Welcome to the Neurexpert Blog

Pain and addiction are intimately entwined- and not just because prescription painkillers can be highly addictive (think vicadin or Percocet).

In an ironic twist of brain evolution, the brain circuits necessary for addiction overlap with points of action for common pain medications. These pathways contain dopamine- a brain chemical that increases in response to natural reward (like food or sex) and to drugs of abuse (like cocaine or amphetamines). New research is discovering that these pathways also re-wire, and dopamine levels change, with chronic pain.

A recent study published in Nature Neuroscience conducted in the labs of D. James Surmeier and A. Vania Apkarian has demonstrated that FDA-approved medications that target dopamine, already used to treat Parkinson’s disease and Parkinson’s-like disorders, could relieve chronic pain. How?

A place in the brain where mental fatigue and physical pain meet

Seated deep in our brains, the Nucleus Accumbens integrates information from brain areas that play key roles in motivated behaviour, including reward evaluation and addiction. Indeed, the nucleus accumbens (and its connections) reorganizes in humans with chronic back pain (Apkarian lab; see reading list).

People with chronic pain can find it difficult to start or finish tasks and can suffer from mental fatigue. Sometimes it’s hard to get up off the sofa and finish the dishes. This is something we all suffer from on occasion, especially when we have an illness like a cold or the flu. Back in 2014 a study from the Malenka lab at Stanford University demonstrated that both arthritic- and neuropathic-type chronic pain caused mice to be less motivated to work for a food reward (sugar), especially when the task was difficult or required more effort. The chronic pain mice still liked sugar – when it was freely available they ate just as much sugar as pain-free mice. These motivation changes were linked to cellular changes in the nucleus accumbens.

The Malenka lab could not improve motivation with painkillers suggesting that this symptom was independent of the pain. Often when lowered motivation accompanies pain it leads to an additional diagnosis of depression. However, new research is raising the possibility that motivation changes in chronic pain sufferers may actually be a symptom of chronic pain itself and not a separate diagnosis of depression.

By activating cortical input to the nucleus accumbens with optogenetics, the Wang lab at Stanford University were able to reduce physical feelings of pain, improve mobility and reduce the emotional symptoms of pain (like depression). Interestingly, increased cortical activity is found in chronic pain patients who have undergone cognitive behavioural therapy. The Surmeier lab also found that the nucleus accumbens contributes to another major symptom of chronic pain: hypersensitivity (a touch or sensation that ordinarily wouldn’t bother you is now painful).

All together this data points to reorganization of parts of the brain important for reward evaluation, addiction development and motivation- and now also physical aspects of pain- in chronic pain conditions. Why?

Information is received, processed and flows through the nucleus accumbens by two populations of neurons: 1) neurons that process rewarding and positive information (like sugar), and, 2) neurons that process punishing and negative information (like pain).

Through these two pathways, the nucleus accumbens evaluates options and controls the motivation to perform reward-oriented behaviours. Sometimes this evaluation is disrupted- for instance, drugs of abuse can lead an addict to seek another “hit” in spite of negative consequences.

It seems that, in chronic pain, the nucleus accumbens negative pathways are being inappropriately selected.

By making the brain cells of the two pathways glow with different fluorescent markers, the researchers were able to separate them out from each other and measure the properties of each population. Both the Malenka and the Surmeier labs found that chronic pain caused structural and activity adaptations only in the “negative” pathway cells (positive pathway cells were unaffected).

Using cutting-edge technology involving designer ligands injected into the negative pathway cells that allowed them to control them with light flashes, the Surmeier lab found that activating “negative” pathway cells made mice more sensitive to non-painful touch five days after nerve injury, but when the pathway was shut off the mice were less sensitive.

Can dopamine fix the problem?

Dopamine can have opposing control over the two nucleus accumbens pathways: it activates positive pathway cells and deactivates negative pathway cells. This is why dopamine is often linked to happy moods and also mood disorders like depression. In light of the Surmeier results- more dopamine (which is what happens in natural reward or in response to drugs of abuse or opiate painkillers) should result in a shut-down of the negative pathway and reduction of sensitivity to pain.

