Downregulation of P2X₃ receptor-dependent sensory functions in A/J inbred mouse strain

There is large variability in the various pain responses including those to tissue injury among inbred mouse strains. However, the determinant factors for the strain-specific differences remain unknown. The P2X₃ sensory-specific ATP-gated channel has been implicated as a damage-sensing molecule that evokes a pain sensation by receiving endogenous ATP from injured tissue. In this study, to clarify the contribution of the sensory P2X₃ signalling to strain-specific differences in tissue injury pain, we examined whether the P2X₃-mediated in vivo and in vitro responses in dorsal root ganglion (DRG) neurons are changed in the A/J inbred mouse strain, which is known to be resistant to tissue injury pain caused by formalin. Here we found that A/J mice exhibited a low magnitude of nocifensive behaviour induced by the P2X agonist α,β-methylene ATP (αβmeATP) into the hindpaw compared with C57BL/6 J mice. This behaviour was blocked by P2X₃ antisense oligodeoxynucleotides. The low magnitude of the in vivo pain sensation could be observed similarly in the in vitro response; the increase in the intracellular Ca²⁺ increase by αβmeATP in capsaicin-sensitive DRG neurons from A/J mice was significantly lower than that from C57BL/6 J mice. In A/J DRG neurons the P2X₃ protein level was significantly lower compared with C57BL/6 J DRG neurons. The change in P2X₃ protein was selective because P2X₂ protein was expressed equally in both strains. The present study suggests that the downregulation of sensory P2X₃ could be one of the molecular predispositions to low sensitivity to tissue injury pain in the A/J inbred mouse strain.