Researchers begin to map chronic pain memory in the brain.


Researchers from the University of Bern have discovered a mechanism that is responsible for the level of chronic pain in the brain. The results of this study point to new targets and therapeutics in treating chronic pain.  Chronic pain is extremely widespread with over one million people classed as sufferers in Switzerland alone. The team state that chronic pain still lacks effective therapies causing a massive physical and emotional burden on patients.

Now the team have identified a cellular mechanism in the brain of mice, which contributes to the development of chronic pain. On the basis of this finding the researchers have also succeeded in developing a promising new therapeutic approach for chronic pain. The opensource study is published in the journal Neuron.

The current study investigated the changes in the nerve cells in chronic pain in the cingulate cortex, a region of the brain responsible for processing pain associated emotions or ‘pain memory’. This makes the formation of a pain memory crucial in the formation and control of chronic pain.  These nerve cells are constantly being activated by noxious stimuli or pain to form a memory trace.  The researchers set out to better understand this mechanism in order to derive potential new therapies.

The team explain that pain is perceived or detected by electrical impulses generated in neurons. Therefore, the researchers looked specifically for changes in the electrical properties of neurons in the cingulate cortex.  The team observed that chronic pain results in a lighter excitability of nerve cells in the brain area studied. This change was attributed to the function of ion channel,  a protein molecule in the membrane of a nerve cell which determines their electrical properties.

The function of the investigated ion channel, specifically the hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the dendrites of layer 5 pyramidal neurons, was reduced or highly sensitised in chronic pain. This meant that nerve impulses are triggered more easily and thus increased the sensation of pain.

The researchers set out to manipulate this ion channel which is activated by a specific receptor for the neurotransmitter serotonin, and establish its function.  The current study succeeded in restoring the normal characteristics of the nerve cell and reducing the perception of pain in animal models.  The team explain that it has been known for some time that serotonin may reduce pain and they were able to identify the specific serotonin receptor type 7 (5-HT7R) which affects the perception of pain. The team state that this result could make the treatment of chronic pain much more efficient.

The results show a new mechanism of action for known pain medicines that belong to the class of drugs called tricyclic antidepressants. Previously it was assumed that these drugs exert their effect on the pain receptors in the spinal cord. The team surmise that this class of drugs can also have a direct influence on pain perception in the brain.

Source:  University of Bern

 

Injections of 5-CT into the ACC Reduces Mechanical Sensitivity in CCI Animals.  (A) Schematic illustration of the experimental design to test mechanical hypersensitivity after CCI surgery and bilateral injection of 5-CT or saline into the ACC.  (B) 3D reconstruction of a brain imaged with 3D ultramicroscopy showing the volume and site of the injection in ACC after ex vivo fixation and clearing of the entire brain. The injections were performed 0.70 mm rostral to Bregma, 0.35 mm lateral to midline, and 1.75 mm below the skull surface in each hemisphere. The bottom right image shows a single coronal section, and dots indicate the center of the injection volume for 5-CT (blue) and saline (white) treatments.  Dysfunction of Cortical Dendritic Integration in Neuropathic Pain Reversed by Serotoninergic Neuromodulation.  Nevian et al 2015.

Injections of 5-CT into the ACC Reduces Mechanical Sensitivity in CCI Animals. (A) Schematic illustration of the experimental design to test mechanical hypersensitivity after CCI surgery and bilateral injection of 5-CT or saline into the ACC. (B) 3D reconstruction of a brain imaged with 3D ultramicroscopy showing the volume and site of the injection in ACC after ex vivo fixation and clearing of the entire brain. The injections were performed 0.70 mm rostral to Bregma, 0.35 mm lateral to midline, and 1.75 mm below the skull surface in each hemisphere. The bottom right image shows a single coronal section, and dots indicate the center of the injection volume for 5-CT (blue) and saline (white) treatments. Dysfunction of Cortical Dendritic Integration in Neuropathic Pain Reversed by Serotoninergic Neuromodulation. Nevian et al 2015.

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