The Dorsal Root Ganglion in the Pathogenesis of Chronic Neuropathic Pain

The dorsal root ganglion (DRG) is a processing gateway for peripheral sensory signals, diversely ranging from touch and proprioception to inflammatory and somatic pain. Neuropathic pain is a syndrome of disordered sensory perception in which pain is felt either without stimulus or at higher intensity, with current knowledge focusing on activation and amplification sites for this aberrant signal processing. Because of its location within the spinal intervertebral foramina, the DRG is anatomically accessible both percutaneously and surgically and has been a target for numerous ablative and modulatory therapies.1 We review here first the structure and function of the normal DRG; second, the multiple animal experimental models used to study neuropathic pain; third, the cellular, molecular, and genetic alterations in the DRG associated with neuropathic pain; and last, the current therapeutic strategies targeting the DRG, along with their proposed mechanisms of action. ANATOMY AND FUNCTION OF THE NORMAL DRG DRGs are located in the vicinity of the neural foramina at each vertebral level. Although their precise location within the neural foramen varies by level, their relative accessibility by either percutaneous extraforaminal or epidural intraforaminal approaches renders them a prime target for multiple therapeutic modalities.1,2 These highly heterogeneous structures contain many cell types, with neurons representing only 15% of cells.3 The somata of these pseudo-unipolar neurons are surrounded by Schwann cells and satellite glial cells; their distal axons constitute primary afferent sensory nerves, whereas proximal axons synapse onto dorsal horn cells via dorsal spinal roots. Although there are no synapses within the DRG itself,4 connections from DRGs to dorsal horn cells have been shown to occur in both a convergent and a divergent fashion,5 partially accounting for the limited success of neuropathic pain therapies targeting the distal peripheral nerves. Although not in abundance under normal conditions, postganglionic sympathetic efferents may sprout onto DRG neurons after peripheral nerve injury, potentiating sympathetically mediated forms of chronic pain.6 Processes of satellite glial cells act as physical barriers between DRG neurons. Satellite glia are also critical in responding to chemical stimuli and mediating glial-glial and neuron-glial interactions via receptors for various chemokines, cytokines, and neurotransmitters.7 The central and peripheral nervous systems are protected by blood-brain and blood-nerve barriers, respectively. The DRG, however, is not protected by such a barrier and is therefore susceptible to infiltration from circulating chemokines and leukocytes, thereby promoting inflammatory mechanisms of neuronal hyperexcitability.8 MODELS OF NEUROPATHIC PAIN Rodent models of neuropathic pain have been used to investigate mechanisms of various neuropathic pain origins and to assess response to treatments. Many intrinsic and extrinsic factors influence reflexive and nonreflexive responses to stimuli, including rodent strain,9 sex,10 diet,11 and suture material used for peripheral nerve ligation.12 The role of the DRG in neuropathic pain has been studied in peripheral nerve injury models, with other systemic, central, and peripheral end-effector models of neuropathic pain reviewed comprehensively in the recent literature.13,14 Even among peripheral nerve injury models, there are significant differences in the range, severity, and duration of responses to standard stimuli,15,16 in the sympathetic dependence of the neuropathic pain response,17 in the central plasticity associated with peripheral sensitization,18 and in the associated cellular, molecular, and genetic changes in the DRG. The earliest peripheral nerve injury model involved complete axotomy of the common sciatic nerve.19 Although not readily translatable clinically, the model was also plagued with ethical concerns resulting from excessive limb autotomy. The commonest models in use currently include chronic constriction injury (CCI), partial sciatic nerve ligation, and spinal nerve ligation (SNL), all of which demonstrate durable, sympathetically mediated, thermomechanical allodynia and hyperalgesia.20-22 Models of sympathetic-independent neuropathic pain include tibial and sural nerve transection, as well as spared nerve injury.23-25 Neuropathic pain has been induced via inflammatory mechanisms in sciatic neuritis models through injection of agents such as zymosan, tumor necrosis factor-α (TNFα), inactivated bacteria, or seaweed protein.26-28 Newer models of ischemic peripheral nerve injury include photochemical and laser-induced sciatic nerve injury.29,30 These models are summarized in Table 1.TABLE 1: Animal Models of Peripheral Nerve Injury–Induced Neuropathic PainaDRG PHENOTYPES ASSOCIATED WITH NEUROPATHIC PAIN Chronic neuropathic pain is characterized by an amplified sensory response that may represent decreased firing threshold of nociceptors and sensory afferents or central amplification of a normal peripheral sensory activation, resulting in the symptoms of allodynia and hyperalgesia. Several changes at the DRG may facilitate both of these processes. Cellular Phenotype After peripheral nerve injury, aberrant and ectopic firing is seen in both C-type fibers, which are normally nociceptive, and larger myelinated A-type fibers, which are not and therefore are thought to contribute to the maintenance of chronic pain and clinical allodynia.31 Specifically in CCI models of neuropathic pain, injured neuronal somata have been demonstrated to increase the release of glutamate within the DRG, with corresponding increases in glutamate receptor expression on both satellite glial cells and sensory neurons.32,33 Local autoimmune and inflammatory processes contribute heavily to the initiation of chronic pain. After primary sensory afferent injury, native Schwann cells and satellite glial cells within the DRG proliferate34 and release multiple proinflammatory mediators, including eicosanoids, serotonin, interleukins, and TNFα, as well as growth factors and multiple chemokines.27,35-38 In neuropathic pain models in which injury is induced peripherally to the DRG, robust astrocytic and microglial proliferation is seen within the DRG, with subsequent release of microglial inflammatory mediators; in contrast, only an astrocytic response is seen in dorsal rhizotomy models, in which the site of injury is proximal to the DRG.39 Molecular Phenotype Ion Channels The common denominator of neuronal hyperexcitability in neuropathic pain is a shift in ion channel composition, and therefore membrane excitation threshold, in sensory afferents. Transduction of stimuli at the end effectors of sensory afferents is performed by transient receptor potential channels, Na channels, and ATP-sensitive receptors.40 Axonal conduction of the signal is maintained by voltage-gated sodium channels (Nav), which are typically excitatory, and voltage-gated potassium channels (Kv), which restore membrane polarization. Synaptic transmission from DRG neurons is conducted by voltage-gated calcium channels and postsynaptic glutamate receptors. Sodium Channels The α subunits of Nav channels are encoded by only 9 genes in humans, with Nav1.7, 1.8, and 1.9 the primary channels in the peripheral nervous system,41 although Nav1.1, 1.3, and 1.6 are also expressed. Nav channels may be further subdivided into tetrodotoxin-sensitive (Nav1.1, 1.3, 1.6, 1.7) and tetrodotoxin-resistant (Nav1.8, 1.9) channels. Under normal conditions, DRG neurons are known to coexpress multiple Nav subtypes, each with different kinetics and voltage thresholds.42 Nav1.3, although not expressed preferentially in DRG neurons, has been shown to be upregulated after peripheral afferent injury.43,44 Deletion of Nav1.3 in global knockout mouse models has shown that the role of this channel in neuropathic pain is both model and symptom specific. Deletion of Nav1.3 reduces the magnitude of both thermal and mechanical allodynia in a CCI mouse model but not in an SNL model.45 Nav1.6 has been shown in DRG cell cultures to be important in generating resurgent sodium currents, contributing to action potential propagation and therefore neuronal excitability. Multiple inflammatory mediators potentiate the frequency and amplitude of these resurgent currents, promoting neuronal hyperexcitability after inflammatory injury.46 In a rat SNL model, Nav1.7 was not overexpressed in the DRG after nerve injury; however, it was upregulated in injured proprioceptive sensory afferents and in their termination in the nucleus gracilis, suggesting that Nav1.7 and other tetrodotoxin-sensitive channels may be important in generating the spontaneous discharges in A-fiber afferents that are seen in chronic neuropathic