Figure 8. Second messengers involved in MOR-EGFR crosstalk.

Rats were treated intradermally with vehicle (5 μL; black bars), salirasib (RAS inhibitor, 1 μg; gray bars) or GW5074 (cRaf1 inhibitor, 1 μg; white bars) on the dorsum of the hind paw. The average baseline mechanical nociceptive threshold, before treatments, was 127.7 ± 2.4 g for the vehicle group, 132.7 ± 2.2 g for the RAS inhibitor group, and 129.3 ± 2.8 g for the cRaf1 inhibitor group. Ten minutes later, repeated (hourly × 4) injections of DAMGO (1 μg) was performed at the same site on the dorsum of the hind paw. Five days later, PGE₂ (100 ng) was injected at the same site and the mechanical nociceptive threshold evaluated 30 min and 4 hours later. Compared to vehicle-treated group, in all inhibitors treated-groups PGE₂ was able to induce hyperalgesia 30 min after its injection (data not shown). A small attenuation in the prolongation of PGE₂ hyperalgesia at the 4^th hour was observed only in the group previously treated with cRaf1 inhibitor (F_(5,30) = 3.10, * p = 0.0226, when inhibitor-treated groups were compared to vehicle-treated group at the 4^th hour after PGE₂; two-way repeated-measures ANOVA followed by Bonferroni post hoc test). The RAS inhibitor and vehicle did not inhibit the prolongation of PGE₂ hyperalgesia at the 4^th hour. These findings indicate that RAS and cRaf1 do not play a role in the induction of prolongation of PGE₂ hyperalgesia.