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28 results on '"Imlach, Wendy L."'

3. Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia

Author

Draper-Joyce, Christopher J., Bhola, Rebecca, Wang, Jinan, Bhattarai, Apurba, Nguyen, Anh T. N., Cowie-Kent, India, O’Sullivan, Kelly, Chia, Ling Yeong, Venugopal, Hariprasad, Valant, Celine, Thal, David M., Wootten, Denise, Panel, Nicolas, Carlsson, Jens, Christie, Macdonald J., White, Paul J., Scammells, Peter, May, Lauren T., Sexton, Patrick M., Danev, Radostin, Miao, Yinglong, Glukhova, Alisa, Imlach, Wendy L., and Christopoulos, Arthur

Published
2021
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6. Therapeutic antagonism of the neurokinin 1 receptor in endosomes provides sustained pain relief

Author

Hegron, Alan, primary, Peach, Chloe J., additional, Tonello, Raquel, additional, Seemann, Philipp, additional, Teng, Shavonne, additional, Latorre, Rocco, additional, Huebner, Harald, additional, Weikert, Dorothee, additional, Rientjes, Jeanette, additional, Veldhuis, Nicholas A., additional, Poole, Daniel P., additional, Jensen, Dane D., additional, Thomsen, Alex R. B., additional, Schmidt, Brian L., additional, Imlach, Wendy L., additional, Gmeiner, Peter, additional, and Bunnett, Nigel W., additional

Published
2023
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15. Positive allosteric mechanisms of adenosine A1receptor-mediated analgesia

Author

Draper-Joyce, Christopher J., Bhola, Rebecca, Wang, Jinan, Bhattarai, Apurba, Nguyen, Anh T. N., Cowie-Kent, India, O’Sullivan, Kelly, Chia, Ling Yeong, Venugopal, Hariprasad, Valant, Celine, Thal, David M., Wootten, Denise, Panel, Nicolas, Carlsson, Jens, Christie, Macdonald J., White, Paul J., Scammells, Peter, May, Lauren T., Sexton, Patrick M., Danev, Radostin, Miao, Yinglong, Glukhova, Alisa, Imlach, Wendy L., and Christopoulos, Arthur

Abstract

The adenosine A1receptor (A1R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain1,2. However, development of analgesic orthosteric A1R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects3. Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the A1R, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the A1R co-bound to adenosine, MIPS521 and a Gi2heterotrimer, revealing an extrahelical lipid–detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine–receptor–G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts.

Published
2021
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18. Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief

Author

Jensen, Dane D., primary, Lieu, TinaMarie, additional, Halls, Michelle L., additional, Veldhuis, Nicholas A., additional, Imlach, Wendy L., additional, Mai, Quynh N., additional, Poole, Daniel P., additional, Quach, Tim, additional, Aurelio, Luigi, additional, Conner, Joshua, additional, Herenbrink, Carmen Klein, additional, Barlow, Nicholas, additional, Simpson, Jamie S., additional, Scanlon, Martin J., additional, Graham, Bimbil, additional, McCluskey, Adam, additional, Robinson, Phillip J., additional, Escriou, Virginie, additional, Nassini, Romina, additional, Materazzi, Serena, additional, Geppetti, Pierangelo, additional, Hicks, Gareth A., additional, Christie, Macdonald J., additional, Porter, Christopher J. H., additional, Canals, Meritxell, additional, and Bunnett, Nigel W., additional

Published
2017
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19. Correction: Corrigendum: Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a

Author

Deuis, Jennifer R., primary, Dekan, Zoltan, additional, Wingerd, Joshua S., additional, Smith, Jennifer J., additional, Munasinghe, Nehan R., additional, Bhola, Rebecca F., additional, Imlach, Wendy L., additional, Herzig, Volker, additional, Armstrong, David A., additional, Rosengren, K. Johan, additional, Bosmans, Frank, additional, Waxman, Stephen G., additional, Dib-Hajj, Sulayman D., additional, Escoubas, Pierre, additional, Minett, Michael S., additional, Christie, Macdonald J., additional, King, Glenn F., additional, Alewood, Paul F., additional, Lewis, Richard J., additional, Wood, John N., additional, and Vetter, Irina, additional

Published
2017
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20. Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a

Author

Deuis, Jennifer R., primary, Dekan, Zoltan, additional, Wingerd, Joshua S., additional, Smith, Jennifer J., additional, Munasinghe, Nehan R., additional, Bhola, Rebecca F., additional, Imlach, Wendy L., additional, Herzig, Volker, additional, Armstrong, David A., additional, Rosengren, K. Johan, additional, Bosmans, Frank, additional, Waxman, Stephen G., additional, Dib-Hajj, Sulayman D., additional, Escoubas, Pierre, additional, Minett, Michael S., additional, Christie, Macdonald J., additional, King, Glenn F., additional, Alewood, Paul F., additional, Lewis, Richard J., additional, Wood, John N., additional, and Vetter, Irina, additional

Published
2017
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25. A Positive Allosteric Modulator of the Adenosine A1Receptor Selectively Inhibits Primary Afferent Synaptic Transmission in a Neuropathic Pain Model

Author

Imlach, Wendy L., Bhola, Rebecca F., May, Lauren T., Christopoulos, Arthur, and Christie, Macdonald J.

Abstract

In the spinal cord and periphery, adenosine inhibits neuronal activity through activation of the adenosine A1receptor (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) amplitude 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 amplitude 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 amplitude 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.

Published
2015
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26. Regulation of Fasciclin II and Synaptic Terminal Development by the Splicing Factor Beag.

Author

Beck, Erin S., Gasque, Gabriel, Imlach, Wendy L., Wei Jiao, Choi, Ben Jiwon, Pao-Shu Wu, Kraushar, Matthew L., and McCabe, Brian D.

Subjects
GENETIC regulation, DEVELOPMENTAL neurobiology, MESSENGER RNA, DROSOPHILA, NEUROTRANSMITTERS, GENE expression, NEURON development
Abstract

Pre-mRNA alternative splicing is an important mechanism for the generation of synaptic protein diversity, 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. [ABSTRACT FROM AUTHOR]

Published
2012
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27. Corrigendum: Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a.

Author

Deuis, Jennifer R., Dekan, Zoltan, Wingerd, Joshua S., Smith, Jennifer J., Munasinghe, Nehan R., Bhola, Rebecca F., Imlach, Wendy L., Herzig, Volker, Armstrong, David A., Rosengren, K. Johan, Bosmans, Frank, Waxman, Stephen G., Dib-Hajj, Sulayman D., Escoubas, Pierre, Minett, Michael S., Christie, Macdonald J., King, Glenn F., Alewood, Paul F., Lewis, Richard J., and Wood, John N.

Published
2017
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28. Pathological Mechanisms and Therapeutic Targets for Trigeminal Neuropathic Pain.

Author

Bista P and Imlach WL

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., Competing Interests: The authors declare no conflict of interest.

Published
2019
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