Opioid-Like Actions of Neuropeptide Y in Rat Substantia Gelatinosa: Y1 Suppression of Inhibition and Y2 Suppression of Excitation

2004 ◽  
Vol 92 (6) ◽  
pp. 3266-3275 ◽  
Author(s):  
Timothy D. Moran ◽  
William F. Colmers ◽  
Peter A. Smith
Keyword(s):  
Neuropathic Pain ◽  
Neuropeptide Y ◽  
Opioid Analgesics ◽  
Substantia Gelatinosa ◽  
Inhibitory Synapses ◽  
Adult Rats ◽  
Release Process ◽  
Postsynaptic Currents ◽  
Y1 Receptors ◽  
Analgesic Opioids

Neuropathic pain that results from injury to the peripheral or CNS responds poorly to opioid analgesics. Y1 and Y2 receptors for neuropeptide Y (NPY) may, however, serve as targets for analgesics that retain their effectiveness in neuropathic pain states. In substantia gelatinosa neurons in spinal cord slices from adult rats, we find that NPY acts via presynaptic Y2 receptors to attenuate excitatory postsynaptic currents (EPSCs) and predominantly on presynaptic Y1 receptors to attenuate glycinergic and GABAergic inhibitory postsynaptic currents (IPSCs). Because NPY attenuates the frequency of TTX-resistant miniature EPSCs and IPSCs, perturbation of the neurotransmitter release process contributes to its actions at both excitatory and inhibitory synapses. These effects, which are reminiscent of those produced by analgesic opioids, provide a cellular basis for previously documented spinal analgesic actions mediated via Y1 and Y2 receptors in neuropathic pain paradigms. They also underline the importance of suppression of inhibition in spinal analgesic mechanisms.

scholarly journals Excitatory and Inhibitory Synapses in Neuropeptide Y–Expressing Striatal Interneurons

2009 ◽  
Vol 102 (5) ◽  
pp. 3038-3045 ◽  
Author(s):  
John G. Partridge ◽  
Megan J. Janssen ◽  
David Y. T. Chou ◽  
Ken Abe ◽  
Zofia Zukowska ◽  
...  
Keyword(s):  
Neuropeptide Y ◽  
Fluorescent Protein ◽  
Input Resistance ◽  
Inhibitory Synapses ◽  
Striatal Neurons ◽  
Decay Kinetics ◽  
Membrane Rupture ◽  
Postsynaptic Currents ◽  
Endogenous Expression ◽  
Striatal Interneurons

Although rare, interneurons are pivotal in governing striatal output by extensive axonal arborizations synapsing on medium spiny neurons. Using a genetically modified mouse strain in which a green fluorescent protein (GFP) is driven to be expressed under control of the neuropeptide Y (NPY) promoter, we identified NPY interneurons and compared them with striatal principal neurons. We found that the bacteria artificial chromosome (BAC)- npy mouse expresses GFP with high fidelity in the striatum to the endogenous expression of NPY. Patch-clamp analysis from NPY neurons showed a heterogeneous population of striatal interneurons. In the majority of cells, we observed spontaneous firing of action potentials in extracellular recordings. On membrane rupture, most NPY interneurons could be classified as low-threshold spiking interneurons and had high-input resistance. Voltage-clamp recordings showed that both GABA and glutamate gated ion channels mediate synaptic inputs onto these striatal interneurons. AMPA receptor–mediated spontaneous excitatory postsynaptic currents (sEPSCs) were small in amplitude and infrequent in NPY neurons. Evoked EPSCs did not show short-term plasticity but some rectification. Evoked N-methyl-d-aspartate (NMDA) EPSCs had fast decay kinetics and were poorly sensitive to an NR2B subunit containing NMDA receptor blocker. Spontaneous inhibitory postsynaptic currents (sIPSCs) were mediated by GABAA receptors and were quite similar among all striatal neurons studied. On the contrary, evoked IPSCs decayed faster in NPY neurons than in other striatal neurons. These data report for the first time specific properties of synaptic transmission to NPY striatal interneurons.

