,066E inhibition of the potassium-evoked release of L-glutamate, but not dynorphin B-like immunoreactivity. These results suggest that kappa opioid agonists inhibit transmitter release from mossy fiber terminals through both kappa opioid and non-kappa opioid receptor mediated mechanisms.

Topics: Animals; Azocines; Calcium; Dynorphins; Endorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Ethylketocyclazocine; Glutamates; Glutamic Acid; Guinea Pigs; Hippocampus; Male; Potassium; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Synaptosomes

The present study was designed to investigate the direct effect of dynorphin on atrial natriuretic polypeptide (ANP) secretion in cultured rat atrial cardiocytes via a kappa-opioid receptor activation as well as the involvement of adenosine 3',5'-cyclic monophosphate (cAMP) system in the secretion of ANP from cardiocytes. Dynorphin stimulated ANP secretion dose and time dependently from 2-day cultured atrial cardiocytes. The dynorphin-induced ANP secretion was partially antagonized by MR2266, a selective kappa-opioid receptor antagonist. U-62066E, a selective kappa-opioid receptor agonist, stimulated ANP secretion. This stimulation was also antagonized by MR2266. However, no stimulation of ANP secretion was seen with [D-Ala2,D-Leu5]enkephalin, methionine (Met)-enkephalin, or [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin. Dynorphin at 10(-6) M significantly decreased the production of cAMP in the cultured cardiocytes. However, 10(-6) M Met-enkephalin had no effect on cAMP at all. The decrease in cAMP production by the addition of dynorphin was partially antagonized with a simultaneous addition of MR2266. The dynorphin-induced ANP secretion, as well as the basal secretion, were significantly decreased by the addition of 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, as compared with the respective controls. Dibutyryl cAMP at 10(-3) M significantly decreased the basal secretion of ANP as compared with the control. Therefore, the present studies show that dynorphin selectively stimulates ANP secretion, at least in part, via the activation of a specific kappa-opioid receptor.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Animals, Newborn; Atrial Natriuretic Factor; Benzomorphans; Cells, Cultured; Diuretics; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine-2-Alanine; Enkephalin, Methionine; Enkephalins; Heart; Heart Atria; Kinetics; Naloxone; Narcotic Antagonists; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, kappa