Anatomical changes which lead to thermal hyperalgesia

The ability of motor cortex stimulation to ease central pain was a mystery at first and remains so. However, new work on the genes which arrange motor nerves suggests more links between pain and motor processing.


One of the things skeptics most taunt CP patients with is the lack of VISUAL evidence anything is wrong. This merely reflects the fact that pain is occurring at the molecular level, but new research shows that one may be able to pick up changes on a light microscope if one knows where to look.

We certainly admired the work A L Basbaum has done at another institution and were interested to see he is collaborating now at UCLA. Villeda et al, including Basbaum, see Neuroscience. 2006 Mar 29 have followed certain genes clear through embryonic life right on into adult life in lab animals. The results are a bit surprising.

One gene has been given the name Reeler, for the effect its knockout has in rats. Reeler creates the protein Reelin. The protein product of the Reeler gene is known as Disabled-1 and the associated intracellular adaptor protein in the signalling pathway is known as Disabled-1 (Dab1) Altered Reelin has been associated with positioning errors in neurons of the cerebral cortex and cerebellum, leading to marked motor deficits. Now Villeda and group have found that the reeler mutant also has profound sensory deficits. These defects occur in association with small diameter pain afferents which process information about painful stimulation.

Here is where the light microscope comes in. Reeler mutants, as mentioned, have positioning errors in the brain, but Villela also showed that neurons are out of position in the cord as well. Certain layers are too crowded and others lack the normal numbers of neurons. This is thought due to buildup on levels of Dab1. This is reflected in Layers I-III of the cord.

If you reread our prior article on “Secret Pain Chemicals” you will recall that we have designed the Substance P, Neurokinin-1, and Protein Kinase C (PKC) pathway as the PnP pathway, as others have done. We will not rehearse matters about Protein Kinase C, except to say that knockout rats which lack PKC cannot get Central pain. NK1 has PKC as a target. Higher levels of neurokinin-1 were detected in Layer I-III and in the lateral spinal nucleus. Keeping in mind Boivie’s rule (one must loose some sensation to be a candidate for central pain) you will find it astonishing that in the reeler mutants, there was DECREASED mechanical sensitivity (loss of touch), but greatly INCREASED thermal hyperalgesia (increased pain sensitivity).

Additionally, there was a great reduction in the number of cells in the lateral spinal nucleus.

Thus, here again, we find the mysterious link between motor signal processing and pain. There is more to be learned about the molecular ties, but it would appear that the motor system is designed to be exquisitely intertwined with pain, probably to permit the greatest possible response to any noxious stimulus.

We still do not know why electromagnetic stimulation of the motor cortex reduces central pain. However, the reeler mice may just provide the answer as this is more studied.