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.

There is a failure in translation from pre-clinical studies of chronic pain to effective therapeutic interventions in humans. A confounding factor is that experimental animals of the same strain are often assumed to be a homogeneous group which overlooks inherent variability in outbred strains, including susceptibility to chronic pain. We want to exploit individual variability, with the overall aim of gaining a better understanding of the neural mechanisms that determine why some individuals are more susceptible to transition from acute to chronic pain, with the goal of determining the underlying neural network dynamics responsible for this transition.
Risk factors that predispose an individual to the development of chronic pain include changes in the functioning of pain networks in the CNS resulting in an enhancement of the pain signal as it ascends from the spinal cord to the brain. This involves a shift from inhibitory to facilitatory control of the transmission of the pain signal by the actions of so-called descending pain modulatory systems (DPMS) that originate in brainstem regions, including an area called the periaqueductal grey (PAG). DPMS controls pain transmission at the spinal level and a shift from inhibitory to facilitatory actions of DPMS are believed to underpin the transition from acute to chronic pain, but why some individuals are more susceptible than others is a key unknown. The hypothesis to be tested is the new concept that the cerebellum plays an important role in regulating the DPMS and changes in this regulation underlie susceptibility.
In an out bred strain of rats, chemogenetic silencing of specific pathways between the cerebellum and the PAG in behavioural and electrophysiological studies will focus on two previously neglected questions; (i) the effect of individual variability (measured by rates of fear extinction) on DPMS and (ii) the role of cerebellar-PAG-DPMS axis in the susceptibility to chronic pain.

The research will be of benefit to:
(i) Patients suffering from chronic pain and their families, charities and organizations seeking to
support patients with such disorders.
(ii) Members of the general public with an interest in chronic pain.
(iii) Pharmaceutical Industry
(iv) Academia.
(v) Research staff employed on the grant.
(vi) Welfare of companion and farmed animals.
How will they benefit from this research?
(i) Patients suffering from chronic pain. Currently available treatments are ineffective for the majority of chronic pain patients. In large part this is because the underlying neurobiology is unknown. Additionally, there is a lack of understanding in the general public that leaves patients, and their wider network (friends, family and employers), confused about why their pain persists, why drugs are often ineffective and the lifestyle choices patients must make to aid recovery. The impact of the research on patient groups and their families will be in terms of identifying potential new targets for therapies and being able to provide a better understanding of the critical contributors to their pain condition. By providing insights into normal and aberrant brain circuit function associated with chronic pain, the research will enable charities to realise their mission of providing education and help to patients, their support network and the wider community.
(ii) Members of the general public. Findings from this project are applicable to understanding chronic pain in humans and in companion and domestic animals. Such knowledge is of wide interest to the general public. The findings will therefore be appropriate to disseminate through public engagement activities.
(iii) Pharmaceutical Industry Despite urgent need, there have been very few approved drugs with novel targets in the last 10 years for the treatment of chronic pain. Available treatments are only effective in around a third of patients and opioids are widely used despite serious issues with addiction. Our research will directly benefit the pharmaceutical industry by (a) identifying disease relevant brain circuitry and neurophysiological alterations within this circuitry that may lead to the identification of more efficacious therapeutic targets and (b) identifying causal relationships between changes in brain network dynamics and functional contributions to the pain phenotype that, together with findings from functional imaging studies in humans, may provide predictors and/or objective markers of chronic pain, and its development.
(iv) Academia. International academia in the fields of pain, psychiatry and cognition, as well as basic scientists in fields of sensory and behavioural neuroscience, and cerebellar function are likely to benefit from the progress made by this research (see 'Academic Beneficiaries').
(v) Research staff employed on the grant will develop expertise in highly novel and state-of-the-art research techniques that will aid their future careers. As indicated in the Academic Beneficiaries section, there is a worldwide skills shortage of researchers with experimental animal in vivo research expertise. By taking a lead role in the research programme the named postdoc will also develop her time/project management, communication, team working and other transferable skills.
(vi) The welfare of companion and farmed animals. Society has a moral and economic responsibility to alleviate pain in managed animals. Yet chronic pain is a common problem that may go undetected and/or untreated. Animals in chronic pain suffer emotional consequences such as anxiety and depression. This means that chronic pain affects general wellbeing and impacts on reproductive success and other measures of productivity. Understanding the mechanisms of chronic pain is essential for effective management and for the development of new therapeutics that treat not only the pain but associated comorbidities such as anxiety and depression.