Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: evidence for synergism between serotonergic and noradrenergic reuptake inhibition

Neuropharmacology. 2006 Dec;51(7-8):1172-80. doi: 10.1016/j.neuropharm.2006.08.005. Epub 2006 Oct 11.


The efficacy of antidepressant drugs with serotonergic, noradrenergic, or dual reuptake inhibition was evaluated in reversing carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats. Duloxetine (1-30mg/kg, i.p.), a balanced serotonergic-noradrenergic reuptake inhibitor (SNRI), was equiefficacious and more potent than the SNRI venlafaxine (3-100mg/kg, i.p.) in reversing both thermal hyperalgesia and mechanical allodynia induced by carrageenan. In addition, the selective noradrenergic reuptake inhibitors (NRIs) thionisoxetine (0.03-10mg/kg, i.p.) and desipramine (1-30mg/kg, i.p.) also produced complete reversals of carrageenan-induced thermal hyperalgesia. However, only thionisoxetine exhibited a greater than 80% reversal of the carrageenan-induced mechanical allodynia. In contrast, the selective serotonergic reuptake inhibitors (SSRIs) paroxetine, sertraline, and fluoxetine (0.3-10mg/kg i.p.) had little or no effect in the carrageenan model. In order to understand whether the observed enhanced effectiveness of the dual SNRIs was due to a possible synergism between serotonergic and noradrenergic reuptake inhibition, the effects of the NRI thionisoxetine alone and in combination with an inactive dose of the SSRI fluoxetine were determined. In the presence of fluoxetine, the potency of thionisoxetine in reversing carrageenan-induced hyperalgesia and allodynia was significantly increased by approximately 100-fold and brain concentrations of thionisoxetine were increased by 1.1- to 5-fold. The present data indicate fluoxetine pharmacodynamically potentiated the analgesic effects of thionisoxetine over and above a metabolic interaction between these two drugs. The present findings thus indicate that, in the carrageenan model, dual serotonergic-noradrenergic reuptake inhibition by dual SNRIs, or SSRI-NRI combinations, produces synergistic analgesic efficacy.

Publication types

  • Comparative Study

MeSH terms

  • Adrenergic Uptake Inhibitors / pharmacology
  • Adrenergic Uptake Inhibitors / therapeutic use*
  • Analgesics, Non-Narcotic / pharmacology
  • Analgesics, Non-Narcotic / therapeutic use*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Brain Chemistry / drug effects
  • Carrageenan / toxicity
  • Cyclohexanols / pharmacology
  • Cyclohexanols / therapeutic use
  • Desipramine / pharmacology
  • Desipramine / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Drug Interactions
  • Duloxetine Hydrochloride
  • Edema / chemically induced
  • Edema / drug therapy
  • Fluoxetine / analogs & derivatives
  • Fluoxetine / analysis
  • Fluoxetine / pharmacology
  • Fluoxetine / therapeutic use
  • Hot Temperature / adverse effects
  • Hyperalgesia / chemically induced
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / physiopathology
  • Male
  • Norepinephrine / physiology*
  • Paroxetine / pharmacology
  • Paroxetine / therapeutic use
  • Pressure / adverse effects
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / physiology*
  • Serotonin Uptake Inhibitors / pharmacology
  • Serotonin Uptake Inhibitors / therapeutic use*
  • Sertraline / pharmacology
  • Sertraline / therapeutic use
  • Thiophenes / pharmacology
  • Thiophenes / therapeutic use
  • Venlafaxine Hydrochloride


  • Adrenergic Uptake Inhibitors
  • Analgesics, Non-Narcotic
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclohexanols
  • Serotonin Uptake Inhibitors
  • Thiophenes
  • Fluoxetine
  • thionisoxetine
  • Serotonin
  • Paroxetine
  • Venlafaxine Hydrochloride
  • Carrageenan
  • Duloxetine Hydrochloride
  • Sertraline
  • Desipramine
  • Norepinephrine