Painful neuropathies: the emerging role of sodium channelopathies

Brouwer, Brigitte A.; Merkies, Ingemar S. J.; Gerrits, Monique M.; Waxman, Stephen G.; Hoeijmakers, Janneke G. J.; Faber, Catharina G.

doi:10.1111/jns5.12071

Cited by 87 publications

(83 citation statements)

References 108 publications

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“…The use of antisense, siRNA and murine mutations have indicated that impairment of Na v 1.3, 1.7,1.8 and 1.9 expression has varying antihyperpathic effects in models of inflammatory and neuropathic pain states [127,130,131]. Specific gain and loss of function mutations in the Na v 1.7 channels have been identified in humans wherein there is an increased and decreased pain state, respectively [132,133].…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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Section: Mechanisms Of Actionmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

View full text Add to dashboard Cite

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“…Its effects could also operate on the soma of C-fiber nociceptors that express VGKC currents, blockade of which could enhance neuronal excitability. Analogously, voltage-gated sodium channels were deemed responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where NaV 1.7, NaV 1.8, and NaV 1.9 sodium channels (encoded by SCN9A, SCN10A, and SCN11A) are preferentially expressed [33].…”

Section: Laboratory Investigation Of Vgkc Complex Autoimmunitymentioning

confidence: 99%

Limbic Encephalitis Associated with Voltage-Gated Potassium Channel-Complex Antibodies: Patient Report and Literature Review

Younger¹

2017

WJNS

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Background: The family of disorders associated with antibodies against neuronal surface antigens is a rapidly expanding category of autoimmune neurologic disease. Methods: Clinical and laboratory findings of a patient with voltage-gated Kv1 potassium channel (VGKC)-complex autoantibodies are reported and the literature is reviewed. Results: New-onset faciobrachial dystonic seizures, distal large and painful small fiber peripheral neuropathy, dysautonomia, cognitive and memory disturbances were associated with hypometabolism of the left temporal lobe without evidence of systemic malignancy in whole-body positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose integrated with computed tomography. Brain MRI and cerebrospinal fluid were normal with absent intrathecal VGKC-complex antibodies consistent with extrathecal production. Epidermal nerve fiber studies confirmed small fiber neuropathy in association with abnormal autonomic laboratory testing. Discussion: Neurologic involvement associated with VGKC complex autoimmunity is a precisely delineated disorder involving the central, peripheral, and autonomic nervous system.

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“…It affects the soma of C-fiber nociceptors that express VGKC currents, blockade of which could alter neuronal excitability. Analogously, voltage-gated sodium channels are responsible for the generation and conduction of action potentials along peripheral nociceptive neuronal pathways where NaV 1.7, NaV 1.8, and NaV 1.9 sodium channels are encoded by SCN9A, SCN10A, and SCN11A [134].…”

Section: Anti-vgkc-complex Encephalitismentioning

confidence: 99%

Autoimmune Encephalitides

Younger¹

2017

WJNS

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Autoimmune encephalitis is a potentially severe disorder of the brain of diverse causes with a complex differential diagnosis. Recent advances in the past decade have led to the elucidation of new syndromes and biological markers transforming the approach to diagnosis and management of autoimmune encephalitis. Limbic encephalitis, the commonest form of autoimmune encephalitis, combines common presentations of cognitive, psychiatric, and epileptic disorders and has until recently been considered paraneoplastic or postinfectious in origin. The autoimmune encephalitides are clinically and histopathologically associated with serum and intrathecal antibodies to intracellular and surface neuronal antigens, and constituents of the limbic system neuropil. This has led to a reconsideration of a number of neuropsychiatric and neurocognitive disorders as having shared mechanisms of origin. This chapter reviews their historical background, clinical presentation, laboratory evaluation, histopathology, diagnosis and management. KeywordsAutoimmune, Encephalitis, Hashimoto, Encephalopathy Historical PerspectiveCorsellis and colleagues [1] coined the term limbic encephalitis (LE) in 1968, noting a relation to bronchial cancer in three patients in the sixth to eighth decade of life, and showing close clinicopathologic similarity to cases described by Brierley and colleagues [2] six years earlier. All three cases had subacute temporal lobe seizures, neuropsychiatric, and memory disturbances for two years before death. Postmortem examination showed inflammatory lesions in limbic grey matter sections of the brain, especially in medial temporal lobe structures of the uncus and amygdala nuclei, and hippocampal, cingulum and dentate gyri. Case 2 had an undifferentiated non-metastatic lung carcinoma removed six months after onset of neurological symptoms, while two others had a clinically unsus- The formulation of the relation of GAD antibodies to SPS has been especially instructive in understanding how far the science of autoimmune neurologic disorder has advanced. In 1988, Solimena and colleagues [28] investigated the existence of non-paraneoplastic CNS autoimmunity in a patient with SPS, epilepsy and type-1 diabetes (T1D), and increased titers of oligoclonal CSF IgG. Both the serum and CSF produced identical intense staining of all gray-matter regions. GAD65 was thence an important autoantigen in T1D, being highly expressed in the cytoplasm of pancreatic β cells. GAD-derived peptides were presentable by main histocompatibility complex (MHC) class I molecules and recognized by CD8+ cells on the surface of β cells [29]. Activation of CD8+ GAD-specific T-cells further differentiated into memory cells suggesting a pathogenic role in T1D [30]. However, only patients with very high titers of GAD were associated with LE [31], and they typically presented with recent-onset temporal lobe epilepsy (TLE) and intrathecal secretion, defining a form of non-paraneoplastic LE. Other patients within the SPS spectrum harbored antibodies agains...

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Painful neuropathies: the emerging role of sodium channelopathies

Cited by 87 publications

References 108 publications

Current and Future Issues in the development of spinal agents for the management of pain

Current and Future Issues in the development of spinal agents for the management of pain

Limbic Encephalitis Associated with Voltage-Gated Potassium Channel-Complex Antibodies: Patient Report and Literature Review

Autoimmune Encephalitides

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