title: Systemic administration of an alpha-7 nicotinic acetylcholine agonist reverses neuropathic pain in male Sprague Dawley rats.
abstract: Alpha-7 nicotinic acetylcholine receptor (α7 nAChR) agonists attenuate pain and inflammation in preclinical models. This study tested whether systemic delivery of an α7 nAChR agonist attenuates neuropathic pain and associated immune-mediated pro-inflammation. Hind paw response thresholds to mechanical stimuli in male Sprague Dawley rats were assessed before and after sciatic chronic constriction injury (CCI) or sham surgery. Osmotic mini-pumps containing TC-7020, an α7 nAChR selective agonist, were implanted 10 to 14 days after surgery. TC-7020 (1, 3, and 10 mg/kg/d; s.c.) significantly attenuated CCI-induced allodynia, which lasted through 2 weeks of test compound administration. Spinal cords were collected after 2 weeks and processed for microglial and astrocyte activation markers within the ipsilateral L4-L6 dorsal horn. In addition, ipsilateral L4-5 dorsal root ganglia (DRGs) were processed for neuronal injury and satellite cell activation markers. CCI-induced central glial cell activation markers were not suppressed by TC-7020, even though TC-7020 is mildly blood-brain barrier permeable. However, TC-7020 downregulated the integrated density of activation transcription factor 3 (ATF3) but not the number of ATF positive cells. TC-7020 also downregulated phosphorylated extracellular signal kinase (p-ERK) and satellite cell activation in the CCI-affected DRGs. Therefore, systemic α7 nAChR agonist may be effective in treating neuropathic pain via reducing neuronal injury and immune cells activation occurring in the periphery.
  
  
  CONCLUSIONS
  These studies demonstrated that TC-7020, an alpha7 nicotinic acetylcholine receptor agonist with partial blood-brain barrier permeability, reversed neuropathic pain in rats, likely via attenuation of inflammation in the DRG and/or the site of sciatic injury.
authors.affiliation: Department of Psychology & Neuroscience, and Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA. Lisa.Loram@colorado.edu
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Loram
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Taylor
authors.forename: Keith A
authors.initials: KA
authors.lastname: Strand
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
authors.forename: Jason D
authors.initials: JD
authors.lastname: Speake
authors.forename: Kristen G
authors.initials: KG
authors.lastname: Jordan
authors.forename: John W
authors.initials: JW
authors.lastname: James
authors.forename: Steven P
authors.initials: SP
authors.lastname: Wene
authors.forename: Robert C
authors.initials: RC
authors.lastname: Pritchard
authors.forename: Heather
authors.initials: H
authors.lastname: Green
authors.forename: Katherine
authors.initials: K
authors.lastname: Van Dyke
authors.forename: Anatoly
authors.initials: A
authors.lastname: Mazarov
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Letchworth
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
mesh_terms: D000818:Animals; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D011812:Quinuclidines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D013876:Thiophenes / Q000008:administration & dosage*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C573434:5-methyl-N-(2-(pyridin-3-ylmethyl)-1-azabicyclo(2.2.2)oct-3-yl)thiophene-2-carboxamide; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D013876:Thiophenes; D064569:alpha7 Nicotinic Acetylcholine Receptor