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

Abstract

5-HT(1A) receptor activation by the very-high-efficacy, selective 5-HT(1A) 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.

• Authors: Liesbeth A Bruins Slot, Wouter Koek, Jean-Pierre Tarayre, Francis C Colpaert
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 466 Issue 3 Pg. 271-9 (Apr 18 2003) ISSN: 0014-2999 [Print] Netherlands
• PMID: 12694810 (Publication Type: Journal Article)

Chemical References

• Analgesics
• F 13640
• Piperidines
• Pyridines

Topics

• Algorithms
• Analgesics (pharmacology)
• Animals
• Body Temperature (drug effects)
• Dose-Response Relationship, Drug
• Drug Tolerance
• Hyperalgesia (physiopathology, prevention & control)
• Male
• Pain (physiopathology, prevention & control)
• Pain Threshold (drug effects)
• Piperidines (pharmacology)
• Pyridines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Time Factors