ADX71943 and ADX71441, novel positive allosteric modulators of the GABA B receptor with distinct central/peripheral profiles, show efficacy in the monosodium iodoacetate model of chronic osteoarthritis pain in the rat

Kalinichev, Mikhail; Donovan-Rodríguez, Tansy; Girard, Françoise; Haddouk, Hasnaà; Royer-Urios, Isabelle; Schneider, Manfred; Bate, Simon T.; Marker, Cheryl L.; Pomonis, James D.; Poli, Sonia

doi:10.1016/j.ejphar.2016.11.056

Cited by 11 publications

(2 citation statements)

References 25 publications

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“…However, since α-conotoxins exhibit analgesic properties when administered in peripheral tissues and conotoxins generally have little or no blood–brain barrier penetration, central activation of GABA B R may not be required for analgesia. A peripheral mode of action is consistent with the observations that α-conotoxins Vc1.1 and RgIA do not produce cognitive side effects or tolerance [ 127 , 129 , 130 ] and that peripherally acting GABA B R PAMs display analgesic activity in acute and chronic pain models but have no effect in cognitive behavioural tests [ 156 , 157 ]. This selectivity for inhibition of peripheral sensory neurons might bestow α-conotoxins with the advantage of greater therapeutic windows compared to conventional analgesics which are heavily limited by invasive injections, severe side effects, tolerance and addiction.…”

Section: Analgesic Venom Peptides Targeting Gpcrssupporting

confidence: 82%

G-Protein Coupled Receptors Targeted by Analgesic Venom Peptides

Daniel

Clark

2017

Toxins

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Chronic pain is a complex and debilitating condition associated with a large personal and socioeconomic burden. Current pharmacological approaches to treating chronic pain such as opioids, antidepressants and anticonvulsants exhibit limited efficacy in many patients and are associated with dose-limiting side effects that hinder their clinical use. Therefore, improved strategies for the pharmacological treatment of pathological pain are urgently needed. G-protein coupled receptors (GPCRs) are ubiquitously expressed on the surface of cells and act to transduce extracellular signals and regulate physiological processes. In the context of pain, numerous and diverse families of GPCRs expressed in pain pathways regulate most aspects of physiological and pathological pain and are thus implicated as potential targets for therapy of chronic pain. In the search for novel compounds that produce analgesia via GPCR modulation, animal venoms offer an enormous and virtually untapped source of potent and selective peptide molecules. While many venom peptides target voltage-gated and ligand-gated ion channels to inhibit neuronal excitability and blunt synaptic transmission of pain signals, only a small proportion are known to interact with GPCRs. Of these, only a few have shown analgesic potential in vivo. Here we review the current state of knowledge regarding venom peptides that target GPCRs to produce analgesia, and their development as therapeutic compounds.

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Section: Analgesic Venom Peptides Targeting Gpcrssupporting

confidence: 82%

G-Protein Coupled Receptors Targeted by Analgesic Venom Peptides

Daniel

Clark

2017

Toxins

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“…Authors have demonstrated that ERBB4 is closely related to gamma-aminobutyric acid transmission and synaptic plasticity [41][42][43] . Gamma-aminobutyric acid receptor B is also involved in the regulation of acute and chronic pain in rats, including chronic OA pain [44][45][46] . However, whether ERBB4 plays a role in the process of OA remains unconfirmed.…”

Section: Discussionmentioning

confidence: 99%

Integrated bioinformatics analysis of cartilage for osteoarthritis

Wang

Zhong

Lin

et al. 2020

Preprint

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Background Osteoarthritis (OA) is a joint disease which threatens the health of older people around the world. However, its pathological mechanism remains unclear. In the current study, we aimed to identify the key genes and underlying pathological mechanisms associated with OA. Methods Firstly, GSE117999 was obtained from the Gene Expression Omnibus (GEO) database. We then obtained the DEGs, hub genes and key genes of the dataset using bioinformatics analysis, after which we analyzed these items using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). Furthermore, the target miRNAs of key genes were predicted by miRDB. The Drug Gene Interaction database (DGIdb) was used to predict target drugs for key genes. Receiver operating characteristic (ROC) analysis was employed to evaluate the effectiveness of key genes. Results: A total of 974 DEGs were identified. Furthermore, we found 19 hub genes and 10 key genes. We then predicted that hsa-mir-3613-3p, hsa-mir-548e-5p and hsa-mir-5692a would be closely related to key genes through web tools, and that two drugs, etoposide and everolimus, were highly specific to some key genes. Finally, we analyzed the receiver operating characteristic (ROC) of key genes in the samples and speculated that ESR1 may be a biomarker of OA. Conclusions This study deepens our understanding of OA and may be beneficial for further explorations of the pathological mechanism of the disease.

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GABAB Receptors and Pain

Benke

2020

Behavioral Neurobiology of GABAB Receptor Function

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ADX71943 and ADX71441, novel positive allosteric modulators of the GABA B receptor with distinct central/peripheral profiles, show efficacy in the monosodium iodoacetate model of chronic osteoarthritis pain in the rat

Cited by 11 publications

References 25 publications

G-Protein Coupled Receptors Targeted by Analgesic Venom Peptides

G-Protein Coupled Receptors Targeted by Analgesic Venom Peptides

Integrated bioinformatics analysis of cartilage for osteoarthritis

GABAB Receptors and Pain

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