Some very fine researchers have differed sharply on precisely which sodium channel is the most important in pain.
Ion channels must open to allow the sodium current to flow and generate an action potential (AP) or nerve firing. The rate at which the nerve fires determines how strong is the pain signal. As the negative voltage outside the cell falls, the ion channels open, and the action potential or spike, follows.
The polite contest between Waxman and Gold over which voltage gated sodium channel is the real culprit in pain has been more than interesting to all observers. Both are outstanding researchers, without peer really, but their results have differed for no reason that has as yet been readily apparent. The controversy has circled around WHICH voltage gated ion channel (of which at least ten are important in humans) was responsible for pain.
It is a marvel that Hains at Yale found relatively early that at least for Central Pain subjects, it was the Nav 1.3 channel. Fluorescent dyes may be attached to antibodies which will adhere to the proteins comprising a given channel, providing a ready way to identify ion channels under the light microscope, although of course electron microscopy would reveal more detail, but is incredibly difficult to set up.
Bryan Hains at Yale seems to have established firmly that Nav1.3 is THE central pain ion channel, since those with CP are the only people who have the channel. Nav1.3 is a fetal ion channel, which is somehow kicked into production when an injured neuron is pushed by growth factors coming from surrounding glial cells, which outnmber neurons 5:1. We say “pushed”, but the real effect is closer to “commandeered”.
Although somewhat overlooked in the studies, Nav1.7 has now moved to the forefront with the discovery by UK doctors that a family in Pakistan who feel no pain have a defective NaV 1.7, such that the channel will not open. These are certainly not the only people who feel no pain. You can read about other such groups using SEARCH at this site. However, it is the first realization that NaV1.7 activity is required for pain.
As we did in a former article, we must point out that defective NaV1.7 in the family is an instance of PERIPHERAL neuropathy. We cannot be sure the conclusions would all apply to central pain. Still, it is worth noting that pain carrying neurons AND NaV1.7 carrying neurons in the Dorsal Root Ganglia BOTH have slow conduction velocities, a prolonged duration of the action potential, and small cell bodies.
It was known as early as 2003 from work in the UK, (see Dhourjhi et al J Physiol. 2003 Jan 15;546(Pt 2):565-76) from studies in guinea pigs that neurons with Nav1.7 express the alpha subunit protein which is essential for all nociceptive neurons.
With increasing diameters of pain neurons, we see increasing conduction velocities, in this order: C fibers, A delta fibers, A beta, A alpha. Conduction velocity can actually be used to identify which type of fiber one is dealing with when tracing out signal. Broadly speaking sensory fibers are divided into nociceptors (pain receiving) and low mechanical threshold (LTM) fibers; however, experiments have shown that the various types can be turned into each other by the genetic activity which occurs in the face of pain.
Experimentally, however, it remains useful to speak of nociceptors (C, A delta, A alpha/beta) vs. LTM fibers. Dhourjhi et al showed that
“All C-, 90 % of Adelta- and 40 % of Aalpha/beta-fibre units, including both nociceptive and LTM units, showed Na(v)1.7 immunoreactivity”. However, the LTM are always considered as pain silent, but convertible. The big A alpha fibers are convertible to pain also, but in a different sense. They carry fast pain, well localized, but can be converted by C fiber activity in the dorsal root ganglion to a CHRONIC pain carrier. This is known as hypersensitization. Whereas 11 of 11 nociceptive C, and Adelta pain fibers were flush with Nav 1.7, only 2 of 9 A alpha fibers showed NaV 1.7 content.
For some time, Dhoujhi’s work was about it for this ion channel, and it was somewhat forgotten in the debate over Nav1.8, which is the active ion channel for NORMAL pain. However, the current edition of Nature (Dec 16) reveals the remarkable role of NaV 1.7 in pain in this one family line of Pakistanis, who do not feel pain. This suggests that if NaV 1.7 could be shut off in others, pain might stop. We do not know if Nav1.7 somehow contributes alpha subunits to other ion channels or just precisely how the NaV defect stops pain. Other ion channels are also made up of varying proportions of the alpha subunit, mixed with other entities. You can read more extensively about the alpha subunit, using SEARCH, at this site. Basically, you need copies of it to make a sodium ion channel.
The Wall/McHenry database was begun by Dr. Patrick Wall at the urging of John Bonica. Dr. Wall’s coauthor of the Textbook of Pain, Ron Melzack, has been kind enough to comment and assist with some of the authorship here. Melzack’s legacy at McGill is obvious in the maturation of studies which have been ongoing there for many years. Much of the work in the recent study discussed here has also been done in collaboration with the absolutely wonderful Canadians in Toronto, the offshoot of Ron Tasker’s work, and also by those currently associated with McGill in Montreal, who can be thought to be influenced by Melzack. Among the Quebecois are Michael Salter and Jeffrey Coull, who has contributed to one of our articles here. Interest in these groups continues the focus on the action of purine 2X4 receptors in glia, which, as Dr. Salter has found, then release BDNF, which destroys inhibitory ability in the central nervous system. (Please review the articles here on purine receptors, as well as the information on BDNF and glia, using SEARCH at this site).
We are certainly happy to see this biochemical sleuthing of the neuronal membrane going on and hope it leads to important information for central pain. Sodium ion channels look like elongated tubes, or ride tubes at a water park, sometimes crossing back and forth across the neuronal membrane in a fairly complicated shape, something like a ride at a water park, yet they are capable of amazingly quick transmission of charged sodium ions. Although not as fast as electrons flowing in house wire, the order of speed is very high. This kind of performance would be expected to require some fairly close tolerances. Apparently, in this one family at least, NaV 1.7 is VERY important.
We would prefer more curiosity about NaV 1.3 which ALL of you with Central Pain have in a surfeit, but pain is perhaps less interesting than the absence of pain. In immunofluorescent studies, the dorsal horn (CNS) and dorsal root ganglia (PNS) literally light up with ugly spots signifying NaV1.3, an occupying army of inimical pain generators in the CP nervous system. Is NaV 1.7 somehow linked to NaV1.3. We simply do not know. The kind of pain which is observed to be absent in the Pakistani cohort study is FAST pain, or nociception, NOT neuropathic pain.
We think severe unremitting pain is an international tragedy. However, it would appear that lack of pain is more sensational. There is something more convincing about watching someone walk on hot coals without feeling pain than watching someone attempting to wear shoes and complaining that it burns terribly. In this one instance, it is easier to prove a negative, constituting an exception to the general rule.
Note: Afferents are pain fibers leading TO the brain from the body. Afferents from the muscle spindles did not display much NaV 1.7 activity in Dhjourhi’s study. Because Central Pain muscle pains seem to localize in the posterior columns, based on correlation of muscle pains with latency in somatosensory evoked potentials measured in the posterior columns, it has been our practice to occasionally refer to kinesthetic dysesthesia or CP muscle pain as “muscle spindle” pain. With greater knowledge, we may be compelled to admit a mistake. Alternatively, it may be that one type of voltage gated sodium ion channel is relatively more important in different types of pain.