Susceptibility to Chronic Pain: role of Cerebellar - Periaqueductal Gray Communication

Acute pain is a necessary sensory function that signals tissue damaging stimuli such as the heat of a fire. It is short lasting and is essential for survival, as it drives simple protective measures such as removing the hand from the fire. Other protective measures triggered by acute pain, such as changes in fear and anxiety, are more complex and involve networks of neurons that encompass many brain regions; the so-called survival network.

Acute pain ends following removal of the stimulus or upon repair of the injury. However, in a significant proportion of individuals pain persists beyond the period of tissue repair and can last for months or years; this is known as chronic pain and it is a massive problem. Current treatments are largely ineffective and so new lines of research are needed to identify novel targets for the development of treatments.

It is clear that some people are more susceptible to the development of chronic pain than others. Susceptibility is also a feature of anxiety disorders (such as post-traumatic stress disorder) as a small population of people cannot 'forget' (extinguish) a fear response to a fearful event that has occurred in the past. Importantly, anxiety disorders and chronic pain often occur together, suggesting they share similar neuronal mechanisms.

A major unanswered question is what makes some people susceptible to the transition from acute to chronic pain and what are the underlying mechanisms?

Survival is promoted by alterations in pain perception. In some instances (such as escaping from danger) stopping pain is advantageous as it allows an animal to escape without distraction of the pain. By contrast, in other situations (such as during recovery from illness) increased awareness of pain becomes an advantage as it encourages resting behaviour.

This is beneficial, as rest allows the individual to focus on recuperation from illness. Suppression or enhancement of pain is mediated by pathways that originate in the brain and travel down to the spinal cord to alter pain transmission (the so-called descending pain modulatory system or DPMS). Brain survival networks can suppress or enhance the pain signal by controlling activity in the DPMS.

In acute pain, activity in these pathways alters the pain experience to promote survival in the ways described. However, in some vulnerable individuals the DPMS becomes abnormal and amplifies the pain signal leading to chronic pain.

Similar to anxiety disorders, such as post-traumatic stress disorder, we propose that a failure of the brain to 'forget' the memory of a painful stimulus triggers changes in brain functioning; thus creating an illusion, which is interpreted by the brain as pain. We hypothesise that the development of chronic pain is due in part to a change in the ability of the survival network to correctly predict the appropriate pain response to injury based on past pain experience, and that this alters the DPMS causing amplification of the pain signal resulting in chronic pain.

The cerebellum is a region of the brain that detects differences between predictable and unpredictable pain information (termed prediction error). The cerebellum has interactions with a brain structure called the periaqueductal gray (PAG), which is a source of DPMS. Both the cerebellum and the PAG are components of the survival network and their dual roles in pain processing and signalling prediction error make them strong candidates for driving the development of chronic pain.

This project will test, in a rat model, whether susceptibility to chronic pain is dependent on changes in the interactions between the cerebellum and the PAG that results in abnormal activity in descending control of pain signalling and, as a consequence, amplifies the perception and the responsiveness to pain. A better understanding of these brain functions will open important new avenues for the development of therapies for chronic pain.