How brain plasticity creates a “pain biography”

Highlights From the 2016 Annual Scientific Meeting of the American Pain Society: Part 3 | Pain Research Forum – How plasticity creates a “pain biography” – by Stephani Sutherland on 28 Jun 2016    

Noxious stimuli activate sensory neurons in the peripheral nervous system, ultimately giving rise to the sensation of pain. But pain is not the product of a simple relay from peripheral nerves to the brain; sensory signals undergo extensive processing along the way, beginning at the first way station, the spinal cord

three researchers examined how plasticity in ascending and descending pain pathways creates a “pain biography,” a lifelong experiential history that shapes the experience of and even future susceptibility to pain.

Micro-circuitry revealed

First, Rebecca Seal, University of Pittsburgh, US, presented data that help to elucidate pain micro-circuitry in the dorsal horn (DH) of the spinal cord. 

Now, the team has performed a complementary experiment using an inhibitory DREADD to reversibly silence the neurons. “When we shut down the cells,” with the inhibitory designer ligand, Seal said in her talk, “it blocked mechanical allodynia” in two inflammatory pain models. Acute pain, in contrast, was unaffected. “Whereas the VGLUT3 transporter itself was important for acute and persistent mechanical pain,” Seal said, the new results indicate that, in adulthood, “these neurons transmit persistent pain, but they don’t seem to be important for acute mechanical pain.”

That finding suggests a developmental role for VGLUT3. “VGLUT3 expressed by the cells is critical for setting up circuits for both acute, high-threshold pain and persistent mechanical allodynia, but the cells themselves appear to be required for only mechanical allodynia” Seal told PRF in an email.

“This work is starting to reveal the circuits for mechanical allodynia, and there appears to be a requirement for different neurons depending on the type of injury, suggesting that different micro-circuits might contribute to allodynia,” Seal said. She postulates that the calretinin neurons are normally not responsive to touch, but that inflammation somehow disinhibits the neurons. PKCγ neurons, she believes, are also normally inhibited and become disinhibited following nerve injury. “That disinhibition allows the sensation of pain to come through, instead of touch.” In future work, Seal aims to identify how the neurons become disinhibited and which primary afferent neurons are driving activity.

Dynamic synapses

In a second talk, Theodore Price, University of Texas at Dallas, US, presented data suggesting that descending neurons from the brain are constantly remodeling spinal pain circuits.

In 2015, Price’s group published work demonstrating that dopaminergic neurons projecting from the hypothalamus to the spinal cord were responsible for maintaining a primed state that rendered animals vulnerable to chronic pain (see PRF related coverage). Now, Price and his team have shown that surprisingly dynamic GABAergic synapses influence the development of chronic pain.

Price took inspiration from a previous report showing that, with persistent inflammation, GABAergic signaling in the spinal cord switches valence from inhibitory to excitatory signaling

Price’s team next wanted to find the root of the priming-related GABA plasticity. They found that the synaptic adhesion molecule neuroligin 2 was persistently upregulated in the spinal cord of primed mice.

the findings begin to sketch out a picture of priming as highly plastic modulation of pain-related synapses in the spinal cord by dopaminergic inputs, and a switch in GABA from an inhibitory, analgesic messenger to an excitatory, pro-nociceptive signal.

“The results have really important implications for treatment, such as the idea that chronic pain is truly a disease of the CNS [central nervous system]. This may help us discover new mechanisms of plasticity that offer disease-modifying therapies to reverse plasticity and chronic pain states,” Price said.

Primed for pain

Simon Beggs, who recently moved from the University of Toronto, Canada, to University College London, UK, presented thought-provoking data from animals “primed” for pain in adulthood by a neonatal incision.

The findings could have clinical implications for the millions of preterm babies born each year who are subjected to repeated needle pokes and other medical procedures.

Beggs and colleagues previously found that rats that received a single incision during a critical period in the first postnatal week experienced longer and more intense hyperalgesia following a minor injury in adulthood than did naïve rats

The researchers determined that the early injury primed rats for a microglial neuroimmune response in the spinal cord activated by adult injury.

Ongoing experiments suggest that minocycline blocks the increased microglial reactivity seen in the spinal cord three days following the neonatal injury—but only in male rats. Pain sensitivity was likewise affected

Minocycline given at the time of the initial injury completely abolished priming in males, which might have implications for neonates undergoing surgery—perhaps we can prevent priming by pretreating with minocycline, at least in boys.” However, Beggs noted, although minocycline is approved by the U.S. Food and Drug Administration for some uses, prophylactic pain treatment in neonates is likely a long way off.

One important thing we found is that the brain changes very rapidly after injury, with the same time course as pain behaviors,”

Brain structures did undergo changes following injury at either age, but how they changed was determined by when the injury occurred. “These are not small, tiny changes,” Beggs said.

We saw up to a 28 percent change in volume in some cases. What they mean is another matter,” he added.

“The second thing we realized is that the changes not only appear quickly, but they’re also long-lasting” into adulthood,

there seemed to be an interaction between the neonatal and adult injuries. For example, adult injury led to a decrease in volume in the cerebellar vermis, but in primed mice, it caused an expansion of the same region. “Priming seems to change the brain’s response to injury.”

Together, the three lines of research begin to reveal an extremely dynamic pain-processing system that can be reshaped by injuries throughout life to influence future pain experiences.

Author: Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.  

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4 thoughts on “How brain plasticity creates a “pain biography”

  1. Dave

    More self servong pseudoscienticlfic nonsense espoused from an organization that has largely failed to have a vision and good results for people in pain. They are quite lost and their maps have failed to lead them to real treasuresbfor people in pain.

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  2. leejcaroll

    Im saddened by the other comment. This sounds promising. Nice not to hear the “scientific” theory pain pathways the result of psychic trauma but instead attempts to delineate the brain circuitry involved. I dont know anatomy but when I had a dorsal column stimulator implanted, for facial pain, it stopped 85% of my pain.

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    1. Zyp Czyk Post author

      I’m glad to see scientific proof that untreated pain primes the brain for more pain later – all the more reason to nip it in the bud as soon as it starts or even to dampen it whenever possible.

      I feel like chronic pain is similar to an allergic reaction where I become more sensitive to it the longer it goes on instead of getting used to it.

      Wow, I’m amazed how well the spinal stimulator worked for you!

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      1. leejcaroll

        so was I and I think so too was the doc. ((*_*)) (Unfortunately I lost it to an unrelated infection. Next one didnt work because too much scar tissue, someone else had been in the area before the stimulator and then putting it in and then taking out made the area impossible to activate when he out it back in. Unfortunately I lost that also to an unrelated infection and he refused to try a thrid time. The next one was 100% experimental in the sensory cortex. Had it working for over 20 years then finally failed (mine was longest they had in their files for being in and on) Not sure if it is the wire or exactly what. Havent had it replaced, the wire that it, at this point although may some time do so in the future. (That helped my phantom pain in the same facial area)
        I like your analogy to allergy.

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