Effects of the triple monoamine uptake inhibitor amitifadine on pain-related depression of behavior and mesolimbic dopamine release in rats

Pain. 2015 Jan;156(1):175-184. doi: 10.1016/j.pain.0000000000000018.


Pain-related depression of behavior and mood is a key therapeutic target in the treatment of pain. Clinical evidence suggests a role for decreased dopamine (DA) signaling in pain-related depression of behavior and mood. Similarly, in rats, intraperitoneal injection of dilute lactic acid (IP acid) serves as a chemical noxious stimulus to produce analgesic-reversible decreases in both (1) extracellular DA levels in nucleus accumbens (NAc) and (2) intracranial self-stimulation (ICSS), an operant behavior reliant on NAc DA. Intraperitonial acid-induced depression of ICSS is blocked by DA transporter (DAT) inhibitors, but clinical viability of selective DAT inhibitors as analgesics is limited by abuse potential. Drugs that produce combined inhibition of both DA and serotonin transporters may retain efficacy to block pain-related behavioral depression with reduced abuse liability. Amitifadine is a "triple uptake inhibitor" that inhibits DAT with approximately 5- to 10-fold weaker potency than it inhibits serotonin and norepinephrine transporters. This study compared amitifadine effects on IP acid-induced depression of NAc DA and ICSS and IP acid-stimulated stretching in male Sprague-Dawley rats. Amitifadine blocked IP acid-induced depression of both NAc DA and ICSS and IP acid-stimulated stretching. In the absence of the noxious stimulus, amitifadine increased NAc levels of both DA and serotonin, and behaviorally, amitifadine produced significant but weak abuse-related ICSS facilitation. Moreover, amitifadine was more potent to block IP acid-induced depression of ICSS than to facilitate control ICSS. These results support consideration of amitifadine and related monoamine uptake inhibitors as candidate analgesics for treatment of pain-related behavioral depression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic Uptake Inhibitors / pharmacology
  • Adrenergic Uptake Inhibitors / therapeutic use
  • Animals
  • Aza Compounds / pharmacology
  • Aza Compounds / therapeutic use*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use*
  • Depression / drug therapy*
  • Depression / metabolism
  • Dopamine / metabolism*
  • Dopamine Uptake Inhibitors / pharmacology
  • Dopamine Uptake Inhibitors / therapeutic use
  • Male
  • Microdialysis / methods
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Pain / drug therapy*
  • Pain / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin Uptake Inhibitors / pharmacology
  • Serotonin Uptake Inhibitors / therapeutic use
  • Treatment Outcome


  • 1-(3,4-dichlorophenyl)-3-azabicyclo-(3.1.0)hexane hydrochloride
  • Adrenergic Uptake Inhibitors
  • Aza Compounds
  • Bridged Bicyclo Compounds, Heterocyclic
  • Dopamine Uptake Inhibitors
  • Serotonin Uptake Inhibitors
  • Dopamine