Fentanyl dose-sparing in polyarthritic rats requires full agonism at 5-HT1A receptors: Comparison between NLX-112, (±)8-OH-DPAT, and buspirone.

Background: NLX-112 (a.k.a. F13640, befiradol) is a highly selective and fully efficacious agonist at 5-hydroxytryptamine (5-HT_1A) receptors. It has been shown to be robustly and potently active in nociceptive, neuropathic and traumatic pain models in rats and mice. In particular, NLX-112 decreases oral fentanyl self-administration (FSA) in polyarthritic rats, ie, it has opioid dose-sparing effects.

Objective: To examine if the dose-sparing effects of NLX-112 in polyarthritic rats are shared by other 5-HT_1A ligands: the prototypical 5-HT_1A receptor agonist 8-HYDROXY-2-(DI-n-PROPYLAMINO)TETRALIN ((±)8-OH-DPAT), and the 5-HT_1A receptor partial agonist and weak dopamine D2 receptor blocker, -buspirone.

Design: Polyarthritis was induced by inoculating rats with heat-killed Mycobacterium butyricum. They then had access to either a fentanyl (0.008 mg/mL) or a sweetened solution in their home cage. NLX-112, (±)8-OH-DPAT, or buspirone was administered via an osmotic minipump (5 µL/h) during a 2-week infusion period from day 14 to day 28 post-inoculation with Mycobacterium butyricum. Control infusions consisted of sterile 0.9 percent NaCl.

Results: NLX-112 (0.63 mg/day) significantly decreased FSA by 47 percent and increased total fluid consumption (TFC) by 7 percent (vehicle-loaded minipumps as controls). Both (±)8-OH-DPAT and buspirone (0.63 and 2.5 mg/day, respectively) failed to reduce FSA; (±)8-OH-DPAT did not modify TFC, while buspirone significantly decreased it by 17 percent.

Conclusions: These results suggest that oral FSA dose-sparing effect, in this rat polyarthritis pain model, requires high efficacy activation of 5-HT_1A receptors, such as that afforded by NLX-112. By contrast, the agonist efficacy of (±)8-OH-DPAT and buspirone seems insufficient for FSA dose-sparing.