Study Design: To examine the innervation of the lumbar spine from patients with lower back pain, and spinal nerve roots from patients with traumatic brachial plexus injuries. Objectives: To demonstrate the presence of nerve fibres in lumbar spine structures and spinal nerve roots, and determine whether they express the sensory neuronespecific sodium channels SNS/PN3 and NaN/SNS2. Summary of background data: The anatomical and molecular basis of low back pain and sciatica is poorly understood. Previous studies have demonstrated sensory nerves in facet joint capsule and prolapsed intervertebral disc, but not in ligamentum flavum. The voltagegated sodium channels SNS/PN3 and NaN/SNS2 are expressed by sensory neurones which mediate pain, but their presence in the lumbar spine is unknown. Methods: Tissue samples (ligamentum flavum n=32; facet joint capsule n=20; intervertebral disc n=15; spinal roots n=8) were immunostained with specific antibodies to protein gene product (PGP) 9.5, a pan-neuronal marker, SNS/PN3 and NaN/SNS2. Results: PGP 9.5-immunoreactive nerve fibres were detected in 72% of ligamentum flavum and 70% of facet joint capsule but only 20% of intervertebral disc specimens. SNS/PN3-and NaN/SNS2-positive fibres were detected in 28% and 3% of ligamentum flavum and 25% and 15% of facet joint capsule specimens respectively. Numerous SNS/PN3 and NaN/SNS2-positive fibres were found in the acutely injured spinal roots, and some were still present in dorsal roots in the chronic state. Conclusions: SNS/PN3 and NaN/SNS2-immunoreactivity is present in a subset of nerve fibres in lumbar spine structures, including ligamentum flavum and injured spinal roots. This is the first time that sensory nerve fibres have been demonstrated in the ligamentum flavum, and this raises the possibility that, contrary to the conclusions of previous studies, this unique ligament may be capable of nociception. Selective SNS/PN3 and NaN/ SNS2 blocking agents may provide new effective therapy for back pain and sciatica, with fewer side effects. Other novel ion channels are being studied in these tissues.
Idiopathic trigeminal neuralgia (TN) is a debilitating pain disorder characterized by episodic unilateral facial pain along the territory of branches of the trigeminal nerve. Human pain disorders, but not TN, have been linked to gain-of-function mutations in peripheral voltage-gated sodium channels (NaV1.7, NaV1.8 and NaV1.9). Gain-of-function mutations in NaV1.6, which is expressed in myelinated and unmyelinated central nervous system (CNS) and peripheral nervous system neurons and supports neuronal high-frequency firing, have been linked to epilepsy but not to pain. Here, we describe an individual who presented with evoked and spontaneous paroxysmal unilateral facial pain and carried a diagnosis of TN. Magnetic resonance imaging showed unilateral neurovascular compression, consistent with pain in areas innervated by the second branch of the trigeminal nerve. Genetic analysis as part of a phase 2 clinical study in patients with TN conducted by Convergence Pharmaceuticals Ltd revealed a previously undescribed de novo missense mutation in NaV1.6 (c.A406G; p.Met136Val). Whole-cell voltage-clamp recordings show that the Met136Val mutation significantly increases peak current density (1.5-fold) and resurgent current (1.6-fold) without altering gating properties. Current-clamp studies in trigeminal ganglia (TRG) neurons showed that Met136Val increased the fraction of high-firing neurons, lowered the current threshold and increased the frequency of evoked action potentials in response to graded stimuli. Our results demonstrate a novel NaV1.6 mutation in TN, and show that this mutation potentiates transient and resurgent sodium currents and leads to increased excitability in TRG neurons. We suggest that this gain-of-function NaV1.6 mutation may exacerbate the pathophysiology of vascular compression and contribute to TN.
This prospective study examined the innervation of lumbar spine in tissues from patients with lower back pain and spine nerve roots from patients with traumatic brachial plexus injuries.To demonstrate the presence of nerve fibers in lumbar spine structures and spine nerve roots, and to determine whether they express the sensory neuron-specific sodium channels SNS/PN3 and NaN/SNS2.The anatomic and molecular basis of low back pain and sciatica is poorly understood. Previous studies have demonstrated sensory nerves in the facet joint capsule and prolapsed intervertebral disc, but not in the ligamentum flavum. The voltage-gated sodium channels SNS/PN3 and NaN/SNS2 are expressed by sensory neurone that mediate pain, but their presence in the lumbar spine is unknown.Tissue samples of ligamentum flavum (n = 32), facet joint capsule (n = 20), intervertebral disc (n = 15), and spine roots (n = 8) were immunostained with specific antibodies to protein gene product 9.5 (a panneuronal marker), SNS/PN3, and NaN/SNS2.Protein gene product 9.5 immunoreactive nerve fibers were detected in 72% of the ligamentum flavum specimens and 70% of the facet joint capsule specimens, but in only 20% of the intervertebral disc specimens. The study detected SNS/PN3- and NaN/SNS2-positive fibers, respectively, in 28% and 3% of the ligamentum flavum specimens and 25% and 15% of the facet joint capsule specimens. Numerous SNS/PN3- and NaN/SNS2-positive fibers were found in the acutely injured spine roots, and some were still present in the dorsal roots in the chronic state.As the findings showed, SNS/PN3- and NaN/SNS2-immunoreactivity is present in a subset of nerve fibers in lumbar spine structures, including ligamentum flavum, and in injured spine roots. Selective SNS/PN3- and NaN/SNS2-blocking agents may provide new therapy for back pain and sciatica.
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