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Ectopic Spontaneous Afferent Activity and Neuropathic Pain

2018; Lippincott Williams & Wilkins; Volume: 65; Issue: CN_suppl_1 Linguagem: Inglês

10.1093/neuros/nyy119

1524-4040

Robert Y. North, Tyler Lazaro, Patrick M. Dougherty,

Peripheral Neuropathies and Disorders

ADP: after-depolarization potential HCN: Hyperpolarization-activated cyclic nucleotide-gated SA: sensory afferent activity SMPO: subthreshold membrane potential oscillation Neuropathic pain has been estimated to afflict 6% to 17% of the general population, is associated with decreased quality of life and functional impairment, and is notoriously challenging to treat.1-5 Ultimately, the significant prevalence and severity of this disease state has led to an expansion of both medical and neurosurgical interventions to treat it, making understanding the pathophysiology of neuropathic pain a critical tool in the practice of neurosurgery. The term "neuropathic pain" likely oversimplifies a heterogeneous collection of pathologies affecting the central and peripheral nervous systems from the level of discrete neural organs down to cellular and subcellular alterations. Though there is an inherent value in attempts to categorize neuropathic pain through examination of unique factors defining each subtype of neuropathic pain, there also remains value in considering neuropathic pain as a unified entity. Neuropathic pain taken as an undivided endpoint emphasizes the shared pathophysiological processes that may be crucial in development of more broadly applicable treatments. One of the most well-studied of these shared processes is spontaneous sensory afferent action potential activity (SA). Though some degree of physiological SA propagates through ascending somatosensory pathways, increased SA has been associated with neuropathic pain from peripheral origins as well as from central lesions such as spinal cord injury or central demyelination.6-15 SA serving as a "raw pain signal" is typically thought of as the primary pathobiology driving spontaneous symptoms associated with neuropathic pain, such as spontaneous pain, paresthesia, and dysesthesia.16 However, onset of SA is temporally associated with development of "central processes," with several authors implicating the process as important in evoked symptoms, hyperalgesia and allodynia, through peripheral and central sensitization.17-22 Though SA has been noted in the laboratory since at least the 1930s, recent investigations of the process continue to provide insights regarding the driving forces behind this activity, as well as its role in human clinical conditions and animal models of neuropathic pain.23 Herein, we provide a brief topical review covering the anatomic origins of SA and electrophysiology important in understanding this fundamental, conserved process that forms the foundation of the current understanding of neuropathic pain. CELLULAR AND ANATOMIC ORIGINS OF SA Clinical examples of neuropathic pain have been associated with neurological lesions occurring at each anatomic level of the sensory system from distal endings and peripheral nerves through the dorsal root ganglia, spinal cord, brainstem, thalamus, and terminal cortical projections (Figure 1). Cellular constituents, particularly immune cells, glia, and neurons, at these anatomic levels are all affected by these neurological lesions and likely each play a role in generation of neuropathic pain.24 Direct interaction via gap junctions, synaptic transmission, and cell-to-cell signaling pathways are just a few mechanisms through which these interactions occur.25-27 In pathological states, the result of these complex interactions between afferent neurons with glia, immune cells, and the extracellular matrix may lead to an excitatory microenvironment that encourage aberrant processes like SA to occur. Peripheral Nerve, Dorsal Root Ganglion, and the Primary Afferent Neuron The primary afferent neuron is often cited as a site for the origin of SA in neuropathic pain.13,14,28-31 Primary afferent SA is thought to be induced by damage to the axon, soma, or neural sheath that may arise from a wide variety of pathologies; trauma, compression or entrapment, inflammation (sterile, infectious, or autoimmune), direct infection, metabolic derangements, nutritional deficiencies, radiation, neurotoxin exposure, vascular insult, or genetic mutations.16 Electrophysiological recordings on dissociated primary neurons, intact dorsal root ganglion, and peripheral projections have all been used to demonstrate associations between primary afferent SA and neuropathic pain. In particular, animal models of partial and complete nerve injury, chronic peripheral nerve constriction, dorsal root ganglion compression, nerve inflammation, diabetes, neurotoxin exposure such as chemotherapy, viral infections, and spinal cord injury share a common link in increased primary afferent activity.6,7,11,12,19,32-35 In human clinical conditions of chronic neuropathic pain, SA has been demonstrated with electroneurography of the peripheral nerves from patients with phantom-limb pain, diabetic neuropathy, erythromelalgia, trigeminal neuralgia and also seen in whole-cell patch clamp of neurons dissociated from patients treated for neuropathic pain with ganglionectomy.36-42 As measurements taken along the initial limb of ascending sensory signals, peripheral nerve or dorsal root ganglia recordings in the above cited studies present straightforward evidence that SA originates from the primary afferent neuron and that it is a frequently shared pathophysiology across many