Anti-hyperalgesic effects of AG490, a Janus kinase inhibitor, in a rat model of inflammatory pain

Interleukin 6 (IL-6) has a critical role in pain mechanisms. IL-6 signals through the Janus-activated kinases 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) pathway. The contribution of JAK2 signaling in inflammation-induced hyperalgesia has not been addressed previously. The role of this pathway was investigated using the JAK2 Inhibitor, AG490, in a rat model of inflammatory pain. Unilateral hind paw inflammatory pain was induced in male Sprague-Dawley rats by intraplantar (i.pl.) injection of 3.5% ʎ-carrageenan. Inflamed rats received an i.pl. injection of either 3.5% of dimethylsulfoxide or AG490 (1-10 µg). The antinociceptive effects of AG490 were assessed by 2 pain behavioral assays 4 h later: The thermal and mechanical hyperalgesia tests. AG490 (1-10 µg) significantly attenuated ʎ-carrageenan-induced thermal hyperalgesia in a dose-dependent manner. AG490 also reduced mechanical hyperalgesia. Co-administration of Opioid Receptor antagonist naloxone (10 µg) and AG490 (10 µg) did not reverse AG490-produced antinociceptive activity, suggesting that the µ-opioid receptor is not responsible for the anti-hyperalgesic effects of AG490. Therefore, we suggest that AG490 produces these effects by blocking JAK2 signaling. In conclusion, JAK2 inhibitors may represent a novel class of non-narcotic drugs to treat inflammatory pain.