Contributions of prefrontal-midbrain-spinal cord network dynamics to the development and maintenance of chronic neuropathic pain.

Long term pain (chronic pain) is widely prevalent, severely impacts upon a patient's health and poses an enormous cost to our economy. Pain relieving drugs developed for acute (normal) pain are ineffective in the majority of chronic pain patients. As a result, chronic pain remains one of the greatest unmet clinical needs. Tissue damage is detected by peripheral nerves that convey pain information to the spinal cord (SC) where initial pain processing occurs. Pain information then travels to the brain for further processing in a distributed network of brain regions that produce sensory and emotional aspects of the pain experience. Recent advances in our understanding of pain indicate that alterations to pain processing in the brain, rather than in the peripheral nervous system, may form a critical locus for chronic pain disorders and, as such, a better understanding of these processes is required if we are to develop more effective treatments for patients.
The pain experience is not fixed, and can be altered by a descending pain modulatory system (DPMS) that affects spinal pain processing, which in turn modulates the flