The Voltage Gated Sodium Channel Biology Essay

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The pulpodentin complex

The dental pulp is surrounded by the dental hard tissue, which is a physical barrier against pathogen and injury. The pulp and dentin are often discussed together as a functional unit, the pulpodentin complex. Pulp is capable to elaborate dentin both physiologically and in response to external stimuli. The permeability properties of dentin regulate the rate of diffusion of irritants that initiate pulpal inflammation. Pulp carries vascularity and nerve supply. Blood vessels are for nutrient supply and cells recruitment, while nerves are for dental sensitivity and defense response following injury either from dental caries or trauma. Due to encapsulation, the dental pulp has a low capacity for defense or repair because of impairment of an adequate blood supply and recruitment of cells following injury (1).

Pulpal innervation

Pulpodentin complex is extremely rich in innervation that influences the defense reactions in the connective tissue of the pulp (Figure 5.3). These consist of sensory fibers, sympathetic fibers, and parasympathetic fibers.

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Among all, the sensory fibers are the great majority. They originate from trigeminal ganglion and terminate in the spinal trigeminal nucleus, then pass through the apical foramen, diverge and branch in the coronal pulp. Finally they terminate in the odontoblast layers, predentin or in the inner 0.1 mm of dentin. There are three subgroups of sensory innervation based on size, conduction velocity, and function. A-beta fibers, the medium-sized myelinated fibers, are the smallest group of sensory fibers that sensitive to mechanical stimuli such as hydrodynamic. Small myelinated A-delta can be seen much greater in dental pulp. The largest portion of sensory fibers is C fibers, the unmyelinated, slow conducting fibers. Both A-delta and C fibers are nociceptive. The sensory fibers provide vitality of the dental pulp by interacting with other pulpal cells, such as odontoblasts, immunocompetent cells, and blood vessels. This can be seen in the previous study of rat molars with occlusal exposure, teeth with sensory denervation have more severe loss of pulp tissue than the innervated one (2).

The sympathetic fibers are from superior cervical ganglion. They are less numerous than sensory fibers and locate along the blood vessels in deeper pulp. Their function is vasoconstriction. The other group of pulpal innervation is parasympathetic fibers which function in regulation of pulpal blood flow but are much less important than the other two mentioned before.

During the maturation and aging, dental pulp becomes narrower with tertiary dentin and dead tracts which are denervation. With increasing loss of primary dentin, tooth innervation decreases and there is reduction in expression of neuropeptides and their receptors (3).

The overall coronal innervations in both primary and permanent teeth extend toward the odontoblast layer but subodontoblastic nerve plexus appear denser in permanent teeth than in primary teeth (4).

In this study, we will study the dental pain associated with dental caries in human primary teeth. Therefore, sensory innervation in primary teeth is what we are interested due to its prominent function as pain transmission. The sensory innervation in primary teeth differs from that of permanent teeth as described below.

The study of Egan et al 1996 (5) demonstrated sensory nerve supply in primary human teeth using immunohistochemistry and unveiled the different between primary and permanent teeth in two way. First, the distribution within the crown of primary teeth were highest at cervical, while the permanent teeth were densely supplied in the pulpal horn dentin. Next, the primary tooth roots were supplied, especially near cervical ends, but the permanent root dentin was virtually uninnervated. The results of this study differ from the other comparing primary and permanent teeth. This may be explained by differences in the methods of fixation and processing used.

There are a plenty of calcitonin gene-related peptide (CGRP) containing fibers, a peptidergic fibers which are subpopulation of nociceptive sensory fibers, in the pulp horn and subodontoblastic plexus of both primary and permanent molars, but overall CGRP expression are greater in permanent teeth (6). Therefore, this can be assumed that primary teeth have less sensitivity than permanent teeth. (The role of CGRP will be explained later in sensory neuropeptides in dental pulp)

In healthy primary teeth with physiological root resorption, there was no significant difference related to physiological resorption and histological structure of primary tooth pulp (7). The pulpal horns are the most densely innervated region with multiple free-ending fibers extending toward the pulp-dentin junction. The overall innervation density has no significant difference due to the degree of root resorption in either pulpal horn or mid-coronal region (8).

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In summary, the location of sensory fibers in dental pulp is approximately the same for primary and permanent teeth but the quantity of those is less in primary teeth. Physiologic root resorption does not affect histological structure and overall innervation.

