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Effects of GAT107, an Allosteric Agonist and Positive Modulator of α7 Nicotinic Acetylcholine Receptors, on Chronic Inflammatory and Neuropathic Pain in Mice
Author(s) -
Bagdas Deniz,
Wilkerson Jenny,
Lichtman Aron,
Thakur Ganesh,
Damaj M Imad
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.616.12
Subject(s) - allosteric modulator , neuropathic pain , nicotinic agonist , pharmacology , chronic pain , allosteric regulation , nociception , nicotine , agonist , acetylcholine receptor , analgesic , medicine , chemistry , neuroscience , receptor , psychology
Agonists and positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (nAChRs) are currently being considered as novel therapeutic approaches for pain modulation. Recent discovery of compounds that can function as dual allosteric agonists and PAMs (ago‐PAMs) added a new pharmacological approach for the regulation of α7 nAChR function. GAT107 [(+)‐enantiomer of racemic 4‐(4‐bromophenyl)‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta[c]quinoline‐8‐sulfonamide] is such an agent which has been shown to be an α7‐selective ago‐PAM. The present study investigated whether GAT107 attenuates chronic inflammatory and neuropathic pain in mice. We found that systemic administration of GAT107 significantly reversed pain behaviors in formalin test, complete Freud adjuvant (CFA)‐ and lipopolysaccharide‐induced inflammatory pain, chronic constriction injury‐induced neuropathic pain, without motor impairment. GAT107 failed to show antinociceptive effects on acute thermal stimulus. The antinociceptive effects of GAT107 were mediated by of α7 nAChRs. Our sites studies suggest that spinal but not peripheral sites mediate in the effect of GAT107 in CFA model. Finally, GAT107 blocked pain‐induced aversion after acetic acid injection, using a conditioned place aversion test. The present results suggest that α7 nAChR modulation by ago‐PAMs may provide new targets in inflammatory and neuropathic pain. This work was supported by VCU Massey Cancer Center, TUBITAK (2219).