Tolerance and inverse tolerance to the hyperalgesic and analgesic actions, respectively, of the novel analgesic, F 13640

Liesbeth A. Bruins Slot, Wouter Koek, Jean Pierre Tarayre, Francis C. Colpaert

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


5-HT1A receptor activation by the very-high-efficacy, selective 5-HT1A receptor agonist F 13640 [(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)- amino]-methyl}piperidin-1-yl]-methanone] was recently discovered to constitute a novel central mechanism of broad-spectrum analgesia that, remarkably, grows rather than decays with chronicity. However, in rodents not exposed to nociception, F 13640 induces its analgesic effect only after having initially induced hyperalgesia. Numerical simulations implementing a signal transduction theory here show that the progressive increase in the intensity of nociceptive stimulation which F 13640 presumably mimics should eventually produce a large analgesic effect without initially causing marked pain. In vivo studies examined the effects of progressively increasing doses of F 13640 on the threshold of mechanically induced vocalization and, also, on the 5-HT syndrome in rats. The infusion of increasing (0.04-0.63 mg/rat/day) doses of F 13640 over a 5-week period induced a large analgesia preceded by a hyperalgesic effect that was small and comparable to that induced by initial exposure to a low, 0.04 mg/rat/day dose. Furthermore, increasing the dose of F 13640 induced tachyphylaxis to the 5-HT syndrome. Producing the mirror opposite of morphine's neuroadaptive actions, F 13640 causes an analgesia that becomes more powerful with chronic administration, and this at the expense of the initial hyperalgesia which it may also produce.

Original languageEnglish (US)
Pages (from-to)271-279
Number of pages9
JournalEuropean Journal of Pharmacology
Issue number3
StatePublished - Apr 18 2003
Externally publishedYes


  • 5-HT receptor
  • Analgesia
  • Hyperalgesia
  • Pain
  • Tolerance

ASJC Scopus subject areas

  • Pharmacology


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