Sensory neuropeptides in dental pulp

The sensory fibers are afferent fibers involved predominantly in perception of pain. The terminals of sensory fibers contain neuropeptides, the protein involved in the nervous system, which are synthesized from neurons. These peptidergic neurons are associated with neurogenic inflammation in order to provide the vitality of dental pulp. They change dynamically during inflammation that caused by stimuli such as dental caries, drilling, probing of the exposed dentin, or percussion of the teeth, by extensive sprouting and result in an increase in potential sites of neuropeptide release. The profuse innervation of pulp and dentin releases neuropeptides. Neuropeptides cannot cross cell membranes, so they trigger biologic effects by activating receptors located on the plasma membrane of the target cells and they are rapidly degraded by the enzyme in pulp tissue after exerting the effects. Functions of sensory neuropeptides are multiple and variable. They could act as neurotransmitters, growth factors, hormones, and immune system signaling molecules. It is generally accepted that neuropeptides contribute to promote neurogenic inflammation and healing of the pulp by modulate vasodilation, increase in vascular permeability, and also immunomodulation. These neuropeptides include calcitonin gene-related peptides (CGRP), substance P (SP), neurokinin A (NKA). Summary of the sensory neuropeptides in dental pulp are shown in table 1. For review please read (9) and (10).

Peptidergic sensory fibers and arterioles within the midcoronal of both primary and permanent tooth pulps are located in close spatial relationship. It is believed that peptidergic afferent fibers are involved in control of pulpal blood flow. They cause vasodilation and inhibit vasoconstriction that induced by sympathetic fibers in response to stimulation. The CGRP-containing fibers are the majority of vessels innervation (11). SP initiates vasodilation, while CGRP is responsible for the continued long-lasting elevation of pulpal blood flow. Thus, CGRP is believed to be associated with prolonged pain. Otherwise, CGRP also produces immunosuppression by inhibiting T-lymphocyte proliferation, blocking H2O2 production in macrophage, reducing antigen presentation of class II antigen-presenting cells, and inhibiting the induction of delayed-type hypersensitivity. CGRP induces histamine release from mast cells and result in an increased vascular permeability and increased blood pressure. It also stimulates growth of fibroblasts and odontoblast-like cells (12).

Immune system in dental pulp

The voltage-gated sodium channel

The voltage-gated sodium channels (VGSCs) are complex transmembrane pores that open within a millisecond in response to electrical change across the membrane to allow sodium ions influx, and then terminate within unextended periods of time to occlude the sodium ions flow. After this process, VGSCs return to resting state and are available to open again in response to new wave of electrical change. VGSCs play the role in the propagation of nerve impulses and continuous activation of VGSCs gives rise to unprovoked spontaneous action potential activity, that finally cause continuous pain (13). The sodium channel is the selective filter composed of 1 large continuous protein, α-subunit and 1 or 2 smaller proteins, β-subunits. The α-subunits, a 220-260 kD polypeptide, contain a functional part of ion channel including voltage sensor, ion pore, activation, and inactivation gate. The β-subunits modulate the functions of the α-subunits and stabilize them to the plasma membrane (14).

In mammals, 9 genes have been identified to encode VGSC α-subunits into 9 isoforms depend on amino acid sequence homology and genetic location. Each isoform differs in function such as tissue distribution, electrophysiology, pharmacology, and response to nerve injury and inflammation. Moreover, each one is associated with variety of receptor molecules to regulate nociceptor excitability, so there are diversified processes of nerve impulse propagation depending on the present of sodium channel α-subunit isoform, for example, varying in opening thresholds, opening time length, amount of inactivation time, or rate of isoform transition from closed inactivated state to the resting close state (14).

Sodium channels can be classified by flow of the current through the channels as low- or high- threshold and by the rate of inactivation as fast or slow. Furthermore, each isoform of sodium channels varies in sensitivity to blockade by tetradotoxin (TTX), a toxin found in the liver of puffer fish. Some isoforms are highly sensitive, while the others are relatively resistant (14). The properties of each VGSC α-subunit isoforms are shown in table 2.

