Antihyperalgesic activity of nucleoside transport inhibitors in models of inflammatory pain in guinea pigs

Sabine S Maes,^1,2 Stefan Pype,¹ Vincent LH Hoffmann,³ Maria Biermans,¹ Theo F Meert<sup>1

1</sup>CNS Discovery Research, Pain and Neurology, Johnson & Johnson Pharmaceutical Research and Development, a Division of Janssen Pharmaceutica, Beerse, Belgium; ²Department of Anaesthesiology, University Hospital Antwerp, Edegem, Belgium; ³Department of Anesthesiology, Intensive Care and Pain Treatment Center, Amphia Hospital, Breda, The Netherlands

Background and methods: The role of the endogenous purine nucleoside, adenosine, in nociception is well established. Inhibition of the equilibrative nucleoside transporter (ENT1) prevents adenosine uptake into cells, and could therefore enhance the antinociceptive properties of adenosine. The effects of ENT1 inhibition were studied in two animal models of inflammatory pain. Analgesic activity was assessed in a complete Freund's adjuvant (CFA)-induced and carrageenan-induced mechanical and thermal hyperalgesia model in the guinea pig.
Results: Draflazine, dipyridamole, dilazep, lidoflazine, soluflazine, and KF24345 showed efficacy in the CFA thermal hyperalgesia model. Draflazine, the most potent compound in this test, was further characterized in the CFA model of mechanical hyperalgesia and the carrageenan inflammation model of thermal and mechanical hyperalgesia, where it completely reversed the hypersensitivity. The antihyperalgesic effects of draflazine (10 mg/kg, administered subcutaneously) were attenuated by the A1 receptor antagonist, cyclopentyltheophylline (5–40 mg/kg, administered intraperitoneally), by the nonselective adenosine antagonist, caffeine (10–40 mg/kg intraperitoneally), and by the A2 antagonist, DMPX (10 mg/kg administered intraperitoneally).
Conclusion: ENT1 inhibition is an effective way of reversing mechanical and thermal inflammatory hyperalgesia in the guinea pig, and these effects are mediated by enhancement of endogenous adenosine levels. Both A1 and A2 adenosine receptor subtypes are likely to be involved.

Keywords: adenosine, nucleoside transport inhibition, nociception, inflammation, hyperalgesia