title: The α7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU-120596 both alleviate inflammatory hyperalgesia and cytokine release in the rat.
abstract: OBJECTIVE
  Agonists selective for the α7 nicotinic acetylcholine (nACh) receptor produce anti-hyperalgesic effects in rodent models of inflammatory pain, via direct actions on spinal pain circuits and possibly via attenuated release of peripheral pro-inflammatory mediators. Increasingly, allosteric modulation of ligand-gated receptors is recognized as a potential strategy to obtain desired efficacy in the absence of the putative adverse effects associated with agonist activation.
  
  
  METHODS
  We compared the anti-hyperalgesic and anti-inflammatory effects of the α7 nACh receptor agonist compound B with the positive allosteric modulator (PAM) PNU-120596 and the standard non-steroidal anti-inflammatory drug (NSAID), diclofenac, in rats with hind paw inflammation induced by either formalin, carrageenan or complete Freund's adjuvant (CFA).
  
  
  RESULTS
  When administered before carrageenan, both diclofenac (30 mg·kg(-1) ) and PNU-120596 (30 mg·kg(-1) ) significantly reduced mechanical hyperalgesia and weight-bearing deficits for up to 4 h. Compound B (30 mg·kg(-1) ) also attenuated both measures of pain-like behaviour, albeit less robustly. Whereas compound B and PNU-120596 attenuated the carrageenan-induced increase in levels of TNF-α and IL-6 within the hind paw oedema, diclofenac only attenuated IL-6 levels. Established mechanical hyperalgesia induced by carrageenan or CFA was also partially reversed by compound B and PNU-120596. However, diclofenac was considerably more efficacious. Formalin-induced nocifensive behaviours were only reversed by compound B, albeit at doses which disrupted motor performance.
  
  
  CONCLUSIONS
  α7 nACh receptor PAMs could prove to be useful in the treatment of inflammatory pain conditions, which respond poorly to NSAIDs or in situations where NSAIDs are contra-indicated.
authors.affiliation: Department of Pharmacology, NeuroSearch A/S, Ballerup, Denmark. gmun@lundbeck.com
authors.forename: G
authors.initials: G
authors.lastname: Munro
authors.forename: Rr
authors.initials: R
authors.lastname: Hansen
authors.forename: Hk
authors.initials: H
authors.lastname: Erichsen
authors.forename: Db
authors.initials: D
authors.lastname: Timmermann
authors.forename: Jk
authors.initials: J
authors.lastname: Christensen
authors.forename: Hh
authors.initials: H
authors.lastname: Hansen
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D053961:Azabicyclo Compounds / Q000627:therapeutic use*; D002351:Carrageenan / Q000633:toxicity; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004008:Diclofenac / Q000627:therapeutic use; D005620:Freund's Adjuvant / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D007555:Isoxazoles / Q000627:therapeutic use*; D008297:Male; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013876:Thiophenes / Q000627:therapeutic use*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D000894:Anti-Inflammatory Agents, Non-Steroidal; D053961:Azabicyclo Compounds; C579165:Chrna7 protein, rat; D016207:Cytokines; D007555:Isoxazoles; C577083:N-(1-azabicyclo(2.2.2)oct-3-yl)(5-(2-pyridyl)thiopene-2-carboxamide); D010671:Phenylurea Compounds; D011978:Receptors, Nicotinic; D013876:Thiophenes; D064569:alpha7 Nicotinic Acetylcholine Receptor; D004008:Diclofenac; D002351:Carrageenan; D005620:Freund's Adjuvant