The change in efficiency of excitatory synaptic transmission by nervous activation plays an important role in the enhancement of pain, as well as memory and learning in the hippocampus. With respect to electrophysiological phenomena, the enhancement of efficiency in excitatory synaptic transmission occurs by windup and long-term potentiation (LTP). Windup is when noxious peripheral stimulation that is more intense or sustained induces primary afferent nociceptors to discharge at higher frequencies (Fig. 31.3①). LTP refers to high-frequency primary afferent stimulation that induces the potentiation of glutamate receptor-mediated responses at synapses onto dorsal horn neurons (Fig. 31.3②). Windup and LTP are considered to be involved in the release of peptide neuromodulators such as substance P, together with glutamate, from central terminal C-fibers. These peptides act on their G-protein-coupled receptors to produce depolarizing synaptic potentials lasting up to tens of seconds. Moreover, both phenomena are also considered to be related to the activation of NMDA receptors by phosphorylation via kinase, and the subsequent current flow through NMDA receptors leads to a rise in intracellular Ca²⁺ levels.

The synaptic network changes dynamically according to neural activity, for example, growth or regression of axons, the appearance of new synapses, or the disappearance of existing synapses. Alterations to the synaptic network (synaptic morphology change) in the dorsal horn have been suggested to lead to pain in chronic inflammation [14] or peripheral nerve injury. Under normal conditions, noxious information is transmitted through Aδ- and C-fibers to the superficial dorsal horn, especially substantia gelatinosa (SG) neurons (lamina II of Rexed), while innocuous mechanical information is transmitted through Aβ-fibers to the deep dorsal horn (lamina III–IV). In past studies, it was shown that C-fibers were missing in the sciatic nerve amputation pain model, and approximately 10 % of Aβ-fibers started to extend axons (sprouting), with input into lamina II [15, 16] (Fig. 31.3③). Moreover, Aβ-fiber sprouting was observed in the inflammation pain model [17]. Aβ-fiber sprouting in these pain models plays an important role in brain-derived neurotrophic factor (BDNF), which is released from C-fibers into the spinal cord. The mechanism of allodynia has been suggested to occur when innocuous mechanical information is converted to noxious information. This process occurs when Aβ-fibers connect to SG neurons, which project noxious information to the more central nervous system during pathological conditions such as chronic inflammation and neuropathic pain.

Neurotrophic factors are supplied to nerve cells by many kinds of cells (e.g., glia cells, dorsal root ganglion (DRG) neurons, Schwann cells, keratinocytes, and fibroblasts) and have various influences on the transmission of noxious information. During inflammation, the production of nerve growth factor (NGF) increases and causes hyperalgesia. NGF interacts with the TrkA receptor at the peripheral terminals of nociceptive fibers and is carried to DRG neurons by a retrograde axial. The NGF-TrkA complex controls gene expression in DRG neurons and promotes the production of neuropeptides, excitatory ion channels, and BDNF. BDNF is transferred to the central terminal of nociceptive fibers, which are projected to the spinal cord, where it acts upon its receptor, TrkB, on dorsal horn neurons. The subsequent activation of TrkB receptors on dorsal horn neurons modulates pain information [18]. Furthermore, BDNF also contributes to the change in the synaptic network in the dorsal horn, as mentioned above, during inflammation and neuropathic pain.

Much attention has been given to ion channels in the central terminals of Aδ- and C-fibers, which enhance nociceptive pain information by increasing glutamate release when these channels are activated by endogenous mediators (Fig. 31.4). For example, these ion channels include the ATP-dependent P2X receptor, the transient receptor potential (TRP) receptor family, voltage-dependent Na⁺ channels, and acid-sensing ion channel 3 (ASIC3). In particular, we focused our attention on the P2X receptor in the dorsal horn. The P2X receptor family consists of at least seven P2X subunits (P2X₁–P2X₇). Each functional P2X receptor is composed of three or more P2X subunits, forming a pore structure that is permeable to cations including Ca²⁺. Therefore, the P2X receptor family is a ligand-gated ion channel family. We examined the role of P2X receptors in modulating excitatory synaptic transmission by using patch-clamp recordings from dorsal horn neurons of the rat spinal cord [6, 7, 19, 20]. 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 enhanced the release of glutamate in various ways. 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 [20]. Pharmacological studies suggested that lamina II neurons were involved in homomeric P2X₃ receptors, while lamina V neurons were involved in non-P2X₃ receptors [20]. Differences among P2X-expressing afferent fibers innervating lamina II and lamina V neurons were also seen in terms of capsaicin sensitivity [19]. P2X-expressing afferent central terminals in lamina II were derived from capsaicin-sensitive primary afferents, while those in lamina V were from capsaicin-insensitive primary afferents [19]. Because 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 capsaicin-insensitive 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. Furthermore, P2X receptors were localized at lamina V neurons to mediate postsynaptic sensory transmissions [21]. Using the whole-cell patch-clamp technique, we investigated whether the activation of postsynaptic P2X receptors can modulate synaptic transmission in lamina V neurons. The ATP analogue generated an inward current in lamina V neurons. These pre- and postsynaptic actions may serve to understand P2X receptor-mediated modulation of various sensations.