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 P2X2/3 receptors. These findings suggest that P2X3 and P2X2/3 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 P2X2/3 receptors in CAP-insensitive fibers leads to the induction of mechanical allodynia.
All Science Journal Classification (ASJC) codes
- Drug Discovery