Publication:
The α7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception in mouse models of inflammatory and neuropathic pain

dc.contributor.authorWilkerson, Jenny L.
dc.contributor.authorKulkarni, Abhijit
dc.contributor.authorToma, Wisam
dc.contributor.authorAlSharari, Shakir
dc.contributor.authorLichtman, Aron H.
dc.contributor.authorPapke, Roger L.
dc.contributor.authorThakur, Ganesh A.
dc.contributor.authorDamaj, M. Imad
dc.contributor.buuauthorBağdaş, Deniz
dc.contributor.buuauthorGül, Zülfiye
dc.contributor.departmentTıp Fakültesi
dc.contributor.departmentTıp Fakültesi
dc.contributor.departmentFarmakoloji Ana Bilim Dalı
dc.contributor.departmentDeney Hayvanları Yetiştirme ve Araştırma Merkezi
dc.contributor.orcid0000-0002-8872-0074
dc.contributor.researcheridAAF-9939-2020
dc.contributor.scopusid15062425700
dc.contributor.scopusid56086542900
dc.date.accessioned2022-10-31T07:34:21Z
dc.date.available2022-10-31T07:34:21Z
dc.date.issued2016-05-17
dc.description.abstractBackground and PurposeOrthosteric agonists and positive allosteric modulators (PAMs) of the 7 nicotinic ACh receptor (nAChR) represent novel therapeutic approaches for pain modulation. Moreover, compounds with dual function as allosteric agonists and PAMs, known as ago-PAMs, add further regulation of receptor function. Experimental ApproachInitial studies examined the 7 ago-PAM, GAT107, in the formalin, complete Freund's adjuvant (CFA), LPS inflammatory pain models, the chronic constriction injury neuropathic pain model and the tail flick and hot plate acute thermal nociceptive assays. Additional studies examined the locus of action of GAT107 and immunohistochemical markers in the dorsal horn of the spinal cord in the CFA model. Key ResultsComplementary pharmacological and genetic approaches confirmed that the dose-dependent antinociceptive effects of GAT107 were mediated through 7 nAChR. However, GAT107 was inactive in the tail flick and hot plate assays. In addition, GAT107 blocked conditioned place aversion elicited by acetic acid injection. Furthermore, intrathecal, but not intraplantar, injections of GAT107 reversed nociception in the CFA model, suggesting a spinal component of action. Immunohistochemical evaluation revealed an increase in the expression of astrocyte-specific glial fibrillary acidic protein and phosphorylated p38MAPK within the spinal cords of mice treated with CFA, which was attenuated by intrathecal GAT107 treatment. Importantly, GAT107 did not elicit motor impairment and continued to produce antinociceptive effects after subchronic administration in both phases of the formalin test. Conclusions and ImplicationsCollectively, these results provide the first proof of principle that 7 ago-PAMs represent an effective pharmacological strategy for treating inflammatory and neuropathic pain.
dc.description.sponsorshipPilot Project from VCU Massey Cancer Center
dc.description.sponsorshipUnited States Department of Health & Human Services
dc.description.sponsorshipNational Institutes of Health (NIH) - USA - DA032246
dc.description.sponsorshipNIH National Institute on Drug Abuse (NIDA)
dc.description.sponsorshipEuropean Commission
dc.description.sponsorshipUnited States Department of Health & Human Services National Institutes of Health (NIH) - USA - GM57481 - EY024717 - DA038493-01A1
dc.description.sponsorshipR01DA032246
dc.description.sponsorshipP30DA033934
dc.description.sponsorshipF32DA038493
dc.identifier.citationBağdaş, D. vd. (2016). "The α7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception in mouse models of inflammatory and neuropathic pain". British Journal of Pharmacology, 173(16), 2506-2520.
dc.identifier.endpage2520
dc.identifier.issn0007-1188
dc.identifier.issn1476-5381
dc.identifier.issue16
dc.identifier.pubmed27243753
dc.identifier.scopus2-s2.0-84979263757
dc.identifier.startpage2506
dc.identifier.urihttps://doi.org/10.1111/bph.13528
dc.identifier.urihttps://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.13528
dc.identifier.urihttp://hdl.handle.net/11452/29268
dc.identifier.volume173
dc.identifier.wos000380886900004
dc.indexed.wosSCIE
dc.language.isoen
dc.publisherWiley
dc.relation.collaborationYurt dışı
dc.relation.journalBritish Journal of Pharmacology
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi
dc.relation.tubitak2219-2013
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectPharmacology & pharmacy
dc.subjectAcetylcholine-receptor
dc.subjectAnimal-models
dc.subjectConcise guide
dc.subjectP38 mapk
dc.subjectActivation
dc.subjectPharmacology
dc.subjectNeuroprotection
dc.subjectPublication
dc.subjectAllodynia
dc.subjectCognition
dc.subject.emtreeFreund adjuvant
dc.subject.emtreeGat 107
dc.subject.emtreeGlial fibrillary acidic protein
dc.subject.emtreeLipopolysaccharide
dc.subject.emtreeMitogen activated protein kinase p38
dc.subject.emtreeNicotinic agent
dc.subject.emtreeUnclassified drug
dc.subject.emtreeAdult
dc.subject.emtreeAnimal experiment
dc.subject.emtreeAnimal model
dc.subject.emtreeAntinociception
dc.subject.emtreeArticle
dc.subject.emtreeCohort analysis
dc.subject.emtreeControlled study
dc.subject.emtreeFormalin test
dc.subject.emtreeHot plate test
dc.subject.emtreeImmunohistochemistry
dc.subject.emtreeMale
dc.subject.emtreeMouse
dc.subject.emtreeNeuropathic pain
dc.subject.emtreeNociception
dc.subject.emtreeNonhuman
dc.subject.emtreePriority journal
dc.subject.emtreeProtein expression
dc.subject.emtreeProtein phosphorylation
dc.subject.emtreeSpinal cord
dc.subject.emtreeTail flick test
dc.subject.scopusInflammation; Methyllycaconitine; 3-(2,4-Dimethoxybenzylidene)Anabaseine
dc.subject.wosPharmacology & pharmacy
dc.titleThe α7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception in mouse models of inflammatory and neuropathic pain
dc.typeArticle
dspace.entity.typePublication
local.contributor.departmentTıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi
local.contributor.departmentTıp Fakültesi/Farmakoloji Ana Bilim Dalı
local.indexed.atScopus
local.indexed.atWOS

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