In two separate studies, researchers have identified how peripheral nerve injury can lead to increased pain sensitivity. The studies were published on May 25, 2022, in Nature and May 26, 2022, in Science, respectively. The mechanisms they identify could lead to new therapeutic approaches to chronic pain and/or pain hypersensitivity.

Both studies used an experimental model called spared nerve injury. Here, one branch of the sciatic nerves, which has three branches that innervate the leg, almost immediately leads to increased pain sensitivity in the areas of the leg that are still innervated.

And over the long term, as innervation is re-established, it can also lead to allodynia, the perception of gentle touches as painful, in the areas of the leg that were once innervated by the damaged sciatic branch.

The first study, published in Nature by a Heidelberg University-led research team, investigated the mechanisms of allodynia in the denervated areas.

Allodynia can be a part of multiple pain experiences. Some, like sunburn, last only days, But in other cases, like migraine, the condition can become recurrent. And sometimes it is permanent.

In their experiments, the authors engineered both mechanical and pain fibers to express fluorescent proteins. This method enabled them to follow nerve regrowth for nearly a year.

Touch is sensed by specialized structures in the skin called Meissner's corpuscles. Like the cochlea translates sound waves into neural firing, Meissner's corpuscles translate the mechanical pressure of touch.

Pain, on the other hand, usually has no help from sensory structures. Instead, it is sensed by free nerve endings in the skin that react to stimuli once they are strong enough to cause tissue damage.

In their experiments, the authors showed that after a nerve injury, pain fibers regrew along the former tracks of sensory fibers -- which means they ended up innervating the Meissner's corpuscles, so that normal touch began to set off activity in the pain fibers.

The work has identified a new form of neuropathic pain, and in a commentary published along with the paper, researchers from the University of Pennsylvania wrote that by shedding light on potential pitfalls of nerve regeneration "it is to be hoped that work such as this will eventually lead to strategies that enable peripheral nerve regeneration and reinnervation without neuropathic pain."

Meanwhile, back in the denervated skin...

Previous studies have focused on what happens in the skin areas innervated by the uninjured branch of the sciatic nerve, where allodynia develops rapidly after an injury, through a different mechanism.

In the work published in Science, researchers from McGill University and colleagues took a look at this more rapid form of pain hypersensitivity. They focused on the area one step up in the pain signaling pathway, in the dorsal horn of the spinal cord where the peripheral nervous system hands off to the central nervous system (CNS).

In chronic pain syndromes, sometimes regular stimuli are interpreted to be painful, as is the case with allodynia. But there is also hypersensitivity, where stimuli that might have once rated a 4 on a 10-point pain scale are now a 7.

Hypersensitivity is partly due to stronger signaling by CNS pain circuits, and other studies have delved into how the neurons themselves change in chronic pain, looking at ion channels and intracellular mechanisms that contribute to neuronal excitability.

But neuronal excitability is also influenced by structural scaffolding of the extracellular matrix, and in their experiments, the team looked at how that extracellular matrix changed in pain hypersensitivity.

Co-corresponding author Jeffrey Mogil and his colleagues have a longstanding interest in how nervous and immune systems interact in pain perception. In previous studies, his team, as well as others, had shown that specifically microglia – the nervous system's equivalent of macrophages – played a role in hypersensitivity.

In their current study, Mogil and his colleagues also used the same spared nerve injury as the Heidelberg team. However, they focused on the rapid increase in pain sensitivity that occurs in the still-innervated area.

That increase in pain sensitivity was caused by microglial degradation of perineuronal nets in the spinal cord, enabling the spinal cord projection neurons to react more strongly to input from the periphery.

The findings come shortly after another report by the McGill team that showed inflammation is important to resolve acute pain and prevent it from turning chronic.

Together, the McGill studies add to a growing awareness that it is not just the nervous system that plays a role in the development of chronic pain.