脊髄内痛覚伝達におけるP2X 受容体の役割

抄録

   The spinal dorsal horn is the first central site for sensory processing and can be divided into structurally and functionally distinct lamina regions. Superficial dorsal horn neurons including lamina II neurons receive synaptic inputs from fine primary afferents that mainly carry nociceptive signals from the periphery. Deep dorsal horn neurons, especially lamina V neurons, receive convergent sensory inputs from both nociceptive and non-nociceptive primary afferents. We examined a role of P2X receptors in modulating excitatory synaptic transmission by using patch-clamp recordings from dorsal horn neurons of the rat spinal cord. Distinct subtypes of P2X receptors were located at central terminals of primary afferents that innervate onto lamina II and lamina V neurons. On activation, these P2X receptors produced glutamate release enhancements in a different fashion from each other. In lamina II neurons, the modulation of glutamate release by presynaptic P2X receptors was mainly transient. In contrast, the P2X receptor-mediated modulation of glutamate release was relatively long-lasting in lamina V neurons. Pharmacologically, both of the transient and long-lasting types of modulation were blocked by PPADS. The transient modulation in lamina II neurons was not observed in the presence of TNP-ATP, suggesting an involvement of homomeric P2X₃ receptors. The P2X receptor-mediated long-lasting modulation of glutamate release in lamina V neurons remained in the presence of TNP-ATP. In addition, the removal of P2X₃ receptor-expressing afferent terminals by the targeting toxin saporin-conjugated IB4 or by surgical removal of superficial dorsal horn did not affect the P2X receptor-mediated long-lasting modulation of glutamate release in lamina V neurons. The pharmacological profiles appeared to be consistent with the involvement of slowly desensitizing P2X₄₊₆ receptors. Differences among P2X-expressing afferent fibers innervating lamina II and lamina V neurons were also seen in terms of capsaicin sensitivity. P2X-expressing afferent central terminals in the lamina II were derived from capsaicin-sensitive primary afferents, while those in the lamina V were from capsaicin-insensitive A primary afferents. Since P2X₃-expressing afferent central terminals directly make synapses with lamina II neurons,the inputs from these afferent terminals could forward excitatory synaptic activities. On the contrary, the activities conveyed to lamina V neurons from P2X₃-expressing primary afferents were polysynaptic; these inputs together with monosynaptic inputs from P2X-expressing and capsaicininsensitive afferents were shown to converge on lamina V neurons. These results indicate that distinct subtypes of P2X receptors are expressed in central terminals of primary afferents innervating onto superficial and deep dorsal horn neurons, and modulate glutamate release in a different manner. These presynaptic actions may serve to understand P2X receptor-mediated modulation of various sensations.