The Sodium Channel Which Will Not Shut

Hereditary pain disorders are shedding new light on the role of sodium ion channels in pain. (There is insufficient room in this article to review the action of sodium channels, but you can find a great deal of related information using SEARCH at this site).

We must first reemphasize the difference between CENTRAL and PERIPHERAL nerve injury pain. One cannot make automatic assumptions about one from the other. Even in the Central Nervous Ssytem, there are differences between cord originated (post SCI pain) and brain originated pain (eg epileptic or schizophrenia cenalgesic pain).

Nevertheless, ALL nerve intramissions in all known pain nerves involve the sudden inrush of sodium current to depolarize the cell and initiate an action potential. The sodium flows into the neuron via an ion channel, which is a kind of long tube, operating like an iris to open and close. Nanomachines in the body are made of contractile proteins. We sometimes forget that life implies motion. Inside the cell, the micromachines are constantly moving. The motion may be driven by actual contraction of a protein but more frequently by a reconfiguration caused by some electrical change which makes the molecule more naturally assume another shape.

In sodium flow, voltage or potential changes open and close the channel. Even the simplest channel has many protein molecules which comprise it. There are many sodium ion channels, each with different characteristics. The main pain channel for humans is NaV1.8. In central pain, a fetal ion channel is suddenly grown by genes which have been altered by growth factors released from the glia. This is called plasticity.

There are two realtively well known types of hereditary pain. One is called PEPD. This stands for Paroxysmal Extreme Pain Disorder. The affected person may suddenly, for no good reason, experience severe pain. This is a disorder of PERIPHERAL nerves however, so we are not certain how much we can learn about central pain from it. Scientists have recently discovered that the affected genes results in a defect in SCN9A, (a protein which is a building block of Nav1.8 and perhaps other voltage gated sodium ion channels as well). See Fertleman and Gardiner et al publishing in Dec. 7 Neuron at 52:767-774

A second hereditary disorder is Primary Erythromyalgia (PE). “Erythro” means “red” and “myalgia” means “muscle pain”. In PE, the pain is triggered by exercise or temperature change. As most of you know, many CP subject have kinesthetic dysesthesia, and may also display some autonomic signs, such as blotchy red skin (livedo) on the palms, and have evoked burning dysesthesia from temperature change. That makes PE even more interesting. People with PE also have defective formation of SCN9A suggesting more than one allele or variant in gene location is required to make SCN9A.

In either case, the defective SCN9A makes the sodium channel fail to snap shut, thus increasing the sodium current duration, and increasing the pain signal. One could call this a form of hypersensitization, although that term is usually reserved for heightened pain chemical at synapses, rather than at the neuronal membrane. There are hundreds of studies on central pain which show that synapses are full of pain exciters, so we are not certain how much peripheral pain disorders can teach us. However, they certainly can heighten the awareness for the need to understand pain.

Supposedly carbamazepine helps PEPD but does not help PE. This is problemmatic. These are disorders of the peripheral nerves and carbamazepine has been shown in double blind studies to help herpetic neuralgia (shingles), but has not been thus shown to help central pain. It must be pointed out that oral ingestion of carbamazepine may behave differently from intrathecal (apinal fluid) administration. Not a few pain centers include carbamazepine in their intrathecal (IT) pumps along with opiates, ziconotide, or other medications. No clear data exists, but anecdotal reports in the surveys obligate us to mention this information. We are as interested in why carbamazepine would help PEPD but not PE, as in the sodium current affects. Hopefully the NIH can fihd sufficient funds to assist the fine researchers at the University Hospital of London as they attempt to unravel these hereditary pain disorders.