Peripheral nerve injury/inflammation produces sensory abnormalities associated with chronic pain. Peripheral tissue inflammation can alter the property of somatic sensory pathways, resulting in behavioral hypersensitivity due to the increased responses to pain caused by noxious stimulation (hyperalgesia) as well as the normally non-noxious stimulation (allodynia). Several different types of animal nerve injury models have been developed to elucidate the neuronal mechanisms underlying these abnormal pain sensations (allodynia and hyperalgesia) 27 28 29 . Among these models, the CCI model shows inflammation and nerve injury, and can mimic neuropathic pain in human 27 30 . CCI of the sciatic nerve is indeed one of the most reliable models of neuropathic pain 31 . Following peripheral nerve injury, primary afferent neurons exhibit high frequency background activity or irregular burst discharges 27 . On the other hand, in the axotomy of primary afferent neuron model (axotomy model), the hyperexcitability of primary afferent neurons induced by peripheral nerve injury is thought to result from extensive changes in the ionic currents of DRG neurons 32 33 . Moreover, changes in the excitability of primary afferent neurons were also observed at the adjacent intact primary afferent neurons after nerve injury (axotomy spared neuron models) 34 35 .

Any discussion of trigeminal neuropathic pain should consider the following points. First, the trigeminal nerve has some unique characteristics that may influence its response to injury, such as its embryological origin, and the proportion of myelinated and unmyelinated nerves, and sympathetic fibers 36 37 38 . In addition, the location of some branches of the nerve within bony canals protects them from exogenous stimuli, but makes them vulnerable to pressure (e.g., edema or displacement of fractured bone fragments) 36 . To elucidate the mechanism underlying trigeminal mechanical allodynia in different neuropathic pain/inflammatory models, we recently investigated four such animal models, as described in the following sections.

Figure 1 summarizes the changes in TRG neuronal excitability associated with the changes in Kv channels using whole-cell patch-clamp recording in our trigeminal neuropathic/inflammatory pain animal models 17 24 25 26 . In each animal model, mechanical allodynia was determined by withdrawal threshold for the mechanical stimulation of the whisker pad area.

Lawson et al. 18 reported that several types of Kv channels have been proposed as potential target candidates for pain therapy. It was recently demonstrated that a selective KCNQ/Kv7 channel opener (retigabine), which mediates M-currents, selectively reduces the activity of axotomized Aδ/C-fibers, but not uninjured axons 19 , and human C-fiber axons 21 . Xu et al. 20 also demonstrated that this KCNQ/Kv7 channel opener could attenuate allodynia due to TMJ inflammation in rats. Similarly, axotomy reduces K_Ca channel activity in the small to medium sized DRG neurons, which would also increase membrane excitability 21 . Thus, these channels may be involved in the development of hyperalgesia and allodynia. On the contrary, spinal nerve ligation suppressed K_ATP channels only in large-diameter neurons, but not in small-diameter neurons, from hyperalgesic rats 23 .

As described in the preceding chapter, experiments in our trigeminal neuropathic/inflammatory pain model indicated that the common changes in the Kv channels, such as I_A, I_K in rats with neuropathic/inflammatory pain, were significantly suppressed compared to those in naïve rats. Since previous reports suggested that I_A and I_K are important for regulating the firing frequency and duration of action potentials in the TRG neuron, respectively 12 13 , these Kv changes caused an incremental spike discharge and prolongation of duration of action potentials in the neuropathic/inflammatory pain rats. The relationship between depression of Kv and excitability of TRG neurons under trigeminal neuropathic/inflammatory pain conditions are summarized in Figure 2. It is well established that the duration of action potentials in primary afferents influences the amount of neurotransmitter released from the soma and the peripheral and central terminals 10 11 . Increased action potential duration and firing frequencies prolong the opening of voltage-gated Ca²⁺ channels, probably potentiating Ca²⁺ influx and causing an increase in the neurotransmitter released from the cell bodies and/or peripheral and central terminals (Figure 2B). Thus, enhancing the amount of neurotransmitter released from central terminals probably contributes to the hyperexcitability of second-order nociceptive and wide dynamic-range neurons in the trigeminal spinal nucleus neurons (central sensitization) 24 25 49 50 51 52 53 54 . In addition, increasing the neurotransmitters/neuromodulators (e.g., SP) released from the cell body of TRG neurons through a paracrine or autocrine mechanism may activate the neighboring TRG neurons 52 53 . Since previous studies suggested that peripheral inflammation can depolarize trigeminal satellite-glial cells via activation of neurokinin 1 receptor (SP release from small diameter TRG neurons) 55 56 , such changes may further promote the interaction between satellite-glial cells and TRG neurons associated with pathological pain within the trigeminal ganglia 55 56 57 .

The precise mechanism by which Kv depression of TRG neurons affects the neuropathic/inflammatory condition remains to be determined. Recent studies demonstrated that small- to medium-diameter TRG neurons express glial cell line-derived neurotrophic factor (GDNF) and its receptor components, such as GFRα1 58 59 . To this end, we recently found that acute application of GDNF enhances the neuronal excitability of adult rat small-diameter TRG neurons, which innervate the facial skin in the absence of neuropathic and inflammatory conditions 60 . This potentiation of small-diameter TRG neuronal excitability is mediated by inhibition of Kv channels, and transection of sciatic nerve in rat upregulated the expression of GDNF and GFRα-1 mRNA in the proximal nerve trunk 61 62 . Thus, GDNF-induced potentiation of sensory neuronal excitability may account for enhanced pain sensitivity, resulting from increased levels of GDNF after tissue injury, and further studies are needed to elucidate possible mechanisms underlying this effect.

Finally, opening of K⁺ channels leads to hyperpolarization of the cell membrane, and a resultant decrease in cell excitability. We thus propose the potential development of I_K and/or I_A channel openers as therapeutic agents for preventing trigeminal neuropathic pain, such as mechanical allodynia. Kv channel subunits, Kv2.1 and Kv2.2, contribute to the I_K channel and play a distinct role in regulating neuronal excitability 63 64 . However, Kv1.4 and 4.1-4.3 channels may also be involved in forming A-type Kv channels in sensory neurons 65 66 67 . Among these Kv channel α subunits, Kv1.4, 2.2, and 4.2 mRNAs are downregulated under neuropathic conditions involving the transection and CCI of sciatic nerves 15 16 . Rasband et al. 65 demonstrated that Kv1.4 is the sole Kv α subunit expressed in smaller diameter DRG neurons, and not Kv4-family channels. Since the pharmacology and gating properties of DRG A-type Kv channels are similar to those of heterogeneously expressed Kv4 channels 66 67 , we could not completely rule out a potential role for Kv4.1, 4.2, and 4.3 in neuropathic pain. Previously, we reported that TMJ inflammation decreased the expression of Kv1.4 subunits in small-/medium-diameter (Aδ-/C-) TRG neurons and that this may contribute to trigeminal inflammatory allodynia associated with TMJ disorders 68 . Nerve injury also induces accelerated reduction in Kv 1.4 expression in the small-diameter nociceptive DRG neurons 65 . Taken together, these findings suggest Kv 1.4 channel as candidate molecular targets, and further studies are needed to explore this possibility.