Small-diameter sensory neurons, such as those of the dorsal root ganglia (DRG) are endowed with homomeric P2X3 receptors (1). They consist of three identical subunits with two transmembrane domains, an extracellular loop, and N- and C-terminal tails, characteristic for the P2X subunit family (P2X1-7). At the peripheral terminals of DRG neurons, P2X3 receptors react to ATP flowing out from all types of cells damaged by noxious stimuli. In the middle of three identical P2X3 subunits there is a pore region, which after agonist binding to the receptor opens to allow the passage of mono- and divalent cations; in consequence a non-selective cationic current inducing depolarization is initiated. Thus, P2X3 receptors are ligand-gated cationic channels shifting the membrane potential above the threshold of action potential generation. The evoked action potentials propagate to the central terminals of DRG cells innervating neurons in the dorsal horn of the spinal cord. The neurotransmitters at these synapses are glutamate, substance P and calcitonin gene related peptide. Both exogenous ATP and some of its structural analogues may stimulate P2X3 receptors and elicit rapidly desensitizing current responses. Electrophysiological measurements of the receptor current after the expression of the wild-type human (h) P2X3 receptor and its mutants in HEK293 cells suggest that at least two agonist molecules have to bind to the P2X3 receptor in order to activate it (2). These data are in perfect agreement with a homology model of the binding pocket of the P2X3 receptor, developed on the basis of the structure of a recently crystallized zebrafish P2X4 receptor (3). It was found that four nucleotide binding segments (NBSs) situated at the interface of two neighbouring subunits act as agonist binding sites. Especially positively charged Lys and Arg residues are of great importance, but additional conserved and non-conserved amino acids also contribute to binding, gating or stabilization of the protein structure (4). High proton concentrations characteristically modify P2X3 receptor channels. They have a dual effect in that the current amplitude at low agonist concentrations is decreased (because of a decrease in the rate of desensitization), and increase at high agonist concentrations (because of a decrease in the rate of desensitization) (5). Replacement of histidine 206 but not histidine 45 by alanine abolished the pH-induced effects on hP2X3 receptors, locating the allosteric binding site for protons at the former amino acid. Eventually, P2X3 receptors may negatively interact with other pain sensing molecules such as the transient receptor potential vanilloid-1 (TRPV1) receptor, reacting to capsaicin, protons and heat. During the co-activation of these two receptors the current amplitude is lower than the sum of the individual currents caused by activation of each receptor alone (6). The inhibitory interaction did not depend on the holding potential, by the replacement of external Ca2+ by Ba2+, or when the buffering of intracellular Ca2+ was altered. However, the C-terminal truncation at Glu362 of P2X3 receptors abolished the TRPV1/P2X3 cross-talk. Co-immunoprecipitation studies with polyclonal antibodies generated against TRPV1 and P2X3 showed a visible signal in HEK293 cells transfected with them. Hence, these two pain-relevant receptors may interact with each other in an inhibitory manner probably by physical association established by a motif located at the C-terminal end of the P2X3 receptor distal to Glu362. In conclusion, P2X3 receptors are important pain sensing molecules activated by extracellular ATP and being regulated by acidic pH. They may interact with other pain-sensing receptors such as TRPV1 to protect an individual from overtly strong pain. Information on the ligand binding site of P2X3 receptors may help to develop new antagonists with analgesic properties.