Analysis of the long-term actions of gabapentin and pregabalin in dorsal root ganglia and substantia gelatinosa

2014 ◽  
Vol 112 (10) ◽  
pp. 2398-2412 ◽  
Author(s):  
James E. Biggs ◽  
Paul A. Boakye ◽  
Naren Ganesan ◽  
Patrick L. Stemkowski ◽  
Aquilino Lantero ◽  
...  
Keyword(s):  
Dorsal Root ◽  
Substantia Gelatinosa ◽  
Inhibitory Neurons ◽  
Long Term Effects ◽  
Drg Neurons ◽  
Adult Rats ◽  
Postsynaptic Currents ◽  
Excitatory Transmission ◽  
Cell Recording

The α2δ-ligands pregabalin (PGB) and gabapentin (GBP) are used to treat neuropathic pain. We used whole cell recording to study their long-term effects on substantia gelatinosa and dorsal root ganglion (DRG) neurons. Spinal cord slices were prepared from embryonic day 13 rat embryos and maintained in organotypic culture for >5 wk (neuronal age equivalent to young adult rats). Exposure of similarly aged DRG neurons (dissociated and cultured from postnatal day 19 rats) to GBP or PGB for 5–6 days attenuated high-voltage-activated calcium channel currents (HVA ICa). Strong effects were seen in medium-sized and in small isolectin B4-negative (IB4−) DRG neurons, whereas large neurons and small neurons that bound isolectin B4 (IB4+) were hardly affected. GBP (100 μM) or PGB (10 μM) were less effective than 20 μM Mn2+ in suppression of HVA ICa in small DRG neurons. By contrast, 5–6 days of exposure to these α2δ-ligands was more effective than 20 μM Mn2+ in reducing spontaneous excitatory postsynaptic currents at synapses in substantia gelatinosa. Spinal actions of gabapentinoids cannot therefore be ascribed to decreased expression of HVA Ca2+ channels in primary afferent nerve terminals. In substantia gelatinosa, 5–6 days of exposure to PGB was more effective in inhibiting excitatory synaptic drive to putative excitatory neurons than to putative inhibitory neurons. Although spontaneous inhibitory postsynaptic currents were also attenuated, the overall long-term effect of α2δ-ligands was to decrease network excitability as monitored by confocal Ca2+ imaging. We suggest that selective actions of α2δ-ligands on populations of DRG neurons may predict their selective attenuation of excitatory transmission onto excitatory vs. inhibitory neurons in substantia gelatinosa.

scholarly journals Analyses of the Mode of Action of an Alpha-Adrenoceptor Blocker in Substantia Gelatinosa Neurons in Rats

2021 ◽  
Vol 22 (17) ◽  
pp. 9636
Author(s):  
Daisuke Uta ◽  
Tsuyoshi Hattori ◽  
Megumu Yoshimura
Keyword(s):  
Substantia Gelatinosa ◽  
Response Ratio ◽  
Patch Clamp Recording ◽  
Adult Rats ◽  
Excitatory Postsynaptic Currents ◽  
Alpha Adrenoceptor ◽  
Postsynaptic Currents ◽  
Inhibitory Mechanisms ◽  
Adrenoceptor Blocker ◽  
Post Hoc

To elucidate why naftopidil increases the frequency of spontaneous synaptic currents in only some substantia gelatinosa (SG) neurons, post-hoc analyses were performed. Blind patch-clamp recording was performed using slice preparations of SG neurons from the spinal cords of adult rats. Spontaneous inhibitory and excitatory postsynaptic currents (sIPSCs and sEPSCs, respectively) were recorded. The ratios of the frequency and amplitude of the sIPSCs and sEPSCs following the introduction of naftopidil compared with baseline, and after the application of naftopidil, serotonin (5-HT), and prazosin, compared with noradrenaline (NA) were evaluated. First, the sIPSC analysis indicated that SG neurons reached their full response ratio for NA at 50 μM. Second, they responded to 5-HT (50 μM) with a response ratio similar to that for NA, but prazosin (10 μM) did not change the sEPSCs and sIPSCs. Third, the highest concentration of naftopidil (100 μM) led to two types of response in the SG neurons, which corresponded with the reactions to 5-HT and prazosin. These results indicate that not all neurons were necessarily activated by naftopidil, and that the micturition reflex may be regulated in a sophisticated manner by inhibitory mechanisms in these interneurons.

scholarly journals Neuropeptide Y acts at Y1 receptors in the rostral ventral medulla to inhibit neuropathic pain

Pain ◽  
2007 ◽  
Vol 131 (1) ◽  
pp. 83-95 ◽  
Author(s):  
Bradley K. Taylor ◽  
Sarang S. Abhyankar ◽  
Ngoc-Tram T. Vo ◽  
Christopher L. Kriedt ◽  
Sajay B. Churi ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Neuropeptide Y ◽  
Ventral Medulla ◽  
Y1 Receptors

scholarly journals Intrathecal neuropeptide Y reduces behavioral and molecular markers of inflammatory or neuropathic pain

