9 research outputs found
Endogenous nociceptin/orphanin FQ contributes to haloperidol-induced changes of nigral amino acid transmission and parkinsonism: a combined microdialysis and behavioral study in naĂŻve and nociceptin/orphanin FQ receptor knockout mice.
The contribution of endogenous nociceptin/orphanin
FQ (N/OFQ) to neuroleptic-induced parkinsonism has
been evaluated in haloperidol-treated mice. Pharmacological
blockade of N/OFQ receptors (NOP) via systemic administration
of 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-
3-ethyl-1,3-dihydro-2H benzimidazol-2-one (J-113397, 0.01–10
mg/kg i.p.) or central injection of [Nphe1,Arg14,Lys15]N/OFQ-NH2
(UFP-101, 10 nmol i.c.v.) attenuated (0.8 mg/kg) haloperidolinduced
motor deficits as evaluated by a battery of behavioral
tests providing complementary information on motor parameters:
the bar, drag and rotarod tests. A combined neurochemical
and behavioral approach was then used to investigate
whether the substantia nigra reticulata could be involved
in antiakinetic actions of J-113397. Microdialysis
combined to the bar test revealed that haloperidol (0.3 and 0.8
mg/kg i.p.) caused a dose-dependent and prolonged elevation
of immobility time (i.e. akinesia) which was associated
with an increase in nigral glutamate and a reduction in GABA
release. Conversely, J-113397 (1 mg/kg) alone reduced glutamate
and elevated nigral GABA release, and when challenged
against haloperidol, counteracted its behavioral and
neurochemical effects. Microdialysis coupled to behavioral
testing also demonstrated that NOP receptor knockout mice
were resistant to haloperidol (0.3 mg/kg) compared to wildtype
mice, lack of response being associated with a reversal
of glutamate release facilitation into inhibition and no change
in nigral GABA release. This study provides pharmacological
and genetic evidence that endogenous N/OFQ contributes to
haloperidol-induced akinesia and changes of amino acid
transmission in mice. Moreover, it confirms the view that
NOP receptor antagonists are capable of reversing akinesia
across species and genotypes and may prove effective in
relieving neuroleptic-induced parkinsonism
The novel delta opioid receptor agonist UFP-512 dually modulates motor activity in hemiparkinsonian rats via control of the nigro-thalamic pathway
The present study aimed to characterize the ability
of the novel delta opioid peptide (DOP) receptor agonist H-Dmt-
Tic-NH-CH(CH2–COOH)-Bid (UFP-512) to attenuate motor deficits
in 6-hydroxydopamine (6-OHDA) hemilesioned rats. Lower
doses (0.1–10 g/kg) of UFP-512 administered systemically
(i.p.) stimulated stepping activity in the drag test and overall
gait abilities in the rotarod test whereas higher doses (100–
1000 g/kg) were ineffective or even worsened Parkinsonism.
Microdialysis coupled to an akinesia test (bar test) was then
used to determine the circuitry involved in the motor actions
of UFP-512. An antiakinetic dose of UFP-512 (10 g/kg) decreased
GABA in globus pallidus (GP) as well as GABA and
glutamate (GLU) release in substantia nigra reticulata (SNr).
On the other hand, a pro-akinetic dose (1000 g/kg) of UFP-
512 increased pallidal GABA, simultaneously producing a decrease
in GABA and an increase in nigral GLU release. Moreover,
to test the hypothesis that changes in motor behavior
were associated with changes in nigro–thalamic transmission,
amino acid release in ventromedial thalamus (VMTh, a target of
nigro–thalamic GABAergic projections) was also measured.
The anti-akinetic dose of UFP-512 reduced GABA and increased
thalamic GLU release while the pro-akinetic dose increased
GABA without affecting thalamic GLU release. Finally, regional
microinjections were performed to investigate the brain areas
involved in motor actions of UFP-512. UFP-512 microinjections
into GP increased akinesia whereas UFP-512 microinjections
into SNr reduced akinesia. Furthermore, the selective DOP receptor
antagonist naltrindole (NTD) increased akinesia when
injected into either area, GP being more sensitive. We conclude
that UFP-512, depending on dose, improves or worsens motor
activity in hemiparkinsonian rats by acting differentially as a
DOP receptor agonist in SNr and a DOP receptor antagonist in
GP, ultimately decreasing or increasing the activity of nigro–
thalamic GABAergc output neurons, respectively
Stimulation of Delta Opioid Receptor and Blockade of Nociceptin/Orphanin FQ Receptor Synergistically Attenuate Parkinsonism
Delta opioid peptide (DOP) receptors are considered a therapeutic target in Parkinson’s disease, although the use of DOP agonists may be
limited by side effects, including convulsions. To circumvent this issue, we evaluated whether blockade of nociceptin/orphanin FQ
(N/OFQ) tone potentiated the antiparkinsonian effects of DOP agonists, thus allowing for reduction of their dosage. Systemic
administration of the N/OFQ receptor (NOP) antagonist J-113397 [(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-
ethyl-1,3-dihydro-2H benzimidazol-2-one] and the DOP receptor agonist SNC-80 [()-4-[(R)--(2S,5R)-allyl-2,5-dimethyl-1-
piperazinyl)-3-methoxy-benzyl]-N-N-diethylbenzamide] revealed synergistic attenuation of motor deficits in 6-hydroxydopamine
hemilesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice. In this model, repeated administration of the combination
produced reproducible antiparkinsonian effects and was not associated with rescued striatal dopamine terminals. Microdialysis studies revealed
that either systemic administration or local intranigral perfusion of J-113397 and SNC-80 led to the enhancement of nigral GABA,
reduction of nigral Glu, and reduction of thalamic GABA levels, consistent with the view that NOP receptor blockade and DOP
receptor stimulation caused synergistic overinhibition of nigro-thalamic GABA neurons. Whole-cell recording of GABA neurons
in nigral slices confirmed that NOP receptor blockade enhanced the DOP receptor-induced effect on IPSCs via presynaptic mechanisms.
