No Pain, No Gain? Evidence for a Relationship Between Peripheral Nerve Regeneration and Pain
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Material below summarizes the article Active Nerve Regeneration with Failed Target Reinnervation Drives Persistent Neuropathic Pain, published on January 26, 2017, in eNeuro and authored by Wenrui Xie, Judith A. Strong, and Jun-Ming Zhang.
Peripheral nerves differ from those in the brain in that they can readily regrow (regenerate) after injury. When a peripheral nerve is cut or crushed, the distal part that was disconnected from the cell body undergoes a process called Wallerian degeneration. Debris from injured axons is cleared, the axon ending dies back, and an environment conducive to regeneration develops. If the gap across the injury site is not too large, there is a window of opportunity — a time period during which axons can regrow (regenerate) down the distal segment and reinnervate (reconnect to) the target tissues.
Many laboratories have studied this process using injuries to the rat sciatic nerve as a model. Such research aims to understand the signals that tell the peripheral neurons to switch into a regenerative mode, to develop methods that allow larger gaps to be bridged by regenerating neurons, or to increase the time window during which regeneration can occur.
The sciatic nerve is also commonly targeted in models of neuropathic pain. Neuropathic pain, which is pain arising from injury to the nervous system itself, is often intractable or resistant to treatment. In this study, we provide evidence that the regeneration process may be intimately related to neuropathic pain.
We first used a well-established rodent model of neuropathic pain called the spinal nerve ligation model. In this model, one of the several spinal nerves that normally merge to form the sciatic nerve is ligated and cut near the spinal cord. This results in pain-related behaviors in the rat hindpaw, which is normally innervated by the sciatic nerve. Rats withdraw their paws in response to mild cold and mechanical stimuli that do not cause a response in normal rats.
For the past 25 years, it has been almost universally assumed that the spinal nerve does not regenerate in this model, but we found that the injured nerve regenerated, growing around the suture and rejoining the sciatic nerve. Using tracers, we found that the hindpaw was reconnected to the cell bodies of the sensory neurons in less than a month. The regenerated axons were functional, with electrical signals and responses to stimulation conducted through the newly regrown nerve as observed with in vivo recording methods.
To explore the relationship between regeneration and pain, we perfused the spinal nerve injury site with semaphorin 3A, a naturally occurring inhibitor of axon growth. This prevented nerve regeneration into the hindpaw and greatly reduced pain behavior responses. An independent method of inhibiting regeneration, namely knocking down production of an important regeneration-related molecule called GAP43, also reduced pain behaviors.
Semaphorin 3A treatment also reduced the abnormal spontaneous activity of sensory nerves induced by the nerve injury. This type of abnormal spontaneous activity is well known and plays an important role in setting up the chronic pain state. Perfusing the injury site with a toxin that blocks neuronal activity also reduced regeneration and pain behaviors.
This suggests that spontaneous activity may also be somehow related to the regeneration process. Unfortunately, in contrast to the literature on pain, the literature on peripheral nerve regeneration has few studies on the possible role of such spontaneous activity.
We next examined another commonly used pain model, the spared nerve injury model. In this model, two of three distal branches of the sciatic nerve are ligated and cut, leaving the third intact (spared). This model was developed as a more long-lasting model, as pain behaviors are essentially permanent. Its originators proposed that this was because regeneration that could culminate in reinnervation was not anatomically feasible in this injury.
We showed that this was true. Instead of effective reconnection to target tissues, we observed a neuroma at the injury site, a tangled mass of GAP43-containing axon ends. Interrupting this futile regeneration process with semaphorin 3A permanently reduced pain behaviors in this model.
Semaphorin 3A was effective even if perfusion started after pain behaviors were well established. This is more relevant to the clinical situation and suggests that disrupting the regeneration process may be helpful in conditions such as phantom limb pain, where reinnervation is not possible, or in patients for whom the window of opportunity for peripheral nerve reinnervation has already passed. In contrast to the semaphorin 3A treatment, we found that simply removing the neuroma surgically did not relieve pain.
It may seem counterintuitive that the large spinal nerve is able to regenerate and reinnervate, while the much smaller peripheral nerves affected by the spared nerve injury model try to regenerate but fail to regrow to their original targets. We think this may reflect anatomical differences: the smaller nerves are under tension and tend to spring back when cut. In addition, that model involves introducing a gap in the nerve instead of just suturing and cutting. It is worth noting that some severe chronic pain conditions, most notably complex regional pain syndrome, may follow seemingly minor injuries to small peripheral nerves.
In all of our experiments in which we disrupted regeneration, the improvements in pain behavior were permanent, long outlasting the duration of drug application or action. It seems that once the regeneration process is successfully interrupted, it does not restart readily, even after regeneration inhibitors are removed.
Our study suggests that it is important for future research to bridge the gaps between these different fields. People who study peripheral regeneration need to consider whether improving regeneration also increases pain behaviors, while people who study methods to block chronic pain need to consider whether this comes at the cost of increased neuronal cell death or failure to achieve reinnervation that was otherwise possible. In some pain conditions, targeting the regeneration process may provide a new treatment mechanism. For nerve injuries where regeneration is possible, it will be important for future studies to determine whether regeneration and pain can be successfully dissociated.
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Active Nerve Regeneration with Failed Target Reinnervation Drives Persistent Neuropathic Pain. Wenrui Xie, Judith A. Strong, Jun-Ming Zhang. eNeuro Jan 2017 DOI: 10.1523/ENEURO.0008-17.2017