ORCID Profile
0000-0002-7521-9969
Current Organisations
Monash University
,
University of Otago
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Central Nervous System | Biochemistry and Cell Biology | Receptors and Membrane Biology | Signal Transduction
ANZSRC Socio-Economic Objective (SEO)
Related Links
Publications
Therapeutic antagonism of the neurokinin 1 receptor in endosomes provides sustained pain relief
Publisher: Proceedings of the National Academy of Sciences
Date: 22-05-2023
Abstract: The hypothesis that sustained G protein-coupled receptor (GPCR) signaling from endosomes mediates pain is based on studies with endocytosis inhibitors and lipid-conjugated or nanoparticle-encapsulated antagonists targeted to endosomes. GPCR antagonists that reverse sustained endosomal signaling and nociception are needed. However, the criteria for rational design of such compounds are ill-defined. Moreover, the role of natural GPCR variants, which exhibit aberrant signaling and endosomal trafficking, in maintaining pain is unknown. Herein, substance P (SP) was found to evoke clathrin-mediated assembly of endosomal signaling complexes comprising neurokinin 1 receptor (NK 1 R), Gα q/i , and βarrestin-2. Whereas the FDA-approved NK 1 R antagonist aprepitant induced a transient disruption of endosomal signals, analogs of netupitant designed to penetrate membranes and persist in acidic endosomes through altered lipophilicity and pKa caused sustained inhibition of endosomal signals. When injected intrathecally to target spinal NK 1 R+ve neurons in knockin mice expressing human NK 1 R, aprepitant transiently inhibited nociceptive responses to intraplantar injection of capsaicin. Conversely, netupitant analogs had more potent, efficacious, and sustained antinociceptive effects. Mice expressing C-terminally truncated human NK 1 R, corresponding to a natural variant with aberrant signaling and trafficking, displayed attenuated SP-evoked excitation of spinal neurons and blunted nociceptive responses to SP. Thus, sustained antagonism of the NK 1 R in endosomes correlates with long-lasting antinociception, and domains within the C-terminus of the NK 1 R are necessary for the full pronociceptive actions of SP. The results support the hypothesis that endosomal signaling of GPCRs mediates nociception and provides insight into strategies for antagonizing GPCRs in intracellular locations for the treatment of erse diseases.
The contribution of endocytosis to sensitization of nociceptors and synaptic transmission in nociceptive circuits
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-11-2022
Glycine transport inhibitors for the treatment of pain
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.TIPS.2014.05.006
Abstract: Opioids, local anesthetics, anticonvulsant drugs, antidepressants, and non-steroidal anti-inflammatory drugs (NSAIDs) are used to provide pain relief but they do not provide adequate pain relief in a large proportion of chronic pain patients and are often associated with unacceptable side effects. Inhibitory glycinergic neurotransmission is impaired in chronic pain states, and this provides a novel target for drug development. Inhibitors of the glycine transporter 2 (GlyT2) enhance inhibitory neurotransmission and show particular promise for the treatment of neuropathic pain. N-arachidonyl-glycine (NAGly) is an endogenous lipid that inhibits glycine transport by GlyT2 and also shows potential as an analgesic, which may be further exploited in drug development. In this review we discuss the role of glycine neurotransmission in chronic pain and future prospects for the use of glycine transport inhibitors in the treatment of pain.
