Patients with spinal cord injury often develop intractable chronic pain. Researchers have discovered a new molecular explanation, which could inform the development of more effective therapies.
Un-abating pain after spinal cord injury may come from nerves that are not directly impacted by the injury. This so-called neuropathic pain is caused by a malfunction of the nerves and is particularly difficult to remedy. Now, researchers at Jefferson have zoomed-in to the molecular players involved in neuropathic pain to investigate what causes the malfunction.
Manuel Covarrubias, in the Department of Neuroscience and the Vickie and Jack Farber Institute for Neuroscience, and colleagues investigated the dorsal root ganglion (DRG), a relaying station of pain signals in the spine. Information from peripheral nerves that receive sensations from the skin, muscles, hands and feet is all routed through the DRG. The researchers found new evidence to explain how nerve cells in the DRG may become altered during spinal cord injury in such a way that they overreact to sensation coming in from the peripheral nerves. The research was published in the Journal of Neuroscience.
One known effect of spinal cord injury is that the DRG neurons become hypersensitive to stimuli. As a result, even mild sensations coming from peripheral nerves – from the skin, or hands – are felt much more strongly and painfully. Normally, in less severe cases, the pain subsides.
Now, in a counterintuitive result, Dr. Covarrubias and colleagues found that the spinal cord’s natural response to injury may be to blame for long-lasting neuropathic pain. Based on strong experimental evidence, Dr. Covarrubias and colleagues proposed that the DRG neurons attempt to compensate for this post-trauma hyperexcitability by producing a factor that inhibits a protein called CaN. The protein helps quiet the overly excitable DRG neurons by dampening electrical signals in the pain pathway. However, in the long term, CaN inhibition ultimately suppresses the function of another protein called Kv3.4, which regulates electrical signaling in DRG neurons. Thus, DRG neurons remain hyperexcitable.
Interestingly, a rare but severe side effect of organ transplantation is peripheral pain. The immunosuppressive drugs used in these patients also inhibit CaN, suggesting that Kv3.4 dysfunction is also implicated in this complication.
If confirmed in human samples and clinical trials, this study could pave the way for developing better treatments for neuropathic pain after spinal cord injury as well as in transplant recipients.
If you are experiencing chronic pain, contact Jefferson’s Pain Center for expert care.