pain.47 Nav1.7 was also shown to be solely required for sympathetic sprouting after SNL injury and may be a particularly important target for sympathetically mediated forms of neuropathic pain.45 Nav1.8, the prototypical tetrodotoxin-resistant channel in the peripheral nervous system, has been shown to be important specifically in thermal allodynia in a CCI mouse model but not for mechanical allodynia. Neither neuropathic pain behavior was seen after SNL injury in an Nav1.8-knockout mouse.45 Like tetrodotoxin-sensitive channels, Nav1.8 is also upregulated in DRG neurons by inflammatory mediators,46 dependent on the protein kinase C–nuclear factor-κB pathway.48 Like Nav1.6 and 1.8, Nav1.9 is known to be involved in DRG neuronal excitability and is upregulated after inflammatory nerve injury.49 Multiple gain-of-function mutations have been found in the gene encoding Nav1.9 in human cohorts of hereditary neuropathic pain disorders and familial episodic pain.50 The heterogeneity in sodium current changes in neuropathic pain between voltage-gated channel subtypes and among animal pain models renders channel-specific therapies unreliable and perhaps overly focused. Although broad sodium channel–blocking agents are among standard pharmacological therapies for neuropathic pain, their lack of specificity may reflect their often variable and transient efficacy. Potassium Channels In contrast to the limited number of Nav channels, Kv channels are tetramers of 30 possible α subunits, each of which can be paired with multiple possible auxiliary subunits with wide spatiotemporal variability.51,52 Although Na channel blockers, typically used as antiepileptics or local anesthetics, have been the predominant pharmacological therapy for neuropathic pain, Kv channels potentially offer a broader range of novel therapeutic targets. Kv dysfunction after nerve injury is known to promote neuronal hyperexcitability and associated neuropathic pain phenotypes.53 These phenomena are Kv subtype and pain phenotype dependent. Kv3.4 and 4.3, expressed in nociceptive DRG neurons, are downregulated in rat SNL models of neuropathic pain, with the corresponding development of mechanical but not thermal hypersensitivity.54 Kv9.1 is expressed only in myelinated sensory neurons, absent from small unmyelinated nociceptive neurons, and after nerve injury leads to both spontaneous and evoked neuronal hyperexcitability and neuropathic pain behaviors.55 As with Na+ currents, inflammatory mediators, including interleukin (IL)-1β and TNFα, attenuate K+ currents, leading to neuronal hyperexcitability and subsequent neuropathic pain phenotypes.56,57 Inflammatory Mediators Tumor Necrosis Factor-α TNFα is a cytokine seen widely in systemic inflammatory responses. It is released by activated microglia in the DRG after distal nerve injury58,59 and locally at the site of tissue injury in CCI models.20,60 It may also be transported to spinal cord dorsal horn cells after distal injury, resulting in neuronal hyperexcitability via the changes in ion permeability discussed previously, in the receptive fields of both injured and noninjured nerves.61,62 Amplification of hyperexcitability by central sensitization is corroborated by spinal nerve crush injury models proximal and distal to the DRG; compared with proximal crush, distal injury with an intact dorsal root resulted in greater neuronal apoptosis and TNFα expression, with correspondingly elevated neuropathic pain behaviors.63 The signaling mechanisms involved in ion current alteration by TNFα may be mediated by the p38–mitogen-activated protein kinase system.57 With ion currents being altered through expressional changes in multiple cation channels in the presence of inflammatory nerve injury, further therapies attenuating systemic and DRG-specific inflammatory responses may provide greater clinical value. Interleukins The interleukins are a class of cytokines produced by leukocytes in inflammatory and immune responses. IL-1β is produced in the spinal cord and DRG in inflammatory rodent pain models.64,65 In neuropathic pain models, as we have discussed previously, injection of exogenous IL-1β is known to facilitate excitatory Na+ currents and to attenuate inhibitory K+ currents, leading to neuronal hyperexcitability. In models in which nerve injury occurs distal to the DRG, microglial activation and proliferation within the DRG result in the secretion of multiple inflammatory cytokines, including