Pain ◽  
2008 ◽  
Vol 137 (2) ◽  
pp. 352-365 ◽  
Author(s):  
A. B. Intondi ◽  
M. N. Dahlgren ◽  
M. A. Eilers ◽  
B. K. Taylor
Keyword(s):  
Neuropathic Pain ◽  
Molecular Markers ◽  
Neuropeptide Y

Renal and cardiac neuropeptide Y and NPY receptors in a rat model of congestive heart failure

2007 ◽  
Vol 293 (6) ◽  
pp. F1811-F1817 ◽  
Author(s):  
Ean Y. Callanan ◽  
Edward W. Lee ◽  
Jason U. Tilan ◽  
Joseph Winaver ◽  
Aviad Haramati ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Neuropeptide Y ◽  
Renal Tissue ◽  
Receptor Expression ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Moderate Disease ◽  
High Output Heart Failure ◽  
Y1 Receptors

Neuropeptide Y (NPY) is coreleased with norepinephrine and stimulates vasoconstriction, vascular and cardiomyocyte hypertrophy via Y1 receptors (R) and angiogenesis via Y2R. Although circulating NPY is elevated in heart failure, NPY's role remains unclear. Activation of the NPY system was determined in Wistar rats with the aortocaval (A-V) fistula model of high-output heart failure. Plasma NPY levels were elevated in A-V fistula animals (115.7 ± 15.3 vs. 63.1 ± 17.4 pM in sham, P < 0.04). Animals either compensated [urinary Na+ excretion returning to normal with moderate disease (COMP)] or remained decompensated with severe cardiac and renal failure (urinary Na+ excretion <0.5 meq/day), increased heart weight, decreased mean arterial pressure and renal blood flow (RBF), and death within 5–7 days (DECOMP). Cardiac and renal tissue NPY decreased with heart failure, proportionate to the severity of renal complications. Cardiac and renal Y1R mRNA expression also decreased (1.5-fold, P < 0.005) in rats with heart failure. In contrast, Y2R expression increased up to 72-fold in the heart and 5.7-fold in the kidney ( P < 0.001) proportionate to severity of heart failure and cardiac hypertrophy. Changes in receptor expression were confirmed since the Y1R agonist, [Leu31, Pro34]-NPY, had no effect on RBF, whereas the Y2R agonist (13–36)-NPY increased RBF to compensate for disease. Thus, in this model of heart failure, cardiac and renal NPY Y1 receptors decrease and Y2 receptors increase, suggesting an increased effect of NPY on the receptors involved in cardiac remodeling and angiogenesis, and highlighting an important regulatory role of NPY in congestive heart failure.

scholarly journals Pharmacological Management of Chronic Neuropathic Pain – Consensus Statement and Guidelines from the Canadian Pain Society

2007 ◽  
Vol 12 (1) ◽  
pp. 13-21 ◽  
Author(s):  
DE Moulin ◽  
AJ Clark ◽  
I Gilron ◽  
MA Ware ◽  
CPN Watson ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Controlled Trial ◽  
Analgesic Efficacy ◽  
Opioid Analgesics ◽  
Ease Of Use ◽  
Control Group ◽  
Pharmacological Management ◽  
Randomized Controlled ◽  
Analgesic Agents ◽  
Third Line

Neuropathic pain (NeP), generated by disorders of the peripheral and central nervous system, can be particularly severe and disabling. Prevalence estimates indicate that 2% to 3% of the population in the developed world suffer from NeP, which suggests that up to one million Canadians have this disabling condition. Evidence-based guidelines for the pharmacological management of NeP are therefore urgently needed. Randomized, controlled trials, systematic reviews and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting. Medications are recommended in the guidelines if their analgesic efficacy was supported by at least one methodologically sound, randomized, controlled trial showing significant benefit relative to placebo or another relevant control group. Recommendations for treatment are based on degree of evidence of analgesic efficacy, safety, ease of use and cost-effectiveness. Analgesic agents recommended for first-line treatments are certain antidepressants (tricyclics) and anticonvulsants (gabapentin and pregabalin). Second-line treatments recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine. Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain. Recommended fourth-line treatments include cannabinoids, methadone and anticonvulsants with lesser evidence of efficacy, such as lamotrigine, topiramate and valproic acid. Treatment must be individualized for each patient based on efficacy, side-effect profile and drug accessibility, including cost. Further studies are required to examine head-to-head comparisons among analgesics, combinations of analgesics, long-term outcomes, and treatment of pediatric and central NeP.

