The University of Newcastle, Australia

Pinpointing the pathways of pain

A fascination with the messages relayed via the spinal cord has maintained Associate Professor Brett Graham’s focus since he graduated with his PhD from UON in 2006. Ten years on, Brett’s research-focus remains intense, with the goal of mapping the nerve cells involved in pain signalling to allow for better treatment.

“This was my first passion in science, and I’ve been lucky enough that for the past 16 years I’ve been able to keep building on and pursuing that passion,” Brett says.

The spinal cord is a complex conductor of messaging from the body to the brain, but Brett has a simple analogy to explain the transmission of messages, and why it’s such a complicated field to research. “The spinal cord is like an international telephone exchange, with lots of calls arriving, in many different languages. The messages come in to the spinal cord and there are populations of nerve cells that perform an initial stage of processing, much like telephone operators connect calls to the intended receivers, before these messages are sent to the brain. It’s only once the information is received by the brain that you acknowledge the pain,” Brett explains.

“In our research we are trying to understand the nerve cells that receive this information from the body and then how these cells are connected to each other. These properties shape what information goes to the brain. We know the connections can disrupted - think of a spinal cord injury where the connections are severed. In this situation we still have sensory signals generated on the body, but the brain doesn’t receive the messages so you don’t feel them.”

Brett’s interest in neuroscience was piqued early. “I studied an undergraduate degree at UON in biomedical science, so I was always into science. The first thing that got me focused on neuroscience was after my neighbour passed away from Motor Neurone Disease. This is a horrible disease that represents a rapid failure of part of the nervous system that controls our movements and takes peoples’ lives in their most productive years - but why and how? That started me thinking about neuroscience, and while I didn’t end up studying Motor Neurone Disease, it did get me to focus on the spinal cord.”

Brett’s research is aimed at understanding the complex relationships between pain and spinal cord signalling. “When signals become cross-wired, the channels that are bringing touch-signals start to excite the pain-related channels and so all of a sudden touch can cause pain. There are many different conditions – such as neuropathic pain which cause people to experience pain due to touch. Most of the work we’re doing is trying to understand the types of nerve cells and the types of channels that send and receive those messages. If we identify those nerve cells we can understand what is unique about them, what signals they are meant to receive, and what they connect to. Once we can understand that circuit, and how it normally works we can then work with models of chronic pain and injury to better understand how to restore normal processing and normal sensations.”

It's a numbers game

The difficulty with this type of research is that much of our understanding is in general terms - that is theoretical, and we know that a lot of pain drugs work in the spinal cord by changing the pain signalling. Despite this general understanding, we still don’t know the exact channels and circuits where many of these drugs act. “It’s a challenge of numbers: throughout the brain there are one hundred billion neurons and the spinal cord is organised into a series of segments that each receive signals from various parts of the body –each segment contains around 20 000 nerve cells that potentially deal with pain.”

“However, only about one nerve cell in every 100 will play the key role of transmitting information to the brain. All the other nerve cells are interconnected into local spinal circuits that adjust the level of pain signalling that is ultimately relayed to the brain. There’s a whole lot of scope to change the signal and therefore change the experience of pain.”

“Thankfully, we’re coming into a time when the techniques we can use to study these connections are circuits are rapidly advancing – and that’s one of the waves that we’re riding here at UON. What we really want to do is identify the different types of sensory nerve cells in the spinal cord, work out how they’re connected and what that means for pain messaging.”

“The challenge we’re dealing with is that, while chronic pain can be considered a disease in its own right, many other diseases and disorders also cause pain – such stroke, arthritis, multiple sclerosis and even cancer. Overall, the statistics say that approximately 1 in 5 people will experience chronic pain in one form or another, which is incredibly debilitating and impacts on all aspects of life.”

Modelling the nerve pathways

“What we’re in the business of is understanding the underlying issues behind what causes pain because it’s with this understanding we can look to develop better drugs. By identifying the nerve cells involved in signalling pain, we’ll be better able to develop drugs that can do that selectively.”

By using mouse modelling in their research, Brett and his team have risen to the challenge of mapping out the complex pathways of nerve cells. “We’re doing our research using transgenic mice, where new genes are introduced to give us a clearer view of things. For example, we use the genes for fluorescent proteins that come from deep-sea jellyfish, and that brings us the capacity to ‘light up’ and ‘label’ certain nerve pathways. By making specific types of nerve cells glow we can study them selectively.”

Otherwise, the challenge that you face is that when you go to record nerve cell signalling in the spinal cord you’ve got 20 000 potential pathways to choose from, so you need to do many, many recordings and see if any patterns emerge. Whereas with the green fluorescent proteins in transgenic mice, a subset of the nerve cells are glowing so you can start to get a signature of what their specific properties are like.”

Using this green fluorescent protein allows Brett and his team the ability to study these nerve cells and start to put together the components – effectively colour-coding the spinal pain circuits.

“We’re also using optogenetics which uses the gene for a different protein expressed in blue-green algae. It’s a really exciting technology that’s rapidly developed over the last five or six years. Optogenics was named Technique of the Year by Nature in 2010 and it’s being applied in research around the world. Essentially, the way the blue-green algae protein works is that when light shines on it, it excites the cell and this allows the algae to swims toward the light. By placing this gene in transgenic mice we can not only see specific nerve cells – we can turn them on using light.”

The reason people are so excited about doing that is that it helps us work out how nerve cells are connected into circuits. “This is allowing us to move rapidly toward understanding the principle pain circuits in the spinal cord. Our goal is to create a ‘map’ of these circuits and start to understand how disrupting them causes the symptoms of chronic pain. One of my PhD students is working on a population of interconnected ‘accelerator’ nerve cells and trying to understand how they might work to amplify pain. “The question we’re asking is ‘In Chronic pain is it the case that these ‘amplifers’ become switched on to enhance pain signalling and really rev everything up?’ That’s what we think is happening.”

“We are really excited about the potential role of these accelerator cells, but coming back to the fact that pain can result from many different diseases and conditions, we don’t think there is one pathway to chronic pain. We think there’s likely many different routes or populations of nerve cells that could become dysfunctional and it’s our long-term goal to understand all those potential routes to pain.

When it comes to treating pain a blanket approach that simply shuts down all spinal circuits doesn’t seem to work very well and typically brings with it a range of side effects. The best pain treatments are much more likely to come from more subtle and specific adjustments. For example, you might need to turn some circuits up and some circuits down.” Fortunately the transgenic studies that Brett and his team are using have them well placed to meet this challenge and continue pinpointing the many pathways to pain.