Dynorphin Agonist Therapy of Parkinsonʼs Disease

Giuffra, M.; Mouradian, M. Maral; Ownby, Jonathan; Chase, T. N.

doi:10.1097/00002826-199310000-00007

Cited by 13 publications

(13 citation statements)

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“…However, it has to be considered that administration of dynorphin-like drugs, which would be expected to inhibit glutamate tone, is associated with negative mood states. 2,3 The specific interaction between amygdala dynorphin and glutamatergic systems in depression behavior has to be directly examined.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 Very few studies have examined the levels of dynorphin peptides or the precursor, prodynorphin, in individuals with psychiatric illnesses. An increase of dynorphin A peptides was detected in the cerebrospinal fluid (CSF) of drug-free schizophrenics, 4,5 and reduced CSF levels of dynorphin (1)(2)(3)(4)(5)(6)(7)(8) immunoreactivity was reported in patients diagnosed with schizophrenia. 6 Although activation of the dynorphin system is normally associated with negative mood states, dynorphin peptides have not been studied in patients with affective disorders.…”

Section: Introductionmentioning

confidence: 99%

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Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex

Hurd

2002

Mol Psychiatry

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The dynorphin system has been associated with the regulation of mood. The expression of the prodynorphin mRNA was currently studied in the amygdaloid complex, a brain region critical for emotional processing, in subjects (14-15 per group) diagnosed with major depression, bipolar disorder, or schizophrenia and compared to normal controls. In situ hybridization histochemistry was used to characterize the anatomical distribution and expression levels of the prodynorphin mRNA within the amygdaloid complex. High prodynorphin mRNA levels were expressed in the parvicellular division of the accessory basal, posterior cortical, periamygdaloid cortex, and amygdalohippocampal area in normal subjects. Individuals with major depression had significantly reduced (41-68%) expression of the prodynorphin mRNA in the accessory basal (both parvicellular and magnocellular divisions; P Ͻ 0.01) and amygdalohippocampal area (P Ͻ 0.001) as compared to controls. The bipolar disorder group also showed a significant reduction (37-38%, P Ͻ 0.01) of the mRNA expression levels in the amygdalohippocampal area and in the parvicellular division of the accessory basal. No other amygdala nuclei studied showed any significant differences for the prodynorphin mRNA levels measured in the major depression and bipolar disorder subjects. Additionally, the prodynorphin mRNA expression levels did not differ significantly between the schizophrenic and normal control subjects in any of the amygdala areas examined. These findings indicate specific prodynorphin amygdala impairment in association with mood disorder. Molecular Psychiatry (2002) 7, 75-81.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex

Hurd

2002

Mol Psychiatry

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“…While these methods are useful for distinguishing the relevance of a particular dopamine subsystem (eg D1 or D2), these pharmacologic manipulations impose changes to neuronal systems that, even in the absence of MA coadministration, can alter motor behavior. In fact, opioid peptides have been employed for years as a potential adjunctive treatment for Parkinson's disease (Giuffra et al, 1993;Hille et al, 2001) and its complications (Henry and Brotchie, 1996). Nevertheless, this work has led to a greater understanding of the role of MA in behavioral disturbances regulated by the dopamine via the direct and indirect striatopallidal GABAergic pathways and their translation to movement disorders humans.…”

Section: Motor Dysfunction Following Ma Preclinical Studiesmentioning

confidence: 99%

Do Preclinical Findings of Methamphetamine-Induced Motor Abnormalities Translate to an Observable Clinical Phenotype?

Caligiuri

Buitenhuys

2005

Neuropsychopharmacol

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This review summarizes the preclinical literature of the effects of methamphetamine (MA) on subcortical dopaminergic and GABAergic mechanisms underlying motor behavior with the goal of elucidating the clinical presentation of human MA-induced movement disorders. Acute and chronic MA exposure in laboratory animal can lead to a variety of motor dysfunctions including increased locomotor activity, stereotypies, diminished or enhanced response times, and parkinsonian-like features. With the exception of psychomotor impairment and hyperkinesia, MA-induced movement disorders are not well documented in humans. This review attempts to draw parallels between the animal and human changes in basal ganglia neurochemistry associated with MA exposure and offers explanations for why a parkinsonian phenotype is not apparent among individuals who use and abuse MA. Significant differences in the expression of neurotoxicity and presence of multiple environmental and pharmacologic confounds may account for the lack of a parkinsonian phenotype in humans despite evidence of altered dopamine function.

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“…Furthermore, this study reported some attenuation of the frequency of tics following a low dose of spiradoline (0.8 ìg/kg), while higher doses either worsened tics, or had no effect, but caused marked sedation. Partly based on the facts that endogenous dynorphin interacts with dopamine (13) and that spiradoline has been found to have effects in animal models of hemi-parkinsonism (12), spiradoline has been evaluated for possible therapeutic effects in patients with Parkinson's disease (16). Spiradoline was tried at doses up to 4 ìg/kg alone, or in combination with L-DOPA; it had no antiparkinsonian effects, and no effects on L-DOPA induced dyskinesia.…”

Section: Diuresis Neuroendocrine Effects and Clinical Effects In Tomentioning

confidence: 99%

A Review of the Properties of Spiradoline: A Potent and Selective k‐Opioid Receptor Agonist

2003

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The selective ê-opioid receptor agonist spiradoline mesylate (U62,066E), an arylacetamide, was synthesized with the intention of creating an analgesic that, while still retaining its analgesic properties, would be devoid of the, mainly ì receptor mediated, side effects such as physical dependence and respiratory depression associated with morphine. Spiradoline is highly selective for the ê receptor with K i of 8.6 nM in guinea pig. Examination of the enantiomers of spiradoline, showed the (-)enantiomer to be responsible for the ê agonist properties. Spiradoline easily penetrates the blood brain barrier, and does not seem to have any significant active metabolites. In preclinical studies, spiradoline has a short duration of action with a peak at around 30 min after administration.The analgesic properties of spiradoline are well documented in mice and rats. Antitussive properties have also been reported in rats. Furthermore, spiradoline was reported to display effects suggestive of neuroprotective properties in animal models of ischemia. In humans, spiradoline is a potent diuretic. It also produces significant sedation presumably due to its antihistamine properties. Preclinical studies have shown that spiradoline reduces blood pressure and heart rate, and has possible antiarrhythmic properties. Clinical studies did not confirm these findings.ê Receptors inhibit dopaminergic neurotransmission. Spiradoline, given systematically to rats, produces a significant and long lasting decrease in dopamine release, and in locomotor activity. It has also antipsychotic-like effect in animal behavioral tests. At low doses spiradoline was reported to decrease tics in patients with Tourette's syndrome. Although spiradoline had promising effects in animal tests of analgesia, and a reasonably good safety profile in preliminary studies, it did not replace morphine as an analgesic. The available clinical data suggest that spiradoline produces disturbing adverse effects such as diuresis, sedation, and dysphoria at doses lower than those needed for analgesic effects. Thus, future development of spiradoline-like analgesic compounds should preferably focus on reduction of unwanted effects on the central nervous system. Spiradoline, which currently is commercially available for preclinical research, might prove useful in some psychiatric conditions and possibly as a neuroprotective agent.

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Dynorphin Agonist Therapy of Parkinsonʼs Disease

Cited by 13 publications

References 0 publications

Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex

Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex

Do Preclinical Findings of Methamphetamine-Induced Motor Abnormalities Translate to an Observable Clinical Phenotype?

A Review of the Properties of Spiradoline: A Potent and Selective k‐Opioid Receptor Agonist

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