Characterization of the Antinociceptive actions of bicifadine in models of acute, persistent, and chronic pain

被引:49
作者
Basile, Anthony S.
Janowsky, Aaron
Golembiowska, Krystyna
Kowalska, Magdalena
Tam, Eyal
Benveniste, Morris
Popik, Piotr
Nikiforuk, Agnieszka
Krawczyk, Martyna
Nowak, Gabriel
Krieter, Philip A.
Lippa, Arnold S.
Skolnick, Phil
Koustova, Elena
机构
[1] DOV Pharmaceut Inc, Somerset, NJ 08873 USA
[2] Oregon Hlth & Sci Univ, Vet Affairs Med Ctr, Portland, OR 97201 USA
[3] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA
[4] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR USA
[5] Polish Acad Sci, Inst Pharmacol, Dept Drug Dev & Behav Neurosci, Smetna Krakow, Poland
[6] Polish Acad Sci, Inst Pharmacol, Dept Neurobiol, Smetna Krakow, Poland
[7] Polish Acad Sci, Inst Pharmacol, Dept Pharmacol, Smetna Krakow, Poland
[8] Tel Aviv Univ, Sackler Sch Med, Dept Physiol & Pharmacol, Ramat Aviv, Israel
[9] Morehouse Sch Med, Dept Anat & Neurobiol, Atlanta, GA 30310 USA
[10] Jagiellonian Univ, Collegium Medicum, Dept Cytobiol & Histochem, Krakow, Poland
关键词
D O I
10.1124/jpet.106.116483
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 ( approximate to 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.
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收藏
页码:1208 / 1225
页数:18
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