Part I. Nicotine and Central Pain

You need to come up with some bad habits better than smoking. How about chocolate or something? This article will prepare you for another one in the future so read through the introductory material on acetyl choline.


We have received some questions as to why central pain may worsen after smoking. This is actually a very difficult question to answer because we prefer to be as simple as possible, and this is one of the more complicated subjects.

Having said that, let us get to it.

To begin with, you are reminded that the body uses neurotransmitters, but the real determinant of the result is the RECEPTOR for any given neurotransmitter. The neurotransmitters are reasonably well known, but the proteins comprising receptors can fold in such a way that only portions of it are available for chemical reaction. We refer to the different folding patterns as configurations, or sometimes conformations. The proteins which make up the receptor also fold and so any number of activators may affect the receptor differently.

Two large types of receptors are ionotropic (often voltage gated) and metabotropic (ligand gated). Both respond to ACh as a neurotransmitter, but the nicotinic also respond to nicotine. The ionotropic are usually circular and act like a pore, looking like an iris that opens and closes, allowing charged ions to pass through.

The metabotropic or ligand gated receptors involve a tie or ligand, such as acetyl choline (Ach), which is a neurotransmitter which attaches to a transmembrane structure of seven parts. The G protein, of which there are four types (differentiated by their susceptibility to various toxins), is inside the cell, attached to the transmembrane structure, and carries the activity onward within the cell by handing off the duty to SECOND MESSENGERS. The G proteins vary in their effect on SECOND MESSENGERS, which actually perform the ultimate functions.

Acetyl choline release and activity is of two varieties. One type involves a diffusion or passage of Ach from varicosities (boutons) near the synapse into the extracellular space where the ACh exerts an effect on a given tissue. The second type of ACh release involves flooding or release of large amounts of ACh directly into the synapse, or gap between two nerves. (There are three synapses from skin to brain.)

ACh receptors are of two types, known as nicotinic and muscarinic. ACh activity is usually called cholinergic activity and is associated with the autonomic (unconscious) nervous system. Ganglia are collections of nerve cell bodies. Nicotinic receptors cause the rapid depolarization (nerve signal) seen in post ganglionic areas, also know as the fast Excitatory Post synaptic Potential or fast EPSP. The subsequent hyperpolarization (IPSP) is mediated by the type 2 muscarinic receptor, and the slow Excitatory Post Synaptic Potential is mediated by the Type 1 muscarinic receptor.

Imagine a cell in the brain sending down a message to (synapsing on a neuron in) a paraympathetic ganglion. (Sympathetic ganglia are located in a chain which is located near the spinal cord, but paraympathetic tend to be located near the end organ). Beyond the ganglion is a neuronal axon connecting to an end organ. Coming down from the brain, this neuron would be post synaptic.

In the parasympathetic system, muscarinic receptors influence the postganglionic neuron and also mediate the response where this neuron contacts the end organ. This gets a little confusing because nerve signals are going both ways, to and from the organ, and hence, to and from the postganglionic neuron.

Muscarinic receptors also are involved pre-synaptically in signal going via the postganglionic neuron. You must think of signal going toward an end organ and a signal coming from an end organ to understand which PRE is meant when we use the word presynaptic. Is it PRE on the way down or PRE on the way back up (sensory)? Here, we use it to mean on the way down.

Although sometimes inaccurate, you can think of nicotinic receptors as causing sympathetic tone and link muscarinic to the parasympathetic system. This oversimplification is useful for the sake of memory, but it ignores the role of purine (P2X) receptors in the cortex. It is believed that there are some muscarinic receptors on post-synaptic sympathetic fibers which allow the parasympathetic system to inhibit the activity of the sympathetics.

Perhaps the best known action of muscarinics is at the neuromuscular junction, where they help regulate release of ACh. Nicotinic receptors are also here. ACh causes the muscle contraction.

Nicotinic receptors are shaped like a loop. The economy of nature is amazing, with ACh being excitatory at some receptors and inhibitory at others. That is why we say pay attention to the receptor, NOT the neurotransmitter.

The nicotinic receptors are made of various combinations of subunits, with the alpha subunit actually binding ACh. The nicotinic ACH receptor opens to allow ions to pass through. These include sodium and potassium. Some conformations of subunits result in a receptor which allows calcium to pass. These latter, because they conduct calcium ion flux, can affect the release of other neurotransmitters.

As we know in this day and age, nicotine causes cancer. It also causes the nicotinic receptor to allow too much ion flux. Usually the pore is only open about one millisecond. In a prior article on NF Kappa B we described Raf-1 as a gene set associated with the MAPK pathway. Jull, et al, writing in J Cancer Res Clin Oncol. 2001 Dec;127(12):707-17, have shown that a tobacco specific nitrosamine known as NNK causes small cell lung cancer by initiating a mitogenic (command to divide, or carcinogen) signal on the alpha 7 nicotinic ACh receptor. This command ultimately causes release of serotonin.

Here is what you have been waiting for to answer your question. NNK causes overexpression of Raf-1 and MAPK (see how MAPK causes pain by using SEARCH at this site). MAPK of course, especially p38 MAPK, is a kinase linked to pERK and other pain chemicals. The association of this kinase with cell division (mitosis) and chemicals which cause cell division (mitogens) is where it got its name, Mitogen Activated Protein Kinase. Presumably in nerve injury, persistent production of growth factors causes them to act as mitogens, kicking off lots of MAPK, which then begins the cascade of pain chemicals. When the body is attempting repair, it sends off inflammatory chemicals to cause pain, so the area will be protected from injury and infection. NNK makes the whole process of cell division turn ugly and cancer results. Central pain is not an effective pain so far as we know, but it does tend to make the patient put the body at reat, which in the end, is a good thing.

Conclusion: Smoking will not be good for your central pain because it may well increase MAPK activity. It isn’t good for your lungs either.