Neuron-specific responses to acetylcholine within the spinal dorsal horn circuits of rodent and primate
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.NEUROPHARM.2021.108755
Abstract: Excitatory and inhibitory neurotransmission within the spinal dorsal horn is tightly controlled to regulate transmission of nociceptive signals to the brain. One aspect of this control is modulation of neuronal activity through cholinergic signaling. Nociceptive neurons in the dorsal horn express both nicotinic and muscarinic cholinergic receptors and activation of these receptors reduces pain in humans, while inhibition leads to nociceptive hypersensitivity. At a cellular level, acetylcholine (ACh) has erse effects on excitability which is dependent on the receptor and neuronal subtypes involved. In the present study we sought to characterize the electrophysiological responses of specific subsets of lamina II interneurons from rat and marmoset spinal cord. Neurons were grouped by morphology and by action potential firing properties. Whole-cell voltage-cl recordings from lamina II dorsal horn neurons of adult rats showed that bath applied acetylcholine increased, decreased or had no effect on spontaneous synaptic current activity in a cell-type specific manner. ACh modulated inhibitory synaptic activity in 80% of neurons, whereas excitatory synaptic activity was affected in less than 50% of neurons. In whole-cell current cl recordings, brief somatic application of ACh induced cell-type specific responses in 79% of rat lamina II neurons, which included: depolarization and action potential firing, subthreshold membrane depolarization, biphasic responses characterized by transient depolarization followed by hyperpolarization and membrane hyperpolarization alone. Similar responses were seen in marmoset lamina II neurons and the properties of each neuron group were consistent across species. ACh-induced hyperpolarization was blocked by the muscarinic antagonist atropine and all forms of acetylcholine-induced depolarization were blocked by the nicotinic antagonist mecamylamine. The cholinergic system plays an important role in regulating nociception and this study contributes to our understanding of how circuit activity is controlled by ACh at a cellular level in primate and rodent spinal cord.
Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia
Publisher: Springer Science and Business Media LLC
Date: 08-09-2021
Pharmacological characterisation of the highly Na v 1.7 selective spider venom peptide Pn3a
Publisher: Springer Science and Business Media LLC
Date: 20-01-2017
DOI: 10.1038/SREP40883
Abstract: Human genetic studies have implicated the voltage-gated sodium channel Na V 1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom of the tarantula P hobeteus nigricolor, potently inhibits Na V 1.7 (IC 50 0.9 nM) with at least 40–1000-fold selectivity over all other Na V subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by Na V 1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically. A broad lack of analgesic activity was also found for the selective Na V 1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective Na V 1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted Na V 1.7 inhibitors can only produce analgesia when administered in combination with an opioid.
The light touch of delta opioid receptors
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.NEURON.2014.03.004
Abstract: Expression of δ-opioid receptors in sensory neurons is controversial. In this issue of Neuron, Bardoni et al. (2014) present evidence that DOPrs are expressed on mechanosensory neurons involved in detecting nonnoxious touch but are very sparse in μ-opioid receptor-rich nociceptive neurons.
Mechanism of action of lolitrem B, a fungal endophyte derived toxin that inhibits BK large conductance Ca(2+)-activated K(+) channels
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.TOXICON.2011.01.013
Abstract: The aim of this study was to compare the mode of action of the commonly used BK inhibitor paxilline with that of the more recently discovered lolitrem B. Similarities and differences in characteristics of inhibition between the two compounds were investigated. We have previously shown that lolitrem B does not affect the BK channel G-V, in contrast to the rightward shift produced by paxilline. These different effects on the voltage-dependence of activation suggest different modes of action for these two compounds. In this study we show that inhibition by both paxilline and lolitrem B is characterized by an open state preference for BK (hSlo) channels. Both compounds had a 3-fold higher apparent affinity under conditions likely to favour the open state, suggesting they have a similar BK conformational preference for binding. Furthermore, both compounds had a calcium concentration-dependence to their inhibitory effects. The G-V shift induced by paxilline was calcium concentration-dependent.
Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission
Publisher: Proceedings of the National Academy of Sciences
Date: 30-10-2017
Abstract: G protein-coupled receptors (GPCRs) have long been considered to function primarily at the plasma membrane. Consequently, most drugs are designed to target GPCRs at the cell surface. Ligand-bound GPCRs undergo clathrin- and dynamin-dependent endocytosis. It is uncertain whether GPCRs in endosomes control complex pathophysiological processes in vivo and are a viable therapeutic target. We report that the CGRP receptor signals from endosomes to regulate activity of pain-transmitting neurons in the spinal cord. Lipid-conjugated CGRP receptor antagonists accumulate in endosomes, selectively inhibit endosomal signals, and block sustained excitation of spinal neurons and persistent nociception. The results suggest that GPCRs in endosomes, in addition to those at the cell surface, control ongoing pathophysiological processes in vivo and identify GPCRs in endosomes as a new target for therapy.