Finally, SNC-80 more potently stimulated stepping activity in mice lacking the NOP receptor than wild-type controls,
confirming the in vivo occurrence of an NOP–DOP receptor interaction. We conclude that endogenous N/OFQ functionally opposes
DOP transmission in substantia nigra reticulata and that NOP receptor antagonists might be used in combination with DOP
receptor agonists to reduce their dosage while maintaining their full therapeutic efficacy
GluN2A and GluN2B NMDA Receptor Subunits Differentially Modulate Striatal Output Pathways and Contribute to Levodopa- Induced Abnormal Involuntary Movements in Dyskinetic Rats
Dual probe microdialysis was used to investigate whether GluN2A and GluN2B NMDA receptor subunits regulate striatal output pathways under dyskinetic conditions. The preferential GluN2A antagonist NVP-AAM077 perfused in the dopamine-depleted striatum of 6-hydroxydopamine hemilesioned dyskinetic rats reduced GABA and glutamate levels in globus pallidus whereas the selective GluN2B antagonist Ro 25-6981 elevated glutamate without affecting pallidal GABA. Moreover, intrastriatal NVP-AAM077 did not affect GABA but elevated glutamate levels in substantia nigra reticulata whereas Ro 25-6981 elevated GABA and reduced
nigral glutamate. To investigate whether GluN2A and GluN2B NMDA receptor subunits are involved in motor pathways underlying dyskinesia expression, systemic NVP-AAM077 and Ro 25-6981 were tested for their ability to attenuate levodopainduced abnormal involuntary movements. NVP-AAM077 failed to prevent dyskinesia while Ro 25-6981 mildly attenuated it. We
conclude that in the dyskinetic striatum, striatal GluN2A subunits tonically stimulate the striato-pallidal pathway whereas striatal GluN2B subunits tonically inhibit striato-nigral projections. Moreover, GluN2A subunits are not involved in dyskinesia expression whereas GluN2B subunits minimally contribute to it
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The delta-specific opioid glycopeptide bbi-11008: Cns penetration and behavioral analysis in a preclinical model of levodopa-induced dyskinesia
In previous work we evaluated an opioid glycopeptide with mixed µ/δ-opioid receptor agonism that was a congener of leu-enkephalin, MMP-2200. The glycopeptide analogue showed penetration of the blood–brain barrier (BBB) after systemic administration to rats, as well as profound central effects in models of Parkinson’s disease (PD) and levodopa (L-DOPA)-induced dyskinesia (LID). In the present study, we tested the glycopeptide BBI-11008 with selective δ-opioid receptor agonism, an analogue of deltorphin, a peptide secreted from the skin of frogs (genus Phyllomedusa). We tested BBI-11008 for BBB-penetration after intraperitoneal (i.p.) injection and evaluated effects in LID rats. BBI-11008 (10 mg/kg) demonstrated good CNS-penetrance as shown by microdialysis and mass spectrometric analysis, with peak concentration levels of 150 pM in the striatum. While BBI-11008 at both 10 and 20 mg/kg produced no effect on levodopa-induced limb, axial and oral (LAO) abnormal involuntary movements (AIMs), it reduced the levodopa-induced locomotor AIMs by 50% after systemic injection. The N-methyl-D-aspartate receptor antagonist MK-801 reduced levodopa-induced LAO AIMs, but worsened PD symptoms in this model. Co-administration of MMP-2200 had been shown prior to block the MK-801-induced pro-Parkinsonian activity. Interestingly, BBI-11008 was not able to block the pro-Parkinsonian effect of MK-801 in the LID model, further indicating that a balance of mu-and delta-opioid agonism is required for this modulation. In summary, this study illustrates another example of meaningful BBB-penetration of a glycopeptide analogue of a peptide to achieve a central behavioral effect, providing additional evidence for the glycosylation technique as a method to harness therapeutic potential of peptides. © 2020 by the authors. Li-censee MDPI, Basel, Switzerland.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]