IL-1β and IL-6.66 The production of IL-6 in rat DRG and its subsequent stimulation of neuropathic pain behaviors are mediated in part by prostaglandin E2, neutralization of which blocks IL-6 production and reduces clinical hyperalgesia.67 Elevated levels of IL-6 have also been demonstrated in cutaneous blister fluid samples of human patients with complex regional pain syndromes in the involved extremity compared with the unaffected extremity.68 Adenosine Triphosphate More commonly thought of as the primary product of cellular respiration, ATP is also a ligand for the P2X family of ligand-gated ion channels, expressed in DRG nociceptive neurons.69 These purinoreceptors have been implicated in the potentiation of capsaicin receptor–mediated nociception, reducing activation thresholds to the point of clinical thermal allodynia.70 Further research into ATP-induced mechanisms of pain is ongoing. Neurotransmitters and Growth Factors Neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor and glial-derived neurotrophic factor have been implicated in the regulation of processes leading to neuropathic pain. Nerve growth factor, functioning normally in the maintenance of the peripheral nervous system, can sensitize peripheral nociceptors with its release by satellite glia in the DRG after nerve injury, increasing neuropathic pain phenomena in a rodent CCI model.71 Brain-derived neurotrophic factor synthesis by DRG glial cells is also upregulated after peripheral injury72; in lamina-I of the dorsal horn, brain-derived neurotrophic factor is known to induce an inversion of postsynaptic inhibitory gamma-aminobutyric acid (GABA) currents, promoting the development of allodynia.73 In contrast, intrathecal infusion of glial-derived neurotrophic factor reverses axotomy-induced neuropathic pain in rats,74 apparently via blockade of sodium currents from tetrodotoxin-sensitive Na channels in the DRG.75 Genetic and Epigenetic Phenotypes Multiple transcriptional changes are seen in DRG neurons after peripheral afferent injury. The transcriptional profile may differ between models; however, full transcriptional profiling has been performed mainly for CCI, SNL, and axotomy models.76-79 In a mouse SNL model, Kiso et al78 found that DRG mRNA levels of Nav1.8 and the opioid μ receptor were decreased compared with sham controls, whereas those of the α2δ-1 calcium channel subunit and the signaling neuropeptide galanin were increased. In axotomized rats, Xiao et al79 similarly found upregulation of the α2δ-1 calcium channel subunit along with the GABAA receptor α5 subunit; however, they also demonstrated upregulation of the Nav channel β2 subunit. By differentially fluorescently labeling injured and uninjured neurons in a CCI model, Reinhold et al77 identified the transcriptional profiles of injured and adjacent uninjured neurons within the same DRG, along with their contralateral uninjured counterparts. They confirmed upregulation of the α2δ-1 calcium channel subunit in injured DRG neurons and demonstrated upregulation of the P2rx3 purinoreceptor. Not surprisingly, multiple potassium channels, including Kcnk2, Kcnj10, Kcnh8, and Kcnn4, were downregulated. Although multiple targets have been identified for possible intervention, further work is required to understand not only the transcriptional but also the epigenetic alterations leading to chronic pain phenotypes. Much of the work to date on epigenetic changes in chronic pain has focused on histone modifications. Histone hyperacetylation has been demonstrated in the spinal cord after CCI in a rat model with consequent upregulation of pronociceptive genes.80 In contrast, the DRG exhibits histone hypoacetylation downregulating Nav1.8 with phenotypes of clinical hypoesthesia and neuropathic pain after partial sciatic nerve ligation in a murine model.81 Aside from acetylation, increased promoter methylation is important in mediating the acute-to-chronic pain transition in a rodent SNL model by epigenetic potassium channel downregulation.82 DNA methylation has been less well studied; however, inhibition of global DNA methylation with intrathecal 5-azacytidine alleviates neuropathic pain behavior in a rat CCI model.83 Novel epigenetic targets, including noncoding and microRNA, continue to emerge and have been reviewed more thoroughly by Ligon et al.84 CURRENT THERAPEUTIC STRATEGIES TARGETING THE DRG Given the multitude of cellular, molecular, genetic, and