Pathological Mechanisms and Therapeutic Targets for Trigeminal Neuropathic Pain
Publisher: MDPI AG
Date: 22-08-2019
Abstract: Trigeminal neuropathic pain is a chronic pain condition caused by damage or inflammation of the trigeminal nerve or its branches, with both peripheral and central nervous system dysfunction contributing to the disorder. Trigeminal pain conditions present with diagnostic and therapeutic challenges to healthcare providers and often require multiple therapeutic approaches for pain reduction. This review will provide the overview of pathophysiology in peripheral and central nociceptive circuits that are involved in neuropathic pain conditions involving the trigeminal nerve and the current therapeutics that are used to treat these disorders. Recent advances in treatment of trigeminal pain, including novel therapeutics that target ion channels and receptors, gene therapy and monoclonal antibodies that have shown great promise in preclinical studies and clinical trials will also be described.
Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression
Publisher: Springer Science and Business Media LLC
Date: 18-07-2022
DOI: 10.1038/S41467-022-31652-2
Abstract: The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is h ered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A 1 receptors (A 1 Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A 1 R-selective agonist, benzyloxy-cyclopentyladenosine (BnOCPA), is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A 1 Rs arises from BnOCPA’s unique and exquisitely selective activation of Gob among the six Gαi/o subtypes, and in the absence of β-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native A 1 R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism.
Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief
Publisher: American Association for the Advancement of Science (AAAS)
Date: 31-05-2017
DOI: 10.1126/SCITRANSLMED.AAL3447
Abstract: Therapeutic targeting of the neurokinin 1 receptor in endosomes provides efficacious and prolonged pain relief.
Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression
Publisher: Cold Spring Harbor Laboratory
Date: 05-04-2020
DOI: 10.1101/2020.04.04.023945
Abstract: The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is h ered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A1 receptors (A 1 Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A 1 R-selective agonist, BnOCPA, is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A 1 Rs arises from BnOCPA’s unique and exquisitely selective activation of Gob among the six Gαi/o subtypes, and in the absence of β-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native A 1 R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism. We describe the selective activation of an adenosine A1 receptor-mediated intracellular pathway that provides potent analgesia in the absence of sedation or cardiorespiratory depression, paving the way for novel medicines based on the far-reaching concept of selective Gα agonism.
Electrophysiological Methods for Recording Synaptic Potentials from the NMJ of Drosophila Larvae
Publisher: MyJove Corporation
Date: 06-02-2009
DOI: 10.3791/1109
A role for BK channels in heart rate regulation in rodents
Publisher: Public Library of Science (PLoS)
Date: 14-01-2010
The Molecular Mechanism of Ryegrass Staggers, a Neurological Disorder of K+ Channels
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 18-09-2008
Abstract: "Ryegrass staggers" is a neurological condition of unknown mechanism that impairs motor function in livestock. It is caused by infection of perennial ryegrass pastures by an endophytic fungus that produces neurotoxins, predominantly the indole-diterpenoid compound lolitrem B. Animals grazing on such pastures develop uncontrollable tremors and become uncoordinated in their movement. Lolitrem B and the structurally related tremor inducer paxilline both act as potent large conductance calcium-activated potassium (BK) channel inhibitors. Using patch cl ing, we show that their different apparent affinities correlate with their toxicity in vivo. To investigate whether the motor function deficits produced by lolitrem B and paxilline are due to inhibition of BK ion channels, their ability to induce tremor and ataxia in mice deficient in this ion channel (Kcnma1(-/-)) was examined. Our results show that mice lacking Kcnma1 are unaffected by these neurotoxins. Furthermore, doses of these substances known to be lethal to wild-type mice had no effect on Kcnma1(-/-) mice. These studies reveal the BK channel as the molecular target for the major components of the motor impairments induced by ryegrass neurotoxins. Unexpectedly, when the response to lolitrem B was examined in mice lacking the beta4 BK channel accessory subunit (Kcnmb4(-/-)), only low-level ataxia was observed. Our study therefore reveals a new role for the accessory BK beta4 subunit in motor control. The beta4 subunit could be considered as a potential target for treatment of ataxic conditions in animals and in humans.
