P2X3 receptors are widely expressed in the dorsal root ganglion (DRG) neurons responsible for primary sensory functions including nociception (Vulchanova et al., 1998). Knockout studies strongly linked P2X3 receptors to inflammatory pain, warm-coding and volume reflexes of the urinary bladder (Cockayne et al., 2000; Souslova et al., 2000b; Shimizu et al., 2005b). In response to ATP application, P2X3 receptors desensitize within tens of milliseconds; at the same time, up to 30 min are required for the recovery. Recent data indicate that desensitization of P2X3 receptors is use-dependent and occurs within a nanomolar range of background ATP concentrations (Pratt et al., 2005a), while in the tissues the ATP level is 20-100 nM, especially rising in inflammation, ischemia, muscle functioning, renal failure, etc. (Vassort, 2001; Li et al., 2003). These findings may suggest that P2X3 subunits may play their strong physiological roles only as heteromeric forms with P2X2 subunits, but not as homomeric channels. Furthermore, our data demonstrate that only 6 ms long application of ATP is suficient to induce almost complete desensitization of P2X3 receptors. This result confirms a high-afinity site hypothesis suggested by Pratt et al. (Pratt et al., 2005b). However, in accordance with the earlier studies, P2X3 receptors are the main subtype of P2X receptors that expressed in nociceptive DRG neurones. Correspondingly, the question arises: how can these receptors be functional?