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 P2X(3) 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 P2X(3) signalling to strain-specific differences in tissue injury pain, we examined whether the P2X(3) -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 alpha,beta-methylene ATP (alphabetameATP) into the hindpaw compared with C57BL/6 J mice. This behaviour was blocked by P2X(3) 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 alphabetameATP 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 P2X(3) protein level was significantly lower compared with C57BL/6 J DRG neurons. The change in P2X(3) protein was selective because P2X(2) protein was expressed equally in both strains. The present study suggests that the downregulation of sensory P2X(3) could be one of the molecular predispositions to low sensitivity to tissue injury pain in the A/J inbred mouse strain.