Sodium channels substance

Neuropathic pain is initiated or caused by a primary lesion in the peripheral or central nervous system. The causative agent may be trauma, nerve-invading cancer, herpes zoster, HIV, stroke, diabetes, alcohol or other toxic substances. Neuropathic pain is refractory to most analgesic drugs. Altered sodium channel activity is characteristics of neuropathic pain states. 

Tamplin et. al. (54) observed that V. cholerae and A. hydrophila cell extracts contained substances with TTX-like biological activity in tissue culture assay, counteracting the lethal effect of veratridine on ouabain-treated mouse neuroblastoma cells. Concentrations of TTX-like activity ranged from 5 to 100 ng/L of culture when compared to standard TTX. The same bacterial extracts also displaced radiolabelled STX from rat brain membrane sodium channel receptors and inhibited the compound action potential of frog sciatic nerve. However, the same extracts did not show TTX-like blocking events of sodium current when applied to rat sarcolemmal sodium channels in planar lipid bilayers. 

Schematic diagram of a primary afferent neuron mediating pain, its synapse with a secondary afferent in the spinal cord, and the targets for local pain control. The primary afferent neuron cell body is not shown. At least three nociceptors are recognized acid, injury, and heat receptors. The nerve ending also bears opioid receptors, which can inhibit action potential generation. The axon bears sodium channels and potassium channels (not shown), which are essential for action potential propagation. Synaptic transmission involves release of substance P, a neuropeptide (NP) and glutamate and activation of their receptors on the secondary neuron. Alpha2 adrenoceptors and opioid receptors modulate the transmission process.

At present, a multitude of novel sodium channel blockers are in preclinical and clinical development. However, most compounds have been applied to many indications, especially epilepsy and stroke. This review includes only those substances for which activities in pain models have been reported. 

More than 30 different substances have been proven or proposed to act as neurotransmitters. Neurotransmitters are either excitatory or inhibitory. As noted, excitatory neurotransmitters (e.g., glutamate and acetylcholine) open sodium channels and promote the depolarization of the membrane in another cell (either another neuron or an effector cell, such as a muscle cell). If the second (post-synaptic) cell is a neuron, the wave of depolarization (referred to as an action potential) triggers the release of neurotransmitter molecules as it reaches the end of the axon. (Most neurotransmitter molecules are stored in numerous membrane-enclosed synaptic vesicles.) When the action potential reaches the nerve ending, the neurotransmitter molecules are released by exocytosis into the synapse. If the postsynaptic cell is a muscle cell, sufficient release of excitatory neurotransmitter molecules results in muscle contraction. Inhibitory neurotransmitters (e.g., glycine) open chloride channels and make the membrane potential in the postsynaptic cell even more negative, that is, they inhibit the formation of an action potential. 

The most famous of the many alkaloids isolated so far is without any doubt batrachotoxin and its derivatives. Batrachotoxin has a LD50 of 2 ug per kg body weight (mouse, i.m.), thus being the most toxic nonprotein substance at all. Because of its special pharmacologic activity to keep open irreversably the sodium channels of nerve cells it has become an important tool in the studies of sodium channels. Chemically the batrachotoxins are esters of a 20-hydroxy steroid, batrachotoxinin A, with different pyrrol carboxylic acids. Although the activities of the different batrachotoxins is qualitatively the same, it differs quantitatively according to the acid part of the molecule (refs. 14, 15). 

Saxitoxin is an extremely toxic substance. It binds to sodium channels and the blocks nerve membrane. In humans, ingestion of this compound can produce tingling and burning in the lip, tongue, face, and the whole body within an hour. This is followed by numbness, muscular incoordination, confusion, headache, and respiratory failure. Death may occur within 12 hours. 

The search for biologically active compounds (natural and synthetic) continued to be a significant inspiration for organic synthesis. Asymmetric catalysis, new synthetic reactions, and advances in separation techniques (HPLC) and analytical techniques (NMR and mass spectrometry) support these advances. In 1995, Kyriacos Costa (K.C.) Nicolaou (1946- ) at Scripps Research Institute reported the total synthesis of brevetoxin B (see the figure on page 375). This toxic substance is produced by algae in red tide and is very deadly to fish. It binds to sodium channels in membranes of muscle and nerve cells producing an excessive influx of Na. ... 

A number of substances increase the sodium permeability of excitable membranes. Their effects on sodium channels are unclear. For example, when a substance causes a permeability increase which is blocked by TTX, then it may be acting directly on the channel or indirectly on some binding site or receptor adjacent to, or some distance from, the channel. It is not easy to distinguish these possibilities in many instances. 

The pyrethrins represent a group of six closely-related monoterpene esters and are invaluable insecticidal substances isolated from pyre-thrum flowers, such as Chrysanthemum cinerariaefolium, and several other species in the Asteraceae family. Pyrethrins are indicated for treatment of skin parasites, such as head lice. They block sodium channel repolarization of the arthropod neurons, which leads to parasite paralysis and death. Permethrin is also used to treat head lice infestation. However, the growing resistance of head lice to pyrethrin and permethrin is becoming a serious concern [88]. 

Additional cellular events linked to the activity of blood pressure regulating substances involve membrane sodium transport mechanisms Na+/K.+ ATPase Na+fLi countertransport Na+ -H exchange Na+-Ca2+ exchange Na+-K+ 2C1 transport passive Na+ transport potassium channels cell volume and intracellular pH changes and calcium channels. 

DDT enters an insect by dissolving the thin layer of fatty substances that repel water from the creature s waxy outer skin. Penetrating the layer, DDT reaches the insect s nerve endings and gradually paralyzes vital nerve centers. After a short period of extraordinary excitement, insects sprayed with DDT become progressively paralyzed, fall on their backs, and die. Later, it was learned that DDT allows sodium ions to enter insect tissue through voltage-sensitive channels and make the nerves fire uncontrollably. Because animals and people absorb much less sodium in their tissues, DDT is selectively toxic to insects. 

Sir Henry Dale noticed that the different esters of choline elicited responses in isolated organ preparations which were similar to those seen following the application of either of the natural substances muscarine (from poisonous toadstools) or nicotine. This led Dale to conclude that, in the appropriate organs, acetylcholine could act on either muscarinic or nicotinic receptors. Later it was found that the effects of muscarine and nicotine could be blocked by atropine and tubocurarine, respectively. Further studies showed that these receptors differed not only in their molecular structure but also in the ways in which they brought about their physiological responses once the receptor has been stimulated by an agonist. Thus nicotinic receptors were found to be linked directly to an ion channel and their activation always caused a rapid increase in cellular permeability to sodium and potassium ions. Conversely, the responses to muscarinic receptor stimulation were slower and involved the activation of a second messenger system which was linked to the receptor by G-proteins. 

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