title: Characterization of the antinociceptive actions of bicifadine in models of acute, persistent, and chronic pain.
abstract: Bicifadine (1-p-tolyl-3-azabicyclo[3.1.0]hexane) inhibits monoamine neurotransmitter uptake by recombinant human transporters in vitro with a relative potency of norepinephrine > serotonin > dopamine (approximately 1:2:17). This in vitro profile is supported by microdialysis studies in freely moving rats, where bicifadine (20 mg/kg i.p.) increased extrasynaptic norepinephrine and serotonin levels in the prefrontal cortex, norepinephrine levels in the locus coeruleus, and dopamine levels in the striatum. Orally administered bicifadine is an effective antinociceptive in several models of acute, persistent, and chronic pain. Bicifadine potently suppressed pain responses in both the Randall-Selitto and kaolin models of acute inflammatory pain and in the phenyl-p-quinone-induced and colonic distension models of persistent visceral pain. Unlike many transport inhibitors, bicifadine was potent and completely efficacious in both phases of the formalin test in both rats and mice. Bicifadine also normalized the nociceptive threshold in the complete Freund's adjuvant model of persistent inflammatory pain and suppressed mechanical and thermal hyperalgesia and mechanical allodynia in the spinal nerve ligation model of chronic neuropathic pain. Mechanical hyperalgesia was also reduced by bicifadine in the streptozotocin model of neuropathic pain. Administration of the D(2) receptor antagonist (-)-sulpiride reduced the effects of bicifadine in the mechanical hyperalgesia assessment in rats with spinal nerve ligations. These results indicate that bicifadine is a functional triple reuptake inhibitor with antinociceptive and antiallodynic activity in acute, persistent, and chronic pain models, with activation of dopaminergic pathways contributing to its antihyperalgesic actions.
authors.affiliation: DOV Pharmaceutical, Inc., 150 Pierce St., Somerset, NJ 08873-4185, USA. abasile@dovpharm.com
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Basile
authors.forename: Aaron
authors.initials: A
authors.lastname: Janowsky
authors.forename: Krystyna
authors.initials: K
authors.lastname: Golembiowska
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kowalska
authors.forename: Eyal
authors.initials: E
authors.lastname: Tam
authors.forename: Morris
authors.initials: M
authors.lastname: Benveniste
authors.forename: Piotr
authors.initials: P
authors.lastname: Popik
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Nikiforuk
authors.forename: Martyna
authors.initials: M
authors.lastname: Krawczyk
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nowak
authors.forename: Philip A
authors.initials: PA
authors.lastname: Krieter
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Lippa
authors.forename: Phil
authors.initials: P
authors.lastname: Skolnick
authors.forename: Elena
authors.initials: E
authors.lastname: Koustova
mesh_terms: D000208:Acute Disease; D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism / Q000494:pharmacology*; D002908:Chronic Disease; D003891:Desipramine / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D050479:Neurotransmitter Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
chemical_list: D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D050479:Neurotransmitter Transport Proteins; D017981:Receptors, Neurotransmitter; D012701:Serotonin; C034438:bicifadine; D003891:Desipramine; D004298:Dopamine; D009638:Norepinephrine