Cytokine Research is Important in Pain

Maybe we can take a note from the Tour de France cyclists.

Research in proinflammatory cytokines and chemoattractants just keeps getting weirder and weirder.

Interleukin-10 has been termed an anti-inflammatory by virtue of its suppression of NF Kappa B. (See NF Kappa B using SEARCH)

Recently, Filippi showed in J Exp Med. 2006 Oct 30;203(11):2461-72 that interleukin-10 blocks the attempts of effector T cells to kill meningitis organisms. Meningitis is often caused by viruses, typically echovirus, enterovirus, or coxsackie virus. Lymphocytes are the body’s defense against viruses, so a lymphocytic meningitis is roughly equivalent to viral meningitis. By using an antibody against the Il-10 receptor, CD8+ cells (a variety of immune cell) were able to kill the organisms resulting in lymphocytic choriomeningitis (viral meningitis), because the Il-10 had been blocking T cells, but was now out of the picture. This is a very novel way to fight viruses, by blocking Il-10. Side effects were minimal.

There has also been study of erythropoietin (Epo) on nerve injury pain by Campana.

Epo is what some cyclists doped with to increase red cell production. Significantly, it turns out Epo also helps any Schwann cell (insulated cell of the nervous system). Campana at UCSD, in Brain Behav Immun. 2007 Feb 23 found that Schwann cells produce interleukin 10 and erythropoietin. Epo and its receptor, EpoR are upregulated in peripheral nerve injury. (Cells in the central nervous system have a similar system of insulation in white matter but have not been studied in this fashion). Yet, Epo and Il-10 can sensitize nociceptors.

Still, EpoR downregulates TNF, which as you know causes glial release of BDNF which block GABA B which leads to hypersensitization of pain neurons in the CNS. In hypersensitization there is approximately a quadrupling of the number of glial cells around the pain neurons in the dorsal horn of the cord.

EpoR nevertheless promotes regeneration of axons and facilitates recovery from chronic pain states.

Also discovered by Campana is that low density lipoprotein receptor (LPR-1) is essential for Schwann cell survival after peripheral nerve injury.

Campana concludes, “Blocking ErbB receptor-initiated cell-signaling in either myelinating or non-myelinating Schwann cells results in unique sensory dysfunctions. Data obtained in gene-targeted animals suggest that sensory alterations can result from changes in Schwann cell physiology without profound myelin degeneration or axonopathy. Aberrations in Schwann cell biology may lie at the foundation of neuropathic pain and represent an exciting target for therapeutic intervention.”

In other words, the dysfunction of pain nerves can occur without the destruction of myelin. This suggests the possibility that malfunction in nerve injury pain may lie in the nerve sheath as well as in the neuron.

In C fibers, which begin the process of hypersensitization, there is no or little myelin. However, in the larger A delta fibers which are recruited once the C fiber gets to the cord, myelin is definitely present and this hookup is essential for hypersensitization, which begins in the dorsal horn of the cord.

Since Il-10 and EpoR seem to oppose the injurious effects of proinflammatory cytokines, it only seems logical to attempt a trial of erythropoietin/EpoR in central pain.

If Il-10 were added to the mix, we would have to anticipate a vulnerability to viral infections, since in inflammation CD8+ cells (blocked by Il-10) are necessary for viral clearance, The CD8+ cell wing of inflammation is opposed by interleukin-10.

Carrying our interest further is the finding by Mizuochi in Transl Res. 2007 Apr;149(4):223-30 that Carvedilol suppresses the production of Tumor Necrosis Factor. Carvedilol is another drug against the inflammation traditionally associated with hypersensitization which catches our interest.

Remembering that TNF leads to BDNF relsase which block GABA B, a pain inhibitor, (an integral part of nerve hypersensitization), another recent finding is also noteworthy. MEK-ERK1/2, also known as MAPK (see using SEARCH), is activated by lipopolysaccaride-1. This mediates tumor necrosis factor alpha by inducing Elk-1 phosphorylation (activation) and Egr-1 expression. (See Blood. 2001 Sep 1;98(5):1429-39). Elk-1 is a ternary (three-way) complex factor which connects the intracellular signaling cascade elicited by activation of P2X(7) receptors with the transcription (copying from DNA) of the Egr-1 gene.

MAPK PHOSPHATASE inactivates ERK in the nucleus. MAPK/ERK are pain chemicals. (See Stefano et al J Cell Physiol. 2007 May 1).

Yamashita et al in Transplantation. 2006 Dec 27;82(12):1720-7 have also shown that that a drug konwn as dehydroxymethylepoxyquinomicin blocks inflammation of transplants by blocking Kappa B.

Finally, Ueki, Yamashita, et al in Indian J Med Res. 2006 Sep;124(3):343-54 have shown that erythropoietin (Epo) blocks nuclear factor NF Kappa B, which would otherwise activate proinflammatory cytokines.

It seems to us with all this knowledge out there on blocking proinflammaotry cytokines, which appear to cause hypersensitization in the dorsal horn in central pain, that newer, more effective drugs for the hypersensitization leading to central pain could and should be developed. Most of the work being done now is done with an eye toward preventing injury by proinflammatory cytokines in heart attack, but central pain deserves attention as well. CP is always the stepchild. The ignoring of this terrible pain state is ugly and heartless.