ATP induced three types of pain behaviors, including allodynia

ATP excites dorsal root ganglion (DRG) neurons in the nociceptive signaling pathway via ATP-gated cation channels (P2X receptors). ATP and its analog α,β-methylene ATP (αβmeATP) activated two types of inward currents; one is a rapidly desensitizing current which is observed in capsaicin (CAP)-sensitive DRG neurons and in C6BU-1 cells expressing homomeric P2X₃ receptors. The other is a slowly desensitizing current which is seen in CAP-insensitive medium-sized DRG neurons and in C6BU-1 expressing heteromeric P2X_2/3 receptors. These findings suggest that P2X₃ and P2X_2/3 are involved in the generation or modulation of pain. To clarify this hypothesis, we investigated the effects of agonists for P2X receptors on pain sensitivities using a behavioral approach. Activation of P2X receptors at a peripheral site by the injection of ATP or αβmeATP into the hindpaw produced three distinct types of pain-related behaviors (nocifensive behavior, thermal hyperalgesia, and mechanical allodynia). Nocifensive behavior and thermal hyperalgesia were blocked by pretreatment with PPADS and were not observed in neonatal CAP-treated adult rats that had selectively lost CAP-sensitive neurons. The αβmeATP-induced allodynia was sensitive to PPADS, was a relatively long-lasting response, and remained in neonatal CAP-treated adult rats. Furthermore, while pretreatment by P2X₃ antisense oligodeoxynucleotide (ODN) diminished all three pain responses, P2X₂ antisense ODN inhibited only the mechanical allodynia. These findings suggests that activation of homomeric P2X₃ receptors in peripheral terminals of CAP-sensitive primary afferent fibers plays a role in the induction of nocifensive behavior and thermal hyperalgesia and that activation of heteromeric P2X_2/3 receptors in CAP-insensitive fibers leads to the induction of mechanical allodynia.