etiologies of neuropathic pain.FIGURE 1: Anatomic sites of origin for ectopic spontaneous somatosensory afferent activity. Sites of ectopy designated in red. ©2017. The University of Texas MD Anderson Cancer Center. Used with permission; all rights reserved.Although dissecting the specific portion of the primary afferent neuron where SA arises is less straightforward, this knowledge could be important in appropriately guiding clinical treatments toward the nerve fiber/endings or axons versus the dorsal root ganglia or cell soma. Distal ends of injured nerve, focal lesions along the course of the nerve, and the dorsal root ganglia have each historically been implicated as sites of ectopic primary SA.8,43-45 Experiments utilizing animal models confirm that SA arises from sites along the axonal projections and from the cell bodies within the dorsal root ganglia.10,46-48 Furthermore, preservation of SA from isolated neuron soma in dissociated preparations of dorsal root ganglia in rodent models of neuropathic pain has also made clear the role of the cell body as a source of SA from within the dorsal root ganglia.12,49-51 Precise localization of ectopia/pain origin within the primary afferent neuron for human clinical conditions remains an area of active study. Direct recordings of peripheral C-fibers on human subjects with neuropathic pain suggest that sites along the distal nerve may be the source of SA.42 Our own recent laboratory investigations confirm that SA is present in isolated neuron soma from dissociated preparations of human dorsal root ganglia from subjects with neuropathic pain (Figure 2).FIGURE 2: Whole-cell patch clamp recording of spontaneously active dissociated human dorsal root ganglion neuron from donor with neuropathic pain.Though there is clear evidence implicating both axons and cell soma as a source of SA in animals and humans, it remains to be determined if there is a dominant source leading to the symptoms of neuropathic pain. Some evidence, however, implicates the cell soma/dorsal root ganglion rather than the axonal projections/stump neuroma as the primary peripheral source of pain/SA in at least one type of painful neuropathy, phantom limb pain. Vaso et al52 utilized local anesthetic to selectively block action potential initiation at the level of the dorsal root ganglion but still allow for propagation of ascending signals from the distal nerve. The selective block resulted in brief relief of painful symptoms consistent with the cell soma/dorsal root ganglion as the chief source of pain.52 Though interesting, further studies are needed to both corroborate these findings and determine if other types of neuropathic pain demonstrate similar response. Spinal Cord and the Secondary Afferent Neuron Increased SA is often noted during spinal cord recordings in animal models of neuropathic pain and has been demonstrated in human subjects with neuropathic pain. However, pinpointing second-order dorsal horn neurons as the origin for this abnormal SA is complicated by the significant amount of normal baseline activity and presence of ascending pathological primary afferent spontaneous activity.53 Despite these limitations, there is evidence that some part of this increased SA in dorsal horn neurons may be driven by automaticity of the second-order neuron. For example, rats that undergo dorsal rhizotomy develop increased spontaneous activity in the dorsal horn and develop self-mutilatory behavior in the deafferented limb despite the surgical disconnection of the primary afferent neuron from higher order neurons.54,55 Similarly, this same type of self-mutilatory behavior has been observed in rats with ipsilateral to C5-T2 ganglionectomies despite the absence of the associated primary afferent neuron, thus implicating a pathology of higher order neurons (such as spinal cord neurons) as the driver of this behavior.56 Thalamus and Somatosensory Cortex Much as in SA recorded from spinal cord neurons, decoding the origin of SA measured at the thalamus or the somatosensory cortex becomes increasingly complex due to significant background and ascending activity. However, neuropathic pain has been associated with both abnormal thalamic bursting from microelectrode recordings and alterations in EEG (electroencephalogram) power band analysis.57-62 These electrophysiological findings paired with the well-established post-stroke pain syndromes arising from thalamic and cortical lesions suggest that altered SA arising from higher order neurons may also be important in neuropathic pain independent of the contributions of first- and second-order afferents. ELECTROPHYSIOLOGY OF SA IN NEUROPATHIC PAIN Though advances in cellular and functional imaging have provided alternative methods for observing SA, electrophysiological recordings are the most direct method for observing SA. These recordings provide much of the basis of our understanding of SA through determination of associated intrinsic membrane properties, the roles of different ion channels, and through identification of involved nerve fiber subtypes. Alterations in intrinsic membrane properties are an important cellular-level measure of the pathophysiology of neuropathic pain. Whole-cell recordings of SA in primary afferents, as shown in Figure 2, have been associated with relatively depolarized resting membrane potential, enlarged subthreshold membrane potential oscillations/variation (SMPO), hyperpolarized threshold potential, decreased rheobase, and depolarizing after-potentials.9,10,12,18,63-65 Taken together, these individual altered membrane properties associated with SA create a framework