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The sensory neurons in dorsal root ganglion (DRG) express both TTX-sensitive (TTX-S) and TTX-resistant (TTX-R) sodium channels. The large neurons are mechanoreceptive with rapid-inactivating TTX-S sodium channels. The small neurons are nociceptive, expressing a mixture of rapid-inactivating TTX-S and slow-inactivating TTX-R sodium channels. NaV1.8 and NaV1.9, the slower TTX-R components, are remarkably found in small DRG neurons that have been identified as nociceptive neurons and believed to be involve in the prolonged duration of action potential in response to painful stimuli (14). Based on distribution, both NaV1.8 and NaV1.9 might be a new target for treatment of pain. NaV1.8 has a high activation threshold, slow inactivation kinetics and contribute to electrogenesis of action potential in C-type peripheral neurons of mice models (15). NaV1.9 activates at potentials near resting membrane potential and generates relatively persistent current (16).

Following inflammation, VGSCs change their expression in sensory neurons and contribute to the activation of pain pathways, leading to an increasing pain states (14). The studies of painful teeth with irreversible pulpitis reveal an increase in expression of NaV1.7 (17), NaV1.8 (18, 19) and NaV1.9 (20), each of which is an isoform of α-subunit of sodium channel, compare to dental pulp of nonpainful teeth. Although may be at least 3 α-subunit isoforms of sodium channel are associated with dental pain, we focus only on NaV1.8 and NaV1.9. For NaV1.8, the reason is that NaV1.8 has been proved to be increase in expression in human permanent tooth pulp with symptomatic irreversible pulpitis using western blot analysis, the same method we will use in this study.

Within the human dental pulp, NaV1.8 immunoreactive fibers are found in subodontoblastic layer (18).

Table 2 Voltage-gated sodium channel α-subunits isoform and their properties (13, 14)

Channel α-subunit isoform

Site of expression

Inactivation rate

Sensitivity to blockade by TTX

NaV1.1

CNS and DRG sensory neurons

Fast

Sensitive

NaV1.2

CNS neurons

Fast

Sensitive

NaV1.3

Immature neurons

Fast

Sensitive

NaV1.4

Skeletal muscle

Fast

Sensitive

NaV1.5

Cardiac muscle

Slow

Resistant

NaV1.6

CNS and DRG sensory neurons

Fast

Sensitive

NaV1.7

DRG sensory neurons and sympathetic ganglia

Fast

Sensitive

NaV1.8

DRG sensory neurons

Slow

Resistant

NaV1.9

Small DRG sensory neurons and trigeminal ganglia

Very slow (persistent)

Resistant

Dental pain assessment

Pain assessment is a complex process to obtain pain information and effects on the person along with quantitative values. The examination and evaluation of pain can be done by taking patient's history, systems review and use of pain measurement tools (21).

Although many tools are often used to measure pain severity in children, visual analogue scale (VAS) is commonly used. VAS is a line of 10 centimeters long, the left end of the line refers to no pain while the right end points of the worst pain a child can imagine of. It requires cognitive ability to understand serial order and translate into a distance measure. According to Piaget's developmental stage of intelligence, the stage at which the children can perform serial ordering operation and able to generalize along a linear dimension is concrete operations, by the age of 7-11 years. Consequently, VAS seems to be difficult to measure pain intensity in children under 7 (reference champion: Measurement of pain by self-report 1998), but widely used to assess pain severity in both adults and older children. However, O' Rourke (21) reported the use of VAS in children from 5 years and older with excellent validity and reliability. Excluding consideration of age, VAS is a powerful tool to quantify magnitude of pain due to more informative and sensitive to changes comparing to faces scales.

Faces scales are popular methods for pain severity measurement in children, consisting of a series of faces that express discriminate degree of pain intensity, from smiling to crying. Faces scales are handled by matching the face that corresponds most closely to the child's feeling. These methods are assumed to be easier than VAS (Champion 1998) because less cognitive ability is needed. Wong-Baker Faces Pain Scales (WBFPS) is one of the faces scales that have shown to be valid and reliable in pediatric setting. It is a scale with 6 faces representing different levels of pain and scales as 0, 2, 4, 6, 8, and 10 (figure 3). Garra et al (22) found that both of VAS and WBFPS had excellent agreement when used in pediatric emergency patients. The same result was demonstrated in Thai children that VAS and WBFPS were significant correlate in children at age 4 years and older (23).

The participants in this study will be the children of age from 5 years. Because, until now, no tool is a gold standard for pain intensity measurement tool, so we will use both VAS and WBFPS to reassure that each participant really understands how to use the pain severity measurement tools.

Figure 2 Visual Analog Scale (VAS)

Figure 3 Wong-Baker Faces Pain Scale (WBFPS)

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