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How Changes in the Cortex Give Rise to Chronic Pain
Nerve damage disinhibits pyramidal neurons in the somatosensory cortex of mice through effects on three populations of interneurons
by Matthew Soleiman on 24 Aug 2017
by Matthew Soleiman
In addressing how pain becomes chronic, researchers have given the lion's share of attention to peripheral nerves and the spinal cord. But now, in a new mouse study, Guang Yang, New York University, US, and colleagues identify enduring changes in the cortex that accompany chronic pain.
The researchers find that spared nerve injury (SNI), a model of neuropathic pain, increases the ongoing activity of inhibitory interneurons in primary somatosensory cortex (S1) that express vasoactive intestinal polypeptide (VIP). These interneurons, in turn, inhibit two other populations of interneurons in S1 that inhibit pyramidal neurons. The end result is disinhibition of the pyramidal cells, leading to their hyperactivity and chronic pain.
"The discovery of disinhibition in S1 cortex demonstrates that chronic pain changes neuronal tone all along the somatosensory axis, from the periphery through the spinal cord and up to the brain," write Erika Harding and Michael Salter, University of Toronto, Canada, in a related "News and Views."
"This is the first time that modifications of the activity of different classes of cortical inhibitory interneurons have been systematically studied in the context of neuropathic pain," says Mirko Santello, University of Zurich, Switzerland, who studies pain processing in the cortex but was not involved in the study.
The results were published online June 26 in Nature Neuroscience.
Overactive pyramidal neurons
In contrast to other cortical regions, such as the anterior cingulate cortex, S1 encodes pain's sensory aspects—location and intensity—rather than its emotional components (see related PRF news story). After nerve damage, however, this processing goes awry.
"Early studies, such as those that used whole-brain imaging, suggested that this part of the cortex is hyperactive in those with chronic pain conditions," said Yang (Peyron et al., 2004). More recently, researchers have zoomed in on S1 pyramidal neurons, which can fall into a similar state, at least in rodents (Eto et al., 2011).
But how? Yang thought interneurons might play a key role. "There are many different kinds of interneurons in the cortex," she said, "but whether different circuit components are differentially altered during chronic pain was not known."
To learn more, lead author Joseph Cichon and colleagues first confirmed that there was a critical change to pyramidal neurons in S1 after SNI. They gauged the cells' somatic activity using two-photon imaging of layer 5 pyramidal neurons expressing the genetically encoded calcium indicator GCaMP6; layer 5 neurons are considered the main output neurons in S1. Compared to neurons from mice that underwent sham surgery, those from SNI animals showed an increase in spontaneous activity. This was apparent as soon as the researchers began imaging calcium, one week following SNI, and even for as long as a month. In other words, it was persistent, much like the mechanical allodynia SNI triggered.
And yet, when the researchers silenced the sciatic nerve with the sodium channel blocker tetrodotoxin two weeks after it had been damaged, they surprisingly saw no effect on pyramidal neuron activity. "At this chronic phase of the neuropathic pain, hyperactivity in the sensory cortex doesn't require peripheral sensory input," said Yang.
All pyramidal neurons have elaborate dendrites that extend from either the base or apical trunk of the pyramidal-shaped cell body, so the researchers next imaged the calcium dynamics in the dendritic spines on the apical branches of layer 5 pyramidal neurons. Overall, the spines in injured mice showed greater calcium activity, suggesting the neurons received more excitatory synaptic input. There were also larger and more frequent calcium spikes that spread across the cells' dendrites compared to sham controls.
"This is particularly important because dendritic spikes have been proposed to be the neuronal correlate of conscious sensory perception," said Santello. "It is intriguing to speculate that an increase in dendritic spikes may therefore correlate with enhancement of pain perception or increased saliency of peripheral stimuli in chronic pain conditions."
"A common motif"
In recent years, researchers have sought to classify neurons based on which genes they express. That strategy has revealed many types of inhibitory interneurons in the cortex, including three distinct classes: those marked by VIP, the peptide somatostatin (SOM), or the calcium-binding protein parvalbumin (PV; Xu et al., 2010).
Yang and colleagues drew upon a recently proposed model of cortical circuitry involving these three interneuron populations (Pi et al., 2013). It maintains that both SOM and PV interneurons directly inhibit pyramidal neurons. Those interneurons themselves are inhibited by VIP interneurons.
The authors hypothesized, then, that pyramidal neuron hyperactivity might result from disinhibition. To test that idea, they monitored calcium signals in each type of interneuron, located in layer 2/3 of S1, and each showed the expected change—nerve damage not only boosted the activity of VIP neurons but also reduced the activity of SOM and PV neurons.
Further support for the disinhibition hypothesis came from tuning the excitability of SOM neurons by expressing designer receptors exclusively activated by designer drugs (DREADDs) in the cells. In injured mice, briefly activating these neurons produced pronounced but short-lived analgesia, an effect not seen in sham controls. And, by activating the cells each day for one week before mechanical allodynia had developed, the researchers could prevent it altogether.
Yet activation of PV neurons in SNI mice could not relieve pain. As for why, the team found that the DREADDs were unable to raise the cells' activity to the same level as they did with SOM neurons. "One possibility could be that we didn't have enough power to drive up PV cell activity" with this technique, said Yang.
Still, Santello praised the study for the advanced techniques it combined. "The experimental strategy was instrumental in disentangling the mechanism of neuronal hyperexcitability in S1, as implicated in neuropathic pain," he said.
S1 is not the only place in the central nervous system where long-lasting disinhibition drives chronic pain. It also manifests in the anterior cingulate cortex and the spinal cord, said Santello. "It therefore seems to be a common motif in several pain-processing circuits."
For Yang, the next step in this line of research involves looking closely across time, rather than only across different types of neurons. At what point, she asks, does the disinhibition they observed no longer depend on pain signals sent by an injured nerve? "Initially, peripheral sensory input is probably important to cause all of these changes, but once the chronic phase is reached, this cortical reorganization is likely complete."
Matthew Soleiman is a science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman.
Activation of cortical somatostatin interneurons prevents the development of neuropathic pain.
Cichon J, Blanck TJJ, Gan W-B, Yang G
Nat Neurosci. 2017 Aug; 20(8):1122-1132.
VIP cortical conductors set the tone for chronic pain.
Harding EK, Salter MW
Nat Neurosci. 2017 Jul 26; 20(8):1037-1038.
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