R-flurbiprofen and MRS2578 are 2 novel analgesics for chronic SCD pain. SCD mice exhibit chronic behavioral and neuronal hypersensitivity to mechanical, cold, and heat stimuli. Peripheral administration of the COX-2 inhibitor R-flurbiprofen decreases cold and mechanical behavioral hypersensitivity in SCD mice as well as spontaneous and mechanically-induced nociceptor firing in in vivo recording preparations from SCD mice. In control mice, peripheral application of PGE2-G, a byproduct of COX-2-mediated 2-AG oxidation, increases behavioral mechanical hypersensitivity, induces nociceptor firing, and increases nociceptor responsiveness to mechanical, cold and heat stimuli. Administration of the P2Y6 antagonist MRS2578 decreases the PGE2-G-induced behavioral hypersensitivity in control mice and the naturally-occurring chronic behavioral hypersensitivity observed in SCD mice. Schematic shows the peripheral terminal of the cutaneous nociceptive sensory neuron and that R-flurbiprofen inhibits the COX2-mediated production of PGE2-G which activates the P2Y6 receptor. Alternatively, MRS2578, blocks P2Y6 receptors on either peripheral nerve terminals or monocytes. Inset shows a C fiber nociceptor from SCD mice (top) and control mice (bottom). The SCD C fiber shows significant spontaneous action potential firing (naïve) compared to the control (naïve). R-flurbiprofen reduces the spontaneous action potential firing in the SCD C fiber. The bottom shows that PGE2-G induces action potential firing in the control C fiber. Professional illustration by Neil Smith.