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Love hurts. Often in life we describe emotional events as if the pain were physical. We have painful memories of past events and we don’t differentiate our language between a painful rejection and a broken arm. It isn’t surprising, therefore, that chronic pain conditions could, partially, develop in centers of the brain overlapping with painful emotional experience.

Human brain scans found enhanced activity in a part of the brain called the anterior cingulate cortex (ACC) in psychological pain circumstances like rejection and in patients with chronic pain conditions. The ACC lays down memories for pain and puts them into context. It adds a component of unpleasantness to physical pain so that we feel sad, fearful or anxious.

The overlap between chronic pain and mental health is becoming more apparent- for instance neural mechanisms of motivation, addiction (see here http://www.neurexpert.com/blog/Blog30032016.html) and stress disorders (see here http://www.neurexpert.com/blog/Blog24022016.html) share commonalities with chronic pain disorders. Much of the time aspects of mental health and chronic pain will exacerbate each other. So when fear, anxiety and chronic pain are interlinked- as they are in the ACC- they aggravate each other.

A review in Nature Reviews Neuroscience, written by researchers Tim Bliss, Graham Collingridge, Bong-Kiun Kaang and Min Zhuo, suggests that chronic pain can be “thought of as a type of persistent sensory memory" – the brain keeps laying down the memory for the pain over and over again, even after the initial trauma has gone.

The ACC seems to be a hub for negative pain-related information- unpleasantness, fear and anxiety- all incoming from different brain networks. When some, or all, of this information arrives together in the ACC it is possible that it worsens painful conditions because connections between nerve cells are strengthened by multiple inputs encoding different aspects of the same message.

Basically, it amplifies the message against all the other incoming messages- telling the brain that that message must be important and I must remember it. When fear and anxiety associated with pain occur at the same time as the unpleasantness of pain itself then all those messages arriving in the ACC will add together at the synaptic level to create a stronger, and possibly more persistent, memory.

The synaptic “code” for plasticity and memory formation is known as Long Term Potentiation (LTP) or Long Term Depression (LTD). These mechanisms help form new connections, retain connections and dampen unwanted connections between neurons- a strengthening of memory. Many studies are demonstrating that ACC neuron connections have prolonged strengthening in chronic pain conditions, like neuropathies, irritable bowel syndrome, chronic inflammatory pain and bone-cancer pain. For instance, ACC neurons have enhanced synaptic responses weeks after initial nerve injury- to the point that the synaptic responses are maximized. Under normal circumstances these synaptic messages that should stop once the initial trauma has passed but in chronic pain the messages seem to be maximized and persistent.

In other words, the ACC neurons are laying down a memory for the painful experience- the pain, the fear of pain, and the anxiety components- over and over again. And this can happen independent of continuing physical pain. For instance in amputation studies, where a local anaesthetic was applied to block nerve activity at the point of amputation, the ACC continued to maintain enhanced connections even after peripheral nerves were blocked.

The LTP and LTD code for synapses to form long-lasting memory connections require many molecular and cellular processes (these include neurotransmitters and their receptors as well as a myriad of intracellular signaling pathways). Understanding the role each plays in maintenance of chronic pain memories could be an avenue for drug development. One example of this is in chronic gastrointestinal pain models- using a drug that lowered anxiety in this model of pain (called ZD7288) reversed the LTP memory code changes that occurred due to the chronic pain. This suggests that there is an anxiety component to laying down the memories of pain so that they become pathological.

Not all pain is necessarily bad- we need acute pain for survival. For instance, even when taking painkillers to treat a chronic pain illness you still want to be able to know you are touching a red-hot flame in order to move your hand quickly. Knowing the differences between the mechanisms behind acute and pathological pain will help develop drugs to treat these independently.

Estimated to affect up to 30% of the world’s population, chronic pain is persistent- lasting from weeks to years. It is debilitating and expensive and the Center for Disease Control and Prevention claims there is an epidemic of opioid overdose in the US (half of those deaths are from drugs obtained by prescription). Understanding the brain circuitry involved in chronic pain is fundamental to helping find therapies for pain sufferers. The persistence of pain memory exacerbated by anxiety and fear, even after the trauma is gone, is another piece of the puzzle.

To view the original paper discussed in this blog “Synaptic plasticity in the anterior Cingulate cortex in acute and chronic pain” in Nature Reviews Neuroscience please click here.

The Blog was written by Carolyn Lacey, Scientific Outreach Manager at Neurexpert. To learn more about Carolyn and Neurexpert, please click here.