title: A selective α2 B adrenoceptor agonist (A-1262543) and duloxetine modulate nociceptive neurones in the medial prefrontal cortex, but not in the spinal cord of neuropathic rats.
abstract: BACKGROUND
  The noradrenergic system contributes to pain modulation, but the roles of its specific adrenoceptors are still being defined. We have identified a novel, potent (rat EC50  = 4.3 nM) and selective α2B receptor agonist, A-1262543, to further explore this adrenoceptor subtype's contribution to pathological nociception.
  
  
  METHODS
  Systemic administration of A-1262543 (1-10 mg/kg, intraperitoneal) dose-dependently attenuated mechanical allodynia in animals with a spinal nerve ligation injury. To further explore its mechanism of action, the activity of nociceptive neurones in the spinal cord and medial prefrontal cortex (mPFC) were examined after injection of 3 mg/kg of A-1262543 (intravenous, i.v.). These effects were compared with duloxetine (3 mg/kg, i.v.), a dual noradrenaline (NA) and serotonin (5-HT) reuptake inhibitor.
  
  
  RESULTS
  Systemic administration of A-1262543 or duloxetine did not alter the spontaneous or evoked firing of spinal wide dynamic range and nociceptive-specific neurones in the neuropathic rats, indicating that neither compound engaged spinal, peripheral or descending pathways. In contrast to the lack of effect on spinal neurones, both A-1262543 and duloxetine reduced the evoked and spontaneous firing of 'pain-responsive' (PR) neurones in the mPFC. Duloxetine, but not A-1262543, also inhibited the firing of pain non-responsive (nPR) neurones in the mPFC probably reflecting duloxetine's contribution to modulating non-pain endpoints.
  
  
  CONCLUSIONS
  These data highlight that activation of the α2B adrenoceptor as well as inhibiting NA and 5-HT reuptake can result in modulating the ascending nociceptive system, and in particular, dampening the firing of PR neurones in the mPFC.
authors.affiliation: Neuroscience Research, AbbVie, North Chicago, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Chu
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: J
authors.initials: J
authors.lastname: Frost
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: E
authors.initials: E
authors.lastname: Gomez
authors.forename: M J
authors.initials: MJ
authors.lastname: Dart
authors.forename: M F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: M D
authors.initials: MD
authors.lastname: Meyer
authors.forename: S
authors.initials: S
authors.lastname: McGaraughty
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000316:Adrenergic alpha-Agonists / Q000627:therapeutic use*; D000814:Aniline Compounds / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride / Q000627:therapeutic use*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D048288:Imidazolines / Q000627:therapeutic use*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy*; D009474:Neurons / Q000187:drug effects*; D009619:Nociceptors / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects*; D013127:Spinal Nerves / Q000293:injuries
chemical_list: C000603948:A-1262543; D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D000814:Aniline Compounds; D048288:Imidazolines; D018341:Receptors, Adrenergic, alpha-2; D000068736:Duloxetine Hydrochloride