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Nociceptin/orphanin FQ receptor antagonists as a novel therapeutic approach to Parkinson’s disease: interaction with levodopa
No full textNociceptin/orphanin FQ receptor antagonists riverse akinesia in rat parkinsonian models
No full textWe recently showed that pharmacological blockade of nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors located in the substantia nigra stimulates the nigrostriatal dopaminergic pathway and motor behavior.
To investigate whether such motor-stimulating action was dependent on functional dopaminergic transmission, the selective
NOP receptor peptide antagonist [Nphe1,Arg14,Lys15]N/OFQ-NH2 (UFP-101) was microinjected into the substantia nigra reticulata of
rats made cataleptic by systemic haloperidol administration. UFP- 101 reduced haloperidol-induced akinesia as measured by immobility time in the bar test. UFP-101 also induced contralateral turning in cataleptic rats. To investigate the mechanisms involved in the anti-akinetic action of UFP-101, nigral glutamate release was monitored by microdialysis technique. The anti-akinetic action of UFP-101 correlated with normalization of nigral glutamate release, previously elevated by haloperidol injection. We conclude that endogenous N/OFQ in the substantia nigra sustains akinesia generated by impaired DA transmission and subthalamic nucleus overactivation. NOP receptor antagonists may be beneficial in the symptomatic therapy of parkinsonism, via normalization of subthalamonigral glutamatergic transmission
L-DOPA-induced modulation of GABA and glutamate release in the substantia nigra pars reticulata and globus pallidus in a rat model of dyskinesia
No full textNovel therapeutic strategies for treatment of motor abnormalities in Parkinson’s disease: focus on opioid receptors
No full textThe opioid receptor family encompasses three classical receptors (mu, delta and kappa, renamed MOP, DOP and KOP according to the IUPHAR recommendations) and a novel entity termed ORL-1 (NOP) receptor. These receptors display structural and functional homologies, but unique pharmacological properties and selectivity for endogenous opioid peptides. Moreover, they show uneven distribution in the CNS. Opioid peptide and receptor expression is altered in animal and human PD brains. Preclinical evidence indicates that KOP and DOP receptor agonists and NOP receptor antagonists attenuate parkinsonian-like akinesia induced by dopamine depletion. KOP receptor agonists are reported to enhance 6-OHDA-induced neurodegeneration of nigral DA cells while DOP receptor agonists are neuroprotective. Indirect evidence that blockade of NOP receptor may also be neuroprotective has been produced. Despite such positive data, clinical attempts to attenuate motor symptoms in PD patients with opioid receptor ligands were made (with KOP receptor agonist and non selective opioid receptor antagonists) and proven unsuccessful. Changes in opioid peptide and receptor expression are also observed in models of levodopa-induced dyskinesia (LID) and in the brain of dyskinetic patients. Preclinical studies aimed at testing the effect of selective or non selective opioid receptor ligands in LID models gave conflicting results either supporting a compensatory or a pathogenetic role of endogenous opioids. Clinical studies failed to prove that non selective opioid receptor antagonists are effective in reducing LID. However, whether these compounds affect the priming process underlying LID development remains to be investigated
Nociceptin/orphanin FQ receptor antagonists riverse akinesia in rat parkinsonian models
No full textWe recently showed that pharmacological blockade of nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors located in the substantia nigra stimulates the nigrostriatal dopaminergic pathway and motor behavior.
To investigate whether such motor-stimulating action was dependent on functional dopaminergic transmission, the selective
NOP receptor peptide antagonist [Nphe1,Arg14,Lys15]N/OFQ-NH2 (UFP-101) was microinjected into the substantia nigra reticulata of
rats made cataleptic by systemic haloperidol administration. UFP- 101 reduced haloperidol-induced akinesia as measured by immobility time in the bar test. UFP-101 also induced contralateral turning in cataleptic rats. To investigate the mechanisms involved in the anti-akinetic action of UFP-101, nigral glutamate release was monitored by microdialysis technique. The anti-akinetic action of UFP-101 correlated with normalization of nigral glutamate release, previously elevated by haloperidol injection. We conclude that endogenous N/OFQ in the substantia nigra sustains akinesia generated by impaired DA transmission and subthalamic nucleus overactivation. NOP receptor antagonists may be beneficial in the symptomatic therapy of parkinsonism, via normalization of subthalamonigral glutamatergic transmission
Differential role of striatal and nigral D1receptors in the expression of L-DOPA induced dyskinesia and its neurochemical correlates
No full textThe selective D3 receptor antagonist, S33084, improves parkinsonian-like motor dysfunction but does not affect L-DOPA-induced dyskinesia in 6-hydroxydopamine hemi-lesioned rats
No full textDespite evidence linking dopamine D3 receptors to the etiology of Parkinson’s disease and L-DOPAinduced
dyskinesia, the potential therapeutic utility of D3 receptor ligands remains unclear. In the
present study, we investigated whether the selective D3 receptor antagonist, S33084, affects development
and expression of abnormal involuntary movements (AIMs), a behavioural correlate of dyskinesia,
in rats hemi-lesioned with 6-hydroxydopamine and chronically treated with L-DOPA. The ability of
S33084, alone or in combination with L-DOPA, to attenuate 6-hydroxydopamine induced motor deficits
was also investigated employing a battery of behavioural tests. Acute administration of S33084
(0.64 mg/kg, s.c.) did not attenuate the induction of AIMs in dyskinetic rats upon challenge with L-DOPA
(6 mg/kg, s.c.). Moreover, S33084 (0.64 mg/kg) did not prevent the development of AIMs affecting axial,
limb and orolingual muscles when chronically administered together with L-DOPA (6 mg/kg for 21 days).
However, both acute and chronic administration of S33084 enhanced L-DOPA-induced contralateral
turning, suggesting potential antiparkinsonian properties. Furthermore, S33084 (0.01–0.64 mg/kg) dosedependently
attenuated parkinsonian disabilities, including bradykinesia, in drag and rotarod tests,
although, in these procedures, the combination of S33084 with L-DOPA did not produce synergistic
effect. It is concluded that sustained D3 receptor blockade does not blunt L-DOPA-induced dyskinesia in
hemiparkinsonian rats. However, D3 receptor antagonism may be associated with antiparkinsonian
properties. The clinical relevance of these observations will be of interest to explore further
L-DOPA-induced modulation of GABA and glutamate release in the substantia nigra pars reticulata and globus pallidus in a rat model of dyskinesia
No full textDifferential role of striatal and nigral D1receptors in the expression of L-DOPA induced dyskinesia and its neurochemical correlates
No full textNociceptin/orphanin FQ receptor antagonists as a novel therapeutic approach to Parkinson’s disease: interaction with levodopa
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