for understanding the basic driving forces behind action potential initiation and patterns of activity in SA. Spontaneous action potentials are initiated by a fluctuating and depolarized resting potential that intermittently crosses a hyperpolarized action potential threshold. Intermittent activity and irregular patterns of activity are likely driven by this mechanism.63 Bursting and continuous activity is likely initiated in the same fashion but is further maintained by depolarizing after potentials that trigger subsequent action potentials by depolarizing the membrane potential beyond threshold during the recovery from a previous action potential.64 The changes in intrinsic membrane properties discussed above are each built on an interplay of changes in ionic currents largely related to sodium, potassium, and calcium channel activity. Ion channel activity can be altered through changes in overall expression, trafficking, or function of ion channels. Studies of their electrophysiology are critical in understanding the generation of SA and neuropathic pain. Increased persistent sodium currents or decreased potassium leak current active around the resting potential are possible drivers of the relative depolarization of resting potential associated with SA. For example, blockade of persistent sodium currents with riluzole abolishes spontaneous activity in injured rodent DRG (dorsal root ganglion) neurons.66 Furthermore, studies investigating the role of decreased potassium leak channels have found a decreased expression of K2P channels TWIK1, TASK3, TREK1, TREK2, and TRAAK in animal models of neuropathic pain.67 Similar to depolarization of the resting membrane potential, SMPO have also been attributed to a balance of persistent sodium and potassium currents active at resting potential, with evidence that SMPO is eliminated by riluzole and increased with depolarizing agents such as tetraethylammonium, CsCl, or 4-aminopyridine.66,68 Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are non-selective cation channels that have some activity around resting potential and could also contribute to SMPO. SMPO in central neurons has been linked to the Ih current carried by these HCN channels. Moreover, HCN expression has been shown to be increased at sites of peripheral nerve injury, whereas blockade decreases SA and hypersensitivity in animal models.69 Nonetheless, ionic mechanisms behind relative hyperpolarization of threshold and decreased step rheobase seen in SA could also be attributed to changes in voltage gated sodium, potassium, and calcium channels that have been associated with setting threshold; Nav 1.7, Kv1.1, Kv 1.2, Cav 3.2.67,70,71 Nav 1.7 gain of function mutations are associated with painful neuropathies, increased expression is associated with neuropathic pain, and selective blockade alters spontaneous electrophysiological activity in rodent spinal cord and dissociated DRG neurons.72-74 Kv1.1 and Kv 1.2 are both decreased in nerve injury and development of neuropathic pain is impaired by overexpression of Kv 1.2.67,75 Cav 3.2 is upregulated in chemotherapy-induced nerve injury that is paralleled by the development of SA and blockade leads to decreased SA and prevention of tactile hypersensitivity reactions in rats.9 Furthermore, after-depolarization potentials (ADP) driving bursting and tonic SA is likely driven by persistent and resurgent sodium currents or T-type calcium channels.76 Nav 1.7 and Cav 3.2 are again featured as strong candidates for driving part of this ADP given both of their associations with SA/neuropathic pain, the known resurgent behavior for Nav 1.7, and increased ADP in Cav 3.2 wild-type vs null mice.9,72,77 As with basic whole-cell electrophysiology, information gathered from single-fiber recordings also seems to provide a framework for understanding the role of SA in driving symptoms of neuropathic pain. SA has been recorded in fibers with conduction velocities distributed across the Aβ, Aδ, and C fiber range in animal models and human subjects with painful neuropathy.19,40,78 It is logical that symptoms of spontaneous burning or sharp pain would be driven by SA in C and Aδ fibers, paresthesia and dysesthesia from Aβ activity, with evoked symptoms due to peripheral and central sensitization causing the barrage of SA. Despite this attractive and simplistic logic, some contend that instead SA in Aβ afferents, forming the bulk of SA fibers around onset of pain, contribute directly to both spontaneous and evoked painful symptoms by becoming nociceptors themselves.16 Evidence for this process, termed phenotypic switching, includes the increased substance P and CGRP in large diameter DRG neurons following spinal nerve injury.79,80 Though the relative roles of SA in each nociceptive fiber subtype continues to evolve, there is little doubt that each likely plays a significant part in the symptomology of neuropathic pain. CONCLUSION Spontaneous SA activity is a fundamental peripheral and central process that is shared by the many seemingly heterogeneous forms of neuropathic pain. The biology of this altered electrophysiology is defined by a complex interplay of changes in ion channel activity occurring at each level of the ascending sensory pathway which forms much of our understanding of the development and persistence of neuropathic pain, and may ultimately hold the key to developing therapeutic options for those affected. Disclosures This work was supported by grants from the National Institutes of Health (CA200263) and the H.E.B. Professorship in Cancer Research. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.