epigenetic alterations underlying the transition to chronic pain, it is unsurprising that a diverse range of therapeutic modalities targeting the DRG have been established. Earlier ablative techniques, including ganglionectomy and radiofrequency (RF) ablation, have been replaced by modulatory therapies, including spinal cord stimulation (SCS), DRG-SCS, pulsed RF, and laser therapy.85,86 Targeted pharmacological therapies, including gene- and cell-based treatments, are also rising to the forefront. A summary of therapies clinically investigated since 2000 is presented in Table 2.87-107TABLE 2: Clinically Investigated Surgical Therapies for Neuropathic Pain Targeting the Dorsal Root GanglionaGanglionectomy was pioneered in the 1970s as a technique to reduce neuropathic pain by removing primary afferent cell bodies, thereby capturing the dorsal and ventral nociceptive afferents that might otherwise be retained after dorsal rhizotomy. However, given the convergence of primary afferents from multiple DRGs onto single dorsal horn neurons and the divergence of primary afferents onto multiple spinal levels, it is not unexpected that this procedure often results in dysesthesias and deafferentation pain in new distributions.88,90,108 Low-intensity electric stimulation has been shown in a number of tissues to alter local growth factor synthesis and to directly alter neuronal currents. SCS is used widely in the treatment of failed back surgery syndrome and other chronic pain conditions. Although a full discussion of SCS is outside the scope of this the technique is plagued by a result in part of the between and the of as leads DRG-SCS, electric leads are percutaneously the to the DRG, has shown in these In a recent clinical in pain, and to SCS but with a The precise of but may include of cation currents and firing and of the proinflammatory of activated microglia after nerve The of clinical for DRG stimulation has been reviewed by et or is an ablative technique in which adjacent tissues are to resulting in necrosis and complete of both myelinated and unmyelinated With relative to local has also to and pain in to of has therefore been studied as a an ablative in which tissues are to to The of action of pulsed but may be to sodium channel in axons and amplification of and inhibitory Although are multiple have that pulsed and for chronic pain, with for failed back surgery The current on therapies has been reviewed thoroughly by et Low-intensity pulsed laser has been shown to peripheral nerve after of laser to the DRG of a rat chronic model demonstrated significant in neuropathic pain behaviors and associated of proinflammatory cytokines within the DRG, including TNFα and no clinical of laser therapy targeting the DRG have been Because the clinical results of modulatory therapies, from electric have been has pharmacological therapies for chronic neuropathic pain. As we have growth factors and proinflammatory cytokines significant in the ion currents, resulting in neuronal hyperexcitability. intrathecal of glial-derived neurotrophic factor or nerve growth factor have been shown to induced neuropathic pain in rodent models, via of inflammatory pronociceptive More have been used to DNA or directly into the DRG, targeting glial activation or their et demonstrated neuropathic pain in a spared nerve injury rodent model after DRG injection of a DNA encoding a calcium channel–blocking et transient in neuropathic pain behavior in a rat model of sciatic inflammatory neuritis by intrathecal of a DNA encoding a known have used to TNFα or Nav1.3 in the DRG of rodent models, with neuropathic pain behaviors and inflammatory cytokine for known growth factors have also been with only transient success to of the cell The DRG may an important role in the of neuropathic pain, particularly in those in which nerve is associated with peripheral neuronal cell These processes are mediated by cellular, molecular, and genetic changes that and more differ between various experimental Because it is readily accessible the DRG is an target for Targeted pharmacological therapies, including gene- and cell-based treatments, significant for pain symptoms the sensory associated with current ablative and modulatory Further work investigate the and changes underlying chronic pain and model systems in which these changes and their therapies be The have no or in of the or in this

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