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Neuropathic pain unmasks subliminal excitation in pain processing circuits

June 01, 2016

Recent discoveries in the laboratory of Steven Prescott, at the Hospital for Sick Children in Toronto, shed new light on the mechanism underlying the establishment of neuropathic pain. Neuropathic pain is spontaneous pain and hypersensitivity to innocuous touch and heat stimuli, causing pain in situations that would normally not be painful. These symptoms arise because of defects in pain processing circuits. Experiments by Kwan Lee and Stéphanie Ratté in Dr. Prescott's lab show that dysregulation of chloride reduces inhibition across these circuits, but that this affects more strongly neurons that promote the transmission of pain signals, as these receive vast amounts of subliminal excitation, which is thus unmasked. These results were presented at the 10th Annual Canadian Neuroscience Meeting, on June 1, in Toronto, Canada.

Neuropathic pain is a major clinical challenge - the International Association for the Study of Pain estimates that 7-8% of adults have chronic pain with neuropathic characteristics, and that this pain is more severe, in general, in every measured dimension compared to non-neuropathic pain. In the normal situation, strong inhibitory signals block the transmission of pain signals, and reduction in this inhibition is a strong contributing factor in neuropathic pain. Neuropathic pain is thus thought to be caused by hyperexcitability of pain transmitting neurons caused by a lack of inhibition.

"We've known for several years that chloride regulation is important for pain processing but we didn't know if different cell types experience the same changes in their chloride, or how this would affect the circuit as a whole."

In neuropathic pain, reduced inhibition is largely due to dysregulation of chloride levels in cells caused by a reduction in the function of a protein called KCC2, a potassium-chloride co-transporter, which regulates the levels of potassium and chloride ions inside neurons of the spinal cord. Precise regulation of chloride levels in neurons is crucial for inhibition, but it was unclear how dysregulation affects the circuits that control the transmission of pain signals. New data from Dr. Prescott suggests that reduced KCC2 function, though it reduces inhibition of both excitatory (pain producing) and inhibitory (pain reducing) neurons, results in allodynia as it allows low-level excitatory signals, which are normally below the threshold that is transmitted, to add up, by a process called spatial summation.

"It turns out that both excitatory and inhibitory spinal neurons experience the same chloride changes but excitatory neurons rely on their synaptic inhibition a lot more because they receive so much excitatory input. When inhibition fails, that excitation gets unmasked. The pattern of excitation and inhibition typically evoked by touching the skin gets completely messed up, resulting in touch-evoked pain."

In a recent review article, Dr. Prescott has also highlighted the fact that though many studies of neuropathic pain have shown changes in various ion channels causing hyperexcitability, treatments targeting these channels usually fail to sustainably reverse the hyperexcitability and are thus ineffective in treating the neuropathic pain. Dr. Prescott argues that this may be due to so-called degeneracy - multiple changes in different ion channels are each sufficient to cause the neuron to become hyperexcitable, which means that no single ion channel is necessary for the hyperexcitability. Because drugs usually target a specific channel, other channels can continue changing, thus undermining the beneficial effect of the drug. An increased knowledge of the mechanisms of the development and maintenance of the neuropathic pain state will inform future therapy development, by helping to identify all the targets that need to be treated, in this large, complex and adaptable system.
About Steven A. Prescott

Steven A. Prescott is an Associate Professor at the University of Toronto and a Senior Scientist at The Hospital for Sick Children. Learn more about Dr. Prescott on his laboratory website:

About the Canadian Neuroscience Meeting

The Canadian Association for Neuroscience is holding its 10th Annual Meeting in Toronto, May 29 to June 1 2016. Held yearly since 2007, it brings together researchers working in all fields of neuroscience research. Organized by neuroscientists and for neuroscientists, it highlights the best and most novel neuroscience research in Canada every year. Learn more about our meeting:

About the Canadian Association for Neuroscience:

The Canadian Association for Neuroscience is the largest association dedicated to the promotion of all fields of neuroscience research in Canada. Learn more about our association:

Canadian Association for Neuroscience

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