Antinociception by tricyclic antidepressants in the rat formalin test: differential effects on different behaviours following systemic and spinal administration

Pain. 2001 Jul;93(1):51-59. doi: 10.1016/S0304-3959(01)00291-3.


The present study (1) examined analgesic effects of systemically and spinally administered antidepressants (ADs) on phase 2 flinching and biting/licking behaviours in the rat formalin test, a model considered to be of greater relevance to clinical pain than acute threshold tests, and (2) determined whether motor or anti-inflammatory effects contributed to such actions. Systemic administration of amitriptyline (3-20 mg/kg) produced a dose-related enhancement of flinching behaviours, while at the same time suppressing biting/licking behaviours. Imipramine (except for 20 mg/kg), nortriptyline, desipramine and fluoxetine had no significant effect on flinching behaviours, while producing a dose-related suppression of biting/licking behaviours. When administered spinally, either by acute lumbar puncture or via chronically implanted intrathecal cannulas, amitriptyline similarly augmented flinching behaviours. When given by lumbar puncture, amitriptyline suppressed biting/licking behaviours, but when intrathecal cannulas were used, this behaviour was not expressed in the formalin group. Other ADs also suppressed biting/licking behaviours without affecting flinching when given by lumbar puncture. Effects on paw volume were determined at the end of behavioural testing. Systemic administration of all ADs produced a dose-related reduction in paw volume. Spinal administration of nortriptyline by lumbar puncture also reduced paw volume, but for other agents, the reduction was not significant. Motor effects were noted qualitatively throughout these experiments, and considered in relation to nociceptive behaviours. These results indicate (a) a marked dissociation between the effects of systemic ADs on flinching and biting/licking behaviours in the formalin test, (b) spinal efficacy of ADs that essentially reproduces effects seen with systemic administration when given by lumbar puncture, (c) a lack of causality between anti-inflammatory effects of ADs and their analgesic properties in the formalin test, and (d) a contribution of motor effects to analgesic actions at higher doses affecting biting/licking but not flinching behaviours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amitriptyline / administration & dosage
  • Amitriptyline / pharmacology
  • Analgesics / administration & dosage
  • Analgesics / pharmacology*
  • Animals
  • Antidepressive Agents, Tricyclic / administration & dosage
  • Antidepressive Agents, Tricyclic / pharmacology*
  • Behavior, Animal / drug effects*
  • Dose-Response Relationship, Drug
  • Foot / pathology
  • Formaldehyde*
  • Hypnotics and Sedatives / pharmacology
  • Injections, Spinal
  • Male
  • Pain Measurement / drug effects*
  • Rats
  • Rats, Sprague-Dawley


  • Analgesics
  • Antidepressive Agents, Tricyclic
  • Hypnotics and Sedatives
  • Amitriptyline
  • Formaldehyde