Different Inhibitory Inputs Onto Neostriatal Projection Neurons as Revealed by Field Stimulation

2005 ◽  
Vol 93 (2) ◽  
pp. 1119-1126 ◽  
Author(s):  
Fatuel Tecuapetla ◽  
Luis Carrillo-Reid ◽  
Jaime N. Guzmán ◽  
Elvira Galarraga ◽  
José Bargas
Keyword(s):  
Channel Blocker ◽  
Inhibitory Synapses ◽  
Projection Neurons ◽  
Medium Spiny Neurons ◽  
Field Stimulation ◽  
Paired Pulse ◽  
Postsynaptic Currents ◽  
Spiny Neurons ◽  
Short Time ◽  
Paired Pulse Depression

This work investigated if diverse properties could be ascribed to evoked inhibitory postsynaptic currents (IPSCs) recorded on rat neostriatal neurons when field stimulation was delivered at two different locations: the globus pallidus (GP) and the neostriatum (NS). Previous work stated that stimulation in the GP could antidromically excite projection axons from medium spiny neurons. This maneuver would predominantly activate the inhibitory synapses that interconnect spiny cells. In contrast, intrastriatal stimulation would preferentially activate inhibitory synapses provided by interneurons. This study shows that, in fact, intensity-amplitude experiments are able to reveal different properties for IPSCs evoked from these two locations (GP and NS). In addition, while all IPSCs evoked from the GP were always sensitive to ω-conotoxin GVIA (CaV2.22.2 or N-channel blocker), one-half of the inhibition evoked from the NS exhibited little sensitivity to ω-conotoxin GVIA. Characteristically, all ω-conotoxin GVIA–insensitive IPSCs exhibited strong paired pulse depression, whereas ω-conotoxin GVIA–sensitive IPSCs evoked from either the GP or the NS could exhibit short-time depression or facilitation. ω-Agatoxin TK (CaV2.12.1+ or P/Q-channel blocker) blocked IPSCs evoked from both locations. Therefore 1) distinct inhibitory inputs onto projection neostriatal cells can be differentially stimulated with field electrodes; 2) N-type Ca2+ channels are not equally expressed in inhibitory terminals activated in the NS; and 3) synapses that interconnect spiny neurons use both N- and P/Q-type Ca2+ channels.

Central neuropeptide Y induces proximal stomach relaxation via Y1 receptors in the dorsal vagal complex of the rat

2006 ◽  
Vol 290 (2) ◽  
pp. R290-R297 ◽  
Author(s):  
Motoi Kobashi ◽  
Yuichi Shimatani ◽  
Keisuke Shirota ◽  
Song-Yu Xuan ◽  
Yoshihiro Mitoh ◽  
...  
Keyword(s):  
Neuropeptide Y ◽  
Fourth Ventricle ◽  
Cholinergic Neurons ◽  
Proximal Part ◽  
Dependent Manner ◽  
Dorsal Vagal Complex ◽  
Proximal Stomach ◽  
Y1 Receptors ◽  
Atropine Methyl Nitrate ◽  
Intermediate Part

Effects of neuropeptide Y (NPY) on motility of the proximal stomach was examined in anesthetized rats. Intragastric pressure was measured using a balloon situated in the proximal part of the stomach. Administration of NPY into the fourth ventricle induced relaxation of the proximal stomach in a dose-dependent manner. Administration of an Y1 receptor (Y1R) agonist [Leu31, Pro34]NPY induced a larger relaxation than NPY. The administration of an Y2 receptor agonist (NPY 13-36) did not induce significant changes in motility. Microinjections of [Leu31, Pro34]NPY into the caudal part of the dorsal vagal complex (DVC) induced relaxation of the proximal stomach. In contrast, similar injections into the intermediate part of the DVC increased IGP of the proximal stomach. Administration of NPY into the fourth ventricle did not induce relaxation after bilateral injections of the Y1R antagonist (1229U91) into the caudal DVC. These results indicate that NPY induces relaxation in the proximal stomach via Y1Rs situated in the DVC. Because bilateral vagotomy below the diaphragm abolished the relaxation induced by the administration of NPY into the fourth ventricle, relaxation induced by NPY is probably mediated by vagal preganglionic neurons. Intravenous injection of atropine methyl nitrate reduced relaxation induced by administration of NPY. Therefore, relaxation induced by NPY is likely mediated by peripheral cholinergic neurons.

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