Profound, non-opioid analgesia produced by the high-efficacy 5-HT(1A) agonist F 13640 in the formalin model of tonic nociceptive pain

Pharmacology. 2003 Apr;67(4):182-94. doi: 10.1159/000068404.


Previously, we have reported that in rat models of chronic pain, in particular, the very-high-efficacy 5-HT(1A) agonist F 13640 induces unprecedented pain relief by novel neuroadaptative mechanisms that involve inverse tolerance and cooperation with nociceptive stimulation in producing analgesia. The present studies detailed the actions of F 13640 and other compounds in the formalin model of tonic nociceptive pain. Intraperitoneal injection of F 13640 (0.01-2.5 mg/kg; t -15 min) caused a dose-dependent and complete inhibition of the paw elevation and paw licking that occurred both early (0-5 min) and late (22.5-27.5 min) after the intraplantar injection of diluted formaldehyde (2.5%) in the rat. The extent to which F 13640 and other 5-HT(1A) receptor ligands inhibited these pain behaviors correlated (p < 0.05) with the extent to which they activated 5-HT(1A) receptors. Under similar conditions, some inhibitory effects were also observed with various agents that are known to produce analgesia by different peripheral and/or central mechanisms (e.g., opioids, NA/5-HT reuptake inhibitors, COX-2 inhibitors and other nonsteroidal anti-inflammatory drugs, gabapentin, and ABT-594). However, with the possible exception of morphine, the effects of all of these agents at nontoxic doses were lower than those of F 13640, in particular in inhibition of early paw elevation. The 5-HT(1A) antagonist WAY 100635, but not naloxone, antagonized the actions of F 13640. These results help to establish large-magnitude 5-HT(1A) receptor activation as a new molecular mechanism of profound, central analgesia and suggest that F 13640 may be particularly effective against pain arising from severe tonic nociceptive stimulation.

MeSH terms

  • Analgesics, Non-Narcotic / pharmacology*
  • Analgesics, Opioid / pharmacology
  • Animals
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hindlimb / drug effects
  • Male
  • Morphine / adverse effects
  • Morphine / pharmacology
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Pain Measurement / drug effects*
  • Pain Measurement / methods
  • Pain Threshold / drug effects*
  • Piperazines / pharmacology
  • Piperidines / pharmacology*
  • Pyridines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin, 5-HT1
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / pharmacology*


  • Analgesics, Non-Narcotic
  • Analgesics, Opioid
  • F 13640
  • Narcotic Antagonists
  • Piperazines
  • Piperidines
  • Pyridines
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Naloxone
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • Morphine