Membranes as part of Pain Mechanisms, by Kory McHenry, NIH Fellow

This article is the follow up to “The Smoking Gun”. It is important for all pain sufferers to understand the huge amount of research being done on pain so they do not lose hope. Drugs which influence membranes are very likely to be part of the pain arsenal in the future.

In one aspect, pain researchers can be roughly grouped into two overlapping categories. The first are those interested in channels and channel chemistry. Channels are structures which rransport charged ions across the cell membrane, exciting or inhibiting action potentials, the voltage spikes which rocket along nerve cells. Channels are surprisingly complex structure, with ends on both sides of the membrane. They resemble bent tubes and represent one of the more interesting activities of structural proteins, which sometimes act like micromachines.

Channels open and close according to the voltage present, according to proteins which help them to open, or in accordance with the kinetic energy of heat, and are named accordingly. For example, the Nav1.3 channel transmits sodium (Na+) and is voltage gated, which explains the “v”. Channel scientists are looking for drugs to silence or suppress such structures as the VR-1 channel, the Nav1.3 channel, or ways to increase proteins carrying chloride to the cell membrane, such as KCC2. Current drugs under investigation include resiniferatoxin.

The second are those interested in membranes themselves, whether it is the membranes of the neuron as a whole, or the membranes around vesicles of neurotransmitters, such as are found in presynaptic areas. Membrane stabilization may be more likely to succeed with regards to the neuron as a whole than presynaptic stabilization, since certain toxins, such as latrotoxin, are known to cause effects directly on the receptors with or without causing pores in the vesicles.

Of course, we have the greatest of praise for both groups, and for other groups which could be defined. Membrane stabilizing drugs include local anesthetics, such as lidocaine.

Drugs in related areas include those which attempt to manipulate specific chemicals which participate in membrane and synaptic events. These drugs include most of those commonly used in pain treatment. We especially find drugs to manipulate serotonin, NMDA, and GABA. Each of these chemicals has a cascade of chemicals feeding into it and away from it, but many drug companies claim impact on one of the three chemicals mentioned, without sufficient specificity. Such information does NOT explain the action of drugs. To say something affects serotonin, is not saying much. Far more specific knowledge is needed. We want to know, for example, which step of serotinin action is involved, and which peripheral events are affected. One ad for a drug claimed it “balances muscle and nerve activity so as to decrease pain.” Such broad descriptions provide no help whatsover.

In order to understand why scientists focus on membranes, it helps to know a little about how neurotransmission occurs. Chemicals which enhance pain are released as a result of activity near the synapses*, or nerve junctions. Little vesicles in the presynaptic area release neurotransmitters into the gap, which act at the far side on post-synaptic structures, such as those which release NMDA (a potent facilitator of chronic pain).

NMDA is activated by protein kinase C (PKC),which also activates the VR-1 receptor (See Dysesthesia is not bizarre, at this site). PKC knockout rats cannot get central pain. In turn, NMDA causes neuron membranes to have LOW resistance to passage of chemicals, so things do happen, such as pain.

By comparison, GABA(B) causes HIGH membrane resistance, so things do not happen, such as pain. Baclofen, an agonist (mimics the effects) of GABA(B) has some anti-pain effect.

Now we go back to the synapse. When studying the effect on nerve firing, scientists look at both the amplitude and frequency of miniature currents in the post-synaptic neuron. In the neuron itself, pain is solely a function of downstream FREQUENCY of action potential, not amplitude. However, with socalled miniature currents both frequency and amplitude are considered. You will undoubtedly read of chemicals affecting either or both.

The science of membranes and vesicles is beginning to come into its own. The reason it is important is that if the vesicle (pack of chemicals inside a membrane) or membrane of the neuron itself (where VR-1 is located) has resistance then the chemicals (neurotransmitters) don’t come out or go across. Anything which stabilizes membranes or vesicles will probably quiet the nervous system.

Latrotoxin, or black widow venom, opens pores in vesicles and causes massive outpouring of neurotransmitters, which floods the synapse, and causes so much post-synaptic response, that death can occur. Latrotoxin activates a membrane active chemical, latrophilin, which causes the membranes to leak all over the place. Knockout rats which lack latrophilin are not harmed by the chemicals which come from latrotoxin. NMDA can be viewed as a facilitator (secretagogue) of activity at the membrane, while GABA(B) can be viewed as an inhibitor.

This research may soon be more or less obsolete clinically for chronic pain as resiniferatoxin use begins. However, over the long term, vesicle inhibiting and membrane resistance chemicals may emerge as very important. The membrane is only one site for research. Of equal importance is the ion channel itself, since the channel may have characteristics of its own which can be blocked, without resorting to block of the entire membrane.

Lidocaine is thought to block more at the membrane, while bupivicaine, more slow acting but more profound, seems to block more at the channel. Recent work (see elsewhere at this site) has not necessarily confirmed this with regard to lidocaine, but the concept still allows refinement of pain therapies. Help is on the way. Don’t give up.

*Synapse. The gap between separate neurons. The gap provides another opportunity for the signal which has moved along the axon of a nerve cell to be excited or inhibited. The general state of the nervous system, or of specific parts, is reflected in events surrounding the synapse. Much of this impact results from chemicals produced by glial cells, which surround neurons. Receptors and chemicals are being identified which impact synaptic events.