Toronto University. Canada: "When you have chronic pain, you develop anxiety. Because you have
anxiety, you suffer more chronic pain," says Professor Min Zhuo.
Researchers have known for a decade what patients have suspected
much longer: chronic pain produces anxiety, and anxiety makes the pain
worse. But why? Scientists have found tantalizing clues, including
intense activity in the same part of the brain during both sensations.
But an answer has been elusive.
Now, neuroscientists at the University of Toronto have mapped a
mechanism in the brain’s anterior cingulate cortex, or ACC, that could
explain the link between anxiety and chronic pain.
Min Zhuo is a professor in the department of
physiology at U of T and the Canada Research Chair in Pain and
Cognition. Zhuo and his lab recently published a paper in the journal Neuron
that showed how neuroplasticity – the brain’s ability to physically
re-organize itself in response to experience – can spur the interplay
between chronic pain and anxiety. They also showed that a drug they
developed for chronic pain can limit anxiety.
Zhuo spoke with Faculty of Medicine writer Jim Oldfield about his findings and what they could mean for patients.
What’s the link between pain and cognition in your work?
Most chronic pain researchers study pain as a sensory experience. They
think that if we reduce the physical pain, the patient will be better.
But I think we need to look at both the mental and physical in the study
of pain. Recently we’ve seen more acknowledgment that patients with
chronic pain are often anxious, and that if this pain lasts a long time
many will suffer depression and lose hope. As well, more researchers are
moving away from the idea that mental disorders are just genetic
– i.e., you have a bad gene and that’s why you have disease. In my view,
if chronic pain causes enough physical change in the brain, anyone can
behave like a mentally ill patient. So to better understand and treat
pain we need to look at its physical cause but also cognition and mental
health, or emotional well-being.
What findings does the Neuron paper describe?
We
found a possible explanation for why chronic anxiety and pain make each
other worse. Neurons communicate through synapses, which are structures
that convey nerve impulses from one neuron to another. These synapses
are plastic, meaning they change physically in response to stimuli.
Repeated experiences can reinforce these changes and over time the
physical changes can become permanent. It’s like a learned memory. And
when that happens, you can experience a sensation without an underlying
cause. You’ve probably heard of amputees who have pain in a limb that
doesn’t exist. Well, we found a similar “learned memory” process for
anxiety, in a different part of the same synapse where we see activity
linked to chronic pain.
So when these two functions become partners, they make each other
worse. When you have chronic pain, you develop anxiety. Because you have
anxiety, you suffer more chronic pain. This is the first evidence that
anxiety is linked to long-lasting changes at synapses.
Is there a way to short-circuit this process?
We identified a channel or genetic process called HCN that maintains
this anxious learning. So theoretically, if we find an inhibitor to
erase the long-term potentiation for anxiety – the learned memory – we
should be able to reduce anxiety through this channel. But a big
challenge is that drugs in the central nervous system often produce side
effects. The HCN channel is also expressed in heart and other types of
cells, so any drug targeting this channel would have to be selective for
neurons.
Fortunately, a drug we’ve been developing for pain called NB001
inhibits a protein called AC1 that is upstream from HCN, and it does so
in a way that is selective for neural cells. It’s a very promising
therapy for chronic pain and anxiety.
What are the challenges in bringing this drug to market?
Our research is still at the pre-clinical stage. But it’s very
difficult to move drug discovery forward, in part due to the world
economic situation. There are few angel funders because of the
recession. Big Pharma is risk-averse. NGOs support experimental
research, but their funds are very tight. On the bright side, we have
teamed with investors and researchers internationally on clinical tests
in cancer patients. Many cancer patients have pain that is badly
managed; in the late stages they’re almost asleep with high-dose
opiates. Others don’t get enough medicine and live with terrible pain
and anxiety. My hope is that one day we can treat these patients with a
drug that works.