The ventral tegmental area (VTA) is one dopamine synthesizing part of the brain that connects to the nucleus accumbens. When dopamine containing VTA cells are activated, dopamine is released into the nucleus accumbens. The Surmeier lab found subdued VTA activity in mice that had chronic pain, leading to less dopamine in the nucleus accumbens. Less dopamine could contribute to greater feelings of pain and other aspects of pain like fatigue, depression and apathy.

Interestingly, people with low levels of dopamine (e.g. Parkinson’s disease) tend to suffer more pain and people with high levels of dopamine (e.g. schizophrenia) tend to experience pain less.

There are already many medications available that have been developed to treat movement disorders like Parkinson’s Disease that make up for low levels of dopamine. The researchers looked at two drugs, levodopa and pramipexole, that modulate the dopamine system and are already used to treat Parkinson’s disease. Levodopa (or L-DOPA) is a naturally occurring brain chemical that is the precursor to dopamine and pramipexole activates dopamine receptors located only on negative pathway cells. When given to mice with chronic pain both drugs returned the negative pathway cells to normal and reduced pain behavioural symptoms such as pain hypersensitivity (in conjunction with naproxen, the NSAID already used to treat arthritis, in the case of levodopa).

Conclusion: where pain, motivation and addiction meet

Feeling constant pain is draining, both physically and emotionally. Numerous studies in humans and rodents have pointed to structural and activity changes in the nucleus accumbens (and brain areas connected to it) in relation to chronic pain (some of these changes are long lasting; a process known as plasticity).

These changes alter how the nucleus accumbens contributes to both the emotional (depression, motivation, fatigue) and physical (hypersensitivity) aspects of chronic pain. Many of the brain areas involved in the transition of pain to chronic pain overlap with brain areas that contain the “rewarding” or “feel good” brain chemical dopamine; and increasing dopamine in the nucleus accumbens could alleviate both the physical and emotional symptoms of persistent pain caused by inflammation (e.g. arthritis) and neuropathic pain (e.g. back pain, sciatica).

Addiction and pain are intimately linked. In a Perspective published in Neuron comparing pain with addiction, Igor Elman and David Borsook make the case that tendency “for addictive behavior is ingrained in pain neuropathology because of neural changes that are comparable to long-term substance abuse even in the absence of prior drug consumption. ”. It beckons the question: are chronic pain patients more likely to succumb to the addictive properties of the medications that are supposed to provide them with relief?

With increasing concern about overdose and abuse related to prescription treatments for chronic pain, the government and pharmaceutical industry are being driven to develop effective and safer painkilling options. The Center for Disease Control has recently published new guidelines for prescribing opiate pain medication in a hope to mitigate some of the addiction and overdose side-effects (see link in further reading).

Although the nucleus accumbens is deeply involved in addiction development, by targeting different aspects of the circuit it is possible that chronic pain symptoms could be alleviated with medications that are not addictive. Or perhaps more natural ways to increase dopamine (dietary changes, sex, sleep and exercise; or make a list and achieve goals) are beneficial to easing chronic pain.

To view the original paper discussed in this blog “The indirect pathway of the nucleus accumbens shell amplifies neuropathic pain” 
in Nature Neuroscience click here.

Other papers mentioned:

“Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens” in Science click here.

“Activation of Corticostriatal Circuitry Relieves Chronic Neuropathic Pain ” in the Journal of Neuroscience click here:

“Common Brain Mechanisms of Chronic Pain and Addiction” in Neuron click here.

“Corticostriatal functional connectivity predicts transition to chronic back pain” in Nature Neuroscience here.

Other Resources:

Northwestern press release: http://www.northwestern.edu/newscenter/stories/2015/12/ending-chronic-pain-with-new-drug-therapy.html

“More pain; less gain” Howard L. Fields; Science 345, 513 (2014): http://science.sciencemag.org/content/3

Naproxen: https://www.nlm.nih.gov/medlineplus/druginfo/meds/a681029.html

Pramipexole: https://www.nlm.nih.gov/medlineplus/druginfo/meds/a697029.html

Levodopa: https://www.nlm.nih.gov/medlineplus/druginfo/meds/a601068.html

https://www.theacpa.org/Pain-Awareness

New CDC guidelines: http://www.cdc.gov/drugoverdose/prescribing/guideline.html

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