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New research identifying a 'brake' which limits spontaneous pain could lead to the development of new pain relief  treatments.

Spontaneous pain is ongoing and can occur constantly (slow burning pain) or intermittently (sharp shooting pain), with no obvious cause. Although they can be very debilitating, the mechanisms behind such conditions can be poorly understood and they are therefore difficult to treat. 

Continuous activity in small sensory nerve fibers, known as C-fiber nociceptors (pain neurons), has been shown to cause spontaneous burning pain, with greater activity resulting in greater pain.

Scientists at the University of Bristol discovered that the presence of a particular ion channel, TREK2, in the membranes of these neurons provides a natural innate protection against this pain.

Ion channels form pores through the neuronal membrane. Leak potassium channels, which are open most of the time, allow positive potassium ions (K+) to leak out of the cell, which is the main cause of negative membrane potentials in all neurons. TREK2 is a leak potassium channel and C-nociceptors that express it have much more negative membrane potentials.

Removal of TREK2 from the proximity of the cell membrane resulted in those neurons becoming less negative. This also occurred when the neuron was prevented from synthesising the TREK2.

Lowering the levels of synthesis of TREK2 in these C-fiber neurons was found to increase spontaneous pain associated with skin inflammation.

The team concluded that TREK2 keeps membrane potentials more negative in these C-fiber nociceptors, stabilising their membrane potential and reducing firing. This limited the the amount of spontaneous burning pain.

Professor Sally Lawson from the School of Physiology and Pharmacology at Bristol University said: "We demonstrated that TREK2 in C-fiber nociceptors is important for stabilizing their membrane potential and decreasing the likelihood of firing. It became apparent that TREK2 was thus likely to act as a natural innate protection against pain. Our data supported this, indicating that in chronic pain states, TREK2 is acting as a brake on the level of spontaneous pain."

It is hoped that the findings will lead to new treatments for sufferers of ongoing spontaneous burning pain by enhancing the actions of TREK2.

A new study published in the Journal of Biology describes how a protein that promotes cell growth allows cells to metastasise and spread through the bloodstream. 

Cancer cells are confined to the tissue in which they arise unless they can find a way into the bloodstream. The growth factor VEGF enables cells to do this by loosening connections between endothelial cells that form the lining of blood vessel walls.

VEGF triggers the phosphorylation of a protein called VEC, which serves to fasten endothelial cells together. As a result of this process, complexes that contain VEC fall apart, opening gaps between endothelial cells. Focal adhesion kinase (FAK), which accumulates at cell-to-cell junctions in the presence of VEGF, may play a role in VEC phosphorylation.

Scientists from the UC San Diego Moores Cancer Center gave a FAK inhibitor to a group of mice with fast-spreading breast cancer and a group with ovarian tumors in an attempt to pinpoint the function of the protein. It was discovered that the inhibitor prevented phosphorylation of a specific amino acid, known as tyrosine 658, in VEC from tumor-associated blood vessels.

VEGF was injected into a group of control mice and into mice with an inactive variant of FAK in their endothelial cells. Phosphorylation of VEC's tyrosine 658 occurred in the control rodents but not in the animals expressing inactive FAK, suggesting FAK controls the event.

Research was then conducted to determine the effect of FAK on endothelial cell layers.
VEGF-releasing tumor cells slipped through endothelial cells in experiments conducted on cell cultures. When endothelial cells produced an inactive version of FAK, however, cells did not pass through.

Further experiments conducted on mice revealed animals that expressed inactive FAK in their endothelial cells developed fewer tumours in their lungs compared with a group of control mice. Metastasis was curbed but tumour growth was unaffected.

The results show how endothelial FAK plays a role in controlling metastasis. They suggests it helps VEGF-expressing cancer cells open endothelial cell layers and clinical trials on FAK inhibitors are now being conducted.

Researchers have identified a protein which plays a role in the development of memory loss that affects patients suffering from Alzheimer's disease.

Scientists at the Cleveland Clinic, Ohio, found that a protein known as Neuroligin-1 (NLGN1), which is known to play a role in the formation of memories, is also linked to amyloid-associated memory loss. The results of the study are published in the journal Nature Neuroscience.

Alzheimer's disease involves the accumulation of amyloid beta proteins in the brains of sufferers, which serve to induce inflammation. As a result of the inflammation, certain gene modifications occur, causing memory loss by interrupting the functioning of synapses in the brain.

The researchers at the Cleveland Clinic conducted a study on animal models and discovered that the epigenetic modification of NLGN1 plays a key role in the neuroinflammatory process by disrupting the brain's synaptic network, which is responsible for developing and maintaining memories. The destruction of this network can lead to the type of memory loss exhibited by patients suffering from Alzheimer's disease.

"Alzheimer's is a challenging disease that researchers have been approaching from all angles," said Mohamed Naguib, the Cleveland Clinic physician who led the study. "This discovery could provide us with a new approach for preventing and treating Alzheimer's disease."

The same group of researchers previously identified a novel compound known as MDA7, which has the potential to halt the neuroinflammatory process that causes the modification of NLGN1. Studies conducted on an animal model found treatment with the compound led to the restoration of cognition, memory and synaptic plasticity – a crucial neurological foundation of learning and memory.

Preliminary work for the first human trial of MDA7 has been completed, including in-vitro studies and preliminary clinical toxicology and pharmacokinetic work. Phase I of the studies on the safety of these compounds is expected to begin in the near future.

More than half a million people suffer from Alzheimer's disease in the UK. It accounts for around two-thirds of the cases of dementia among elderly people.

A new study on the effects of vitamin D on Parkinson's Disease (PD) suggests early intervention may be a fruitful method of preventing or delaying cognitive impairment and depression.

Scientists conducted a cross-sectional analysis of 286 patients suffering from PD. Higher plasma vitamin D levels were associated with lower symptom severity, better cognition, and less depression in the entire group. The results were stronger in the group which was not suffering from dementia.

Patients were given a number of tests measuring global cognitive function, verbal memory, semantic verbal fluency, executive function, and depression. Measurements of serum 25-hydroxyvitamin D levels were also taken.

Some 61 of the subjects were considered to be suffering from dementia, according to a consensus panel using the Diagnostic and Statistical Manual of the American Psychiatric Association (4th edition). 

Researchers found there were significant negative associations between vitamin D levels and disease severity.

Higher levels of serum vitamin D3 were associated with greater fluency for naming vegetables and animals and immediate and delayed recall on a verbal learning test across the whole group.

Dividing the group into those suffering from dementia and those who were not, significant findings with vitamin D were found for fluency and verbal learning only for those not suffering from the condition. 

"The fact that the relationship between vitamin D concentration and cognitive performance seemed more robust in the non-demented subset suggests that earlier intervention before dementia is present may be more effective," said Amie Peterson, MD, of the Oregon Health and Sciences University.

It was also found that there was a significant negative association between vitamin D levels and depression, covering the entire group and those subjects not suffering from dementia. No such relationship was found in the sub-set who were suffering from dementia.

The study's authors said that causation could not determined – low vitamin D levels could affect cognitive performance, but patients suffering from dementia could have low levels due to the fact that they spend a lot of time indoors and are thus not exposed to sunlight.

In recent years, a number of studies have linked low vitamin D levels to a range of conditions, including multiple sclerosis and type 2 diabetes mellitus.