Received for publication September 20, 2004.
Revised November 2, 2004.
Accepted for publication November 3, 2004.

Dual, hyperalgesic and analgesic effects of the high-efficacy 5-HT_1A agonist, F 13640: relationship with 5-HT_1A receptor occupancy and kinetic parameters

Abstract

The aim of the present study was to establish the relationship between the plasma and brain concentration-time profiles of F 13640 after acute administration and both its hyper- and hypo-analgesic effects in rats. The maximal plasma concentration (C_max) of F 13640 after i.p. administration of 0.63 mg/kg was obtained at 15min, decreasing to half its maximal value after about 1h. The amount of F 13640 collected by means of in vivo microdialysis in hippocampal dialysates could be measured reliably after 0.63 and 2.5 mg/kg, reached its maximum at about 1h, and fell to half of its maximal value at about 3h. 5-HT_1A receptor occupancy was estimated by ex vivo binding in rat brain sections. F 13640 inhibited [3H] 8-OH-DPAT binding ex vivo in rat hippocampus, entorhinal cortex and frontal cortex (ED₅₀: 0.34 mg/kg, i.p.). Maximal inhibition was reached at approximately 30min after 0.63 mg/kg F 13640, and fell to half of its value after about 4-8h. Fifteen minutes after injection in the paw pressure test, F 13640 (0.63 mg/kg, i.p.) induced an initial hyperalgesia followed 4h later, by a paradoxical analgesia that lasted until 8h. In contrast, in the formalin test, F 13640 inhibited pain behaviors until 4h post drug administration. F 13640 produced also elements of the 5-HT syndrome that lasted up to 4h after administration. These results demonstrate that F 13640 induces hyperalgesia and/or analgesia, with a time-course that parallels the occupancy of 5-HT_1A receptors and the presence of the compound in blood and brain.

Key words: 5-HT1A, F 13640, analgesics, microdialysis, nociception, pharmacokinetic