Research:Wnt blockade a possible Double Whammy

Yuan S et al. Wnt Signaling in the Pathogenesis of Multiple Sclerosis-Associated Chronic PainJ Neuroimmune Pharmacol. 2012 May 2. [Epub ahead of print]

Many multiple sclerosis (MS) patients develop chronic pain, but the underlying pathological mechanism is unknown. Mice with experimental autoimmune encephalomyelitis (EAE) have been widely used to model MS-related neurological complications, including CNS demyelination, neuroinflammation and motor impairments. Similar to MS patients, EAE mice also develop pain. We are interested in elucidating the potential involvement of Wnt signaling in the pathogenesis of chronic pain in EAE mice. In this study, we characterized the expression of Wnt signaling proteins in the spinal cord dorsal horn (SCDH) of EAE mice, by immunoblotting and immunostaining.

The EAE model was created by immunization of adult mice (C57BL/6, 10 weeks) with myelin oligodendrocyte glycoprotein (MOG) 35-55. Robust mechanical hyperalgesia (a painful sensation sucha nipping a toe, becomes more painful) and allodynia (a non painful stimulus becomes painful) were developed in both fore- and hindpaws of the EAE mice. 

In my opinion this is not the same as neuropathic pain, pain generated by the action of the nerves, as occurs in MS and probably responds to a differnt set of drugs.

Wnt3a, a prototypical Wnt ligand for the canonical pathway, was significantly increased in the SCDH of the EAE mice. Another key protein in the canonical pathway, ß-catenin, was also significantly up-regulated. In addition, Wnt5a, a prototypic Wnt ligand for the non-canonical pathway, and its receptor (co-receptor) Ror2 were also up-regulated in the SCDH of the EAE mice. We further found that Wnt5a antagonist Box5 and β-catenin inhibitor indomethacin (actually it is better known as a prostaglandin inhibitor) attenuated mechanical allodynia in the EAE mice. Our data collectively suggest that Wnt signaling pathways are up-regulated in the SCDH of the EAE mice and that aberrant activation of Wnt signaling contributes to the development of EAE-related pain.

The Wnt (named after a gene that resulted in wingless fruitflies) signaling pathway is a network of protein that are involved in development of the embryo (embryogenesis ), The study here suggests that it may be involved in the developmnet of some aspects of altered sensation or pain. Whilst this may have some significance to MS,the reason I have highlighted this research paper is because of another interest in Wnt pathway is in myelination. It has been suggested that Wnt-beta-catenin signaling in oligodendrocyte precurosir cells can result in a profound delay of both developmental myelination and remyelination. Therefore the stimulating wnt such as wnt3a is blocking repair via preventing immature oligodendrocytes from maturing into myelinating oligodendrocytes as shown in previous studies and the blocking of Wnt function may facilitate remyelination. Therefore as blocking Wnt may also have some beneficial effect on inhibiting pain responses, this target may give us a double Whammy to also stimulate remyelination. As ever this is just theorectical and proff in MS is lacking, but this data suggests a way to offer benefit in MS.