Glycinergic dysfunction in a subpopulation of dorsal horn interneurons in a rat model of neuropathic pain
Publisher: Springer Science and Business Media LLC
Date: 14-11-2016
DOI: 10.1038/SREP37104
Abstract: The development of neuropathic pain involves persistent changes in signalling within pain pathways. Reduced inhibitory signalling in the spinal cord following nerve-injury has been used to explain sensory signs of neuropathic pain but specific circuits that lose inhibitory input have not been identified. This study shows a specific population of spinal cord interneurons, radial neurons, lose glycinergic inhibitory input in a rat partial sciatic nerve ligation (PNL) model of neuropathic pain. Radial neurons are excitatory neurons located in lamina II of the dorsal horn, and are readily identified by their morphology. The litude of electrically-evoked glycinergic inhibitory post-synaptic currents (eIPSCs) was greatly reduced in radial neurons following nerve-injury associated with increased paired-pulse ratio. There was also a reduction in frequency of spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSC) in radial neurons without significantly affecting mIPSC litude. A subtype selective receptor antagonist and western blots established reversion to expression of the immature glycine receptor subunit GlyRα2 in radial neurons after PNL, consistent with slowed decay times of IPSCs. This study has important implications as it identifies a glycinergic synaptic connection in a specific population of dorsal horn neurons where loss of inhibitory signalling may contribute to signs of neuropathic pain.
The p150Glued CAP-Gly Domain Regulates Initiation of Retrograde Transport at Synaptic Termini
Publisher: Elsevier BV
Date: 04-2012
SMN Is Required for Sensory-Motor Circuit Function in Drosophila
Publisher: Elsevier BV
Date: 10-2012
An SMN-Dependent U12 Splicing Event Essential for Motor Circuit Function
Publisher: Elsevier BV
Date: 10-2012
Orf virus immuno-modulation and the host immune response
Publisher: Elsevier BV
Date: 09-2002
DOI: 10.1016/S0165-2427(02)00087-9
Abstract: Orf virus encodes a range of immuno-modulatory genes that interfere with host anti-virus immune and inflammatory effector mechanisms. The function of these reflects the pathogenesis of orf. The orf virus interferon resistance protein (OVIFNR) and virus IL-10 (vIL-10) inhibit interferon production and activity. In addition the vIL-10 suppresses inflammatory cytokine production by activated macrophages and keratinocytes. The virus GM-CSF inhibitory factor (GIF) is a novel virus protein that binds to and inhibits the biological activity of GM-CSF and IL-2. Together, these immuno-modulators target key effector mechanisms of host anti-virus immunity to allow time for virus replication in epidermal cells.
A Sleep/Wake Circuit Controls Isoflurane Sensitivity in Drosophila
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.CUB.2013.02.021
Abstract: General anesthesia remains a mysterious phenomenon, even though a number of compelling target proteins and processes have been proposed [1]. General anesthetics such as isoflurane abolish behavioral responsiveness in all animals, and in the mammalian brain, these erse compounds probably achieve this in part by targeting endogenous sleep mechanisms [2, 3]. However, most animals sleep [4], and they are therefore likely to have conserved sleep processes. A decade of neurogenetic studies of arousal in Drosophila melanogaster have identified a number of different neurons and brain structures that modulate sleep duration in the fly brain [5-9], but it has remained unclear until recently whether any neurons might form part of a dedicated circuit that actively controls sleep and wake states in the fly brain, as has been proposed for the mammalian brain [10]. We studied general anesthesia in Drosophila by measuring stimulus-induced locomotion under isoflurane gas exposure. Using a syntaxin1A gain-of-function construct, we found that increasing synaptic activity in different Drosophila neurons could produce hypersensitivity or resistance to isoflurane. We uncover a common pathway in the fly brain controlling both sleep duration and isoflurane sensitivity, centered on monoaminergic modulation of sleep-promoting neurons of the fan-shaped body.
Regulation of Fasciclin II and Synaptic Terminal Development by the Splicing Factor Beag
Publisher: Society for Neuroscience
Date: 16-05-2012
DOI: 10.1523/JNEUROSCI.3717-11.2012
Abstract: Pre-mRNA alternative splicing is an important mechanism for the generation of synaptic protein ersity, but few factors governing this process have been identified. From a screen for Drosophila mutants with aberrant synaptic development, we identified beag , a mutant with fewer synaptic boutons and decreased neurotransmitter release. Beag encodes a spliceosomal protein similar to splicing factors in humans and Caenorhabditis elegans . We find that both beag mutants and mutants of an interacting gene dsmu1 have changes in the synaptic levels of specific splice isoforms of Fasciclin II (FasII), the Drosophila ortholog of neural cell adhesion molecule. We show that restoration of one splice isoform of FasII can rescue synaptic morphology in beag mutants while expression of other isoforms cannot. We further demonstrate that this FasII isoform has unique functions in synaptic development independent of transsynaptic adhesion. beag and dsmu1 mutants demonstrate an essential role for these previously uncharacterized splicing factors in the regulation of synapse development and function.
A comparison of the anti-inflammatory and immuno-stimulatory activities of orf virus and ovine interleukin-10
Publisher: Elsevier BV
Date: 12-2002
DOI: 10.1016/S0168-1702(02)00252-6
Abstract: Orf virus causes pustular skin lesions (orf) in sheep, goats and humans. The virus encodes an interleukin-10 (orfvIL-10) that is identical in amino acid composition to ovine IL-10 (ovIL-10) over the C terminal two-thirds of the polypeptide, but not in the N terminal third. The immuno-suppressive and immuno-stimulatory activities of orfvIL-10 and ovIL-10 were compared. Both orfvIL-10 and ovIL-10 inhibited TNF-alpha and IL-8 cytokine production from stimulated ovine macrophages and keratinocytes and IFN-gamma and GM-CSF production from peripheral blood lymphocytes. OrfvIL-10 and ovIL-10 co-stimulated both ovine and murine mast cell proliferation in conjunction with IL-3 (ovine) or IL-4 (murine). Isoleucine at position 87 (Ile(87)) of the mature human IL-10 (huIL-10) has been reported as essential for the immuno-stimulatory activity of huIL-10. In spite of the differences in amino acids within the N-terminal third of orfvIL-10 compared with ovIL-10 and substitution of Ile(87) with Ala(87) in ovIL-10, these variants of ovIL-10 and orfvIL-10 all co-stimulated mast cell proliferation and inhibited macrophage IL-8 production. As ovIL-10 and orfvIL-10 have a similar structure to huIL-10 and conserved receptor-binding residues, it was concluded that Ile(87) is not essential for IL-10 immuno-stimulatory activity. Finally, ovine keratinocytes do not express ovIL-10. This might explain why orf virus has evolved a viral IL-10.
Structural determinants of lolitrems for inhibition of BK large conductance Ca(2+)-activated K(+) channels
Publisher: Elsevier BV
Date: 03-2009
DOI: 10.1016/J.EJPHAR.2008.12.031
Abstract: Lolitrem B is an indole-diterpenoid neurotoxin which is the main causative agent of ryegrass staggers, an animal disease associated with tremors and incoordination. It is also a potent inhibitor of large conductance calcium-activated potassium (BK) channel activity (IC(50)=4 nM). Furthermore, we have recently shown that the motor function deficits induced by lolitrem B are specifically mediated by BK channels, making the toxin a valuable tool for investigating the molecular function and physiological roles of these channels. To determine what structural features of BK channel agents are required for high potency, the effect of lolitrem B and seven structurally-related lolitrems on BK channel activity has been measured. Concentration-responses and conductance-voltage (G-V) relationships were determined for each compound and related to the different structure types. This study has identified seven new BK channel inhibitors and has allowed the identification of two key structural features required for high potency BK channel activity by lolitrems.
New approaches to target glycinergic neurotransmission for the treatment of chronic pain
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.PHRS.2016.12.019
Abstract: Inhibitory glycinergic neurotransmission in the spinal cord dorsal horn plays an important role in regulating nociceptive signalling by inhibiting neuronal excitation. Blocking glycinergic transmission in the dorsal horn causes normally innocuous stimuli to become painful (allodynia) and increases sensitivity to noxious stimuli (hyperalgesia). Loss of inhibitory signalling is thought to contribute to the development of pathological pain. Management of neuropathic pain with current therapeutics is challenging and there is a great need for more effective treatments. Preclinical studies using drugs that increase glycinergic signalling by potentiating glycine receptor activity or inhibiting transporter activity suggest that targeting this system is a good therapeutic strategy. The spatially restricted expression of glycine receptors and transporters is an advantage for targeting specific pathologies such as pain. However, until recently there have been few pharmacological modulators identified and most of which do not specifically target glycinergic signalling. This mini-review provides an overview of recent advances in the development of therapeutics and novel approaches that aim to increase glycinergic neurotransmission for the treatment of persistent pain.
Activity of novel lipid glycine transporter inhibitors on synaptic signalling in the dorsal horn of the spinal cord
Publisher: Wiley
Date: 14-04-2018
DOI: 10.1111/BPH.14189
A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain
Publisher: Springer Science and Business Media LLC
Date: 04-11-2019
A positive allosteric modulator of the adenosine A1 receptor selectively inhibits primary afferent synaptic transmission in a neuropathic pain model
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 23-06-2015
Abstract: In the spinal cord and periphery, adenosine inhibits neuronal activity through activation of the adenosine A1 receptor (A1R), resulting in antinociception and highlighting the potential of therapeutically targeting the receptor in the treatment of neuropathic pain. This study investigated the changes in adenosine tone and A1R signaling, together with the actions of a novel A1R positive allosteric modulator (PAM), VCP171 [(2-amino-4-(3-(trifluoromethyl)phenyl)thiophen-3-yl)(phenyl)methanone], on excitatory and inhibitory neurotransmission at spinal cord superficial dorsal horn synapses in a rat partial nerve-injury model of neuropathic pain. In the absence of A1R agonists, superfusion of the A1R antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX 1 μM), produced a significantly greater increase in electrically evoked α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated synaptic current (eEPSC) litude in both lamina I and II neurons from nerve-injured animals than in controls, suggesting that endogenous adenosine tone is increased in the dorsal horn. Inhibitory GABAergic and glycinergic synaptic currents were also significantly increased by DPCPX in controls but there was no difference after nerve injury. The A1R agonist, N6-cyclopentyladenosine, produced greater inhibition of eEPSC litude in lamina II but not lamina I of the spinal cord dorsal horn in nerve-injured versus control animals, suggesting a functional increase in A1R sensitivity in lamina II neurons after nerve injury. The A1R PAM, VCP171, produced a greater inhibition of eEPSC litude of nerve-injury versus control animals in both lamina I and lamina II neurons. Enhanced adenosine tone and A1R sensitivity at excitatory synapses in the dorsal horn after nerve injury suggest that new generation PAMs of the A1R can be effective treatments for neuropathic pain.
Related Organisations
Related Funding Activities
Discovery Projects - Grant ID: DP190102854
Start Date: 06-2019
End Date: 12-2024
Amount: $401,651.00
Funder: Australian Research Council
View Funded Activity