Researchers at the University of Texas MD Anderson Cancer Center conducted a study of the underlying mechanisms of chronic neuropathic pain, a difficult-to-treat condition that affects many cancer patients, and were able to develop a specific gene therapy strategy that could represent a promising treatment for the condition.
The related research article, ”Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain,” was published in the journal Cell Reports.
Chronic neuropathic pain, or nerve pain, refers to the damage or injury inflicted upon the peripheral or central nervous systems, and it can have multiple possible causes. Besides the obvious sensory discomfort, this type of pain has severe emotional effects and a significant impact on quality of life, general health, psychological health, and social and economic well-being. The condition is associated with several diseases, such as diabetes, and certain medical procedures, including surgery.
According to some studies, chronic neuropathic pain is especially important in cancer, as it affects about 90 percent of patients with nerve damage caused by tumors or cancer treatments, primarily chemotherapy. Analgesic treatments such as anti-depressants, opioids, and gabapentinoids, are associated with limited efficacy and debilitating side effects.
Nerve damage due to surgery or toxic chemotherapy effects is accompanied by an imbalance in chloride, a mineral essential to nerve function. This imbalance leads to loss of efficacy by the inhibitory neurotransmitters GABA and glycine, which in turn increases the activity by excitatory NMDA nerve receptors.
“Diminished synaptic inhibition by GABA and glycine and increased NMDA receptor activity are two key mechanisms underlying neuropathic pain,” explained the study’s senior author, Dr. Hui-Lin Pan, in an MD Anderson press release. “However, the reciprocal relationship between the two is unclear. By using KCC2 gene transfer, we were able to restore chloride balance which also unexpectedly normalized NMDA receptor activity increased by nerve injury.”
The researchers delivered the K+-Cl− cotransporter-2 (KCC2) using lentiviral vectors, and observed that its expression produced a long-lasting reversal of pain hypersensitivity induced by previous nerve injury, in spinal and primary sensory neurons.
“The development of highly effective patient treatments with minimal effects is urgently needed,” Pan said. “Our study addressed the need to change the intracellular concentration of chloride which can profoundly alter the strength and polarity of GABA and glycine.”