title: The α7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception in mouse models of inflammatory and neuropathic pain.
abstract: Orthosteric agonists and positive allosteric modulators (PAMs) of the α7 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.
  
  
  
  Initial studies examined the α7 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.
  
  
  
  Complementary pharmacological and genetic approaches confirmed that the dose-dependent antinociceptive effects of GAT107 were mediated through α7 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.
  
  
  
  Collectively, these results provide the first proof of principle that α7 ago-PAMs represent an effective pharmacological strategy for treating inflammatory and neuropathic pain.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.|Experimental Animals Breeding and Research Center, Faculty of Medicine, Uludag University, Bursa, Turkey.
authors.forename: Deniz
authors.initials: D
authors.lastname: Bagdas
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wilkerson
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Wisam
authors.initials: W
authors.lastname: Toma
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.|Department of Pharmacology and Toxicology, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Shakir
authors.initials: S
authors.lastname: AlSharari
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Uludag University, Bursa, Turkey.
authors.forename: Zulfiye
authors.initials: Z
authors.lastname: Gul
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Papke
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
authors.forename: Ganesh A
authors.initials: GA
authors.lastname: Thakur
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: M Imad
authors.initials: MI
authors.lastname: Damaj
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000188:drug therapy* / Q000517:prevention & control*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: C578201:4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinoline-8-sulfonamide; D011804:Quinolines; D013449:Sulfonamides; D064569:alpha7 Nicotinic Acetylcholine Receptor