Journal club 2013-04-26

The sensations of pain, itch and cold often interact with each other. Pain inhibits itch, whereas cold inhibits both pain and itch. TRPV1 and TRPA1 channels transduce pain and itch, whereas TRPM8 transduces cold. The pruritogen chloroquine (CQ) was reported to excite TRPA1, leading to the sensation of itch. It is unclear how CQ excites and modulates TRPA1+, TRPV1+ and TRPM8+ neurons and thus affects the sensations of pain, itchand cold. Here, we show that only 43% of CQ-excited dorsal root ganglion (DRG) neurons express TRPA1; as expected, the responses of these neurons were completely prevented by the TRPA1 antagonist HC-030031. The remaining 57% of CQ-excited neurons did not express TRPA1, and excitation was not prevented by either a TRPA1 or a TRPV1 antagonist, but was prevented by the general TRPC channel blocker BTP2 and the selective TRPC3 inhibitor Pyr3. Furthermore, CQ caused potent sensitization of TRPV1 in 51.9% of TRPV1+ neurons, and concomitant inhibition of TRPM8 in 48.8% of TRPM8+ DRG neurons. Sensitization of TRPV1 is mainly caused by activation of the PLC-PKC pathway following activation of the CQ receptor MrgprA3. By contrast, inhibition of TRPM8 is caused by a direct action of activated Galpha q independently of the PLC pathway. Our data suggest the involvement of TRPC3 channel acting together with TRPA1 to mediate CQ-induced itch. CQ not only elicits itch by directly excitingitch-encoding neurons, but also exerts previously unappreciated widespread actions on pain-, itch- and cold-sensing neurons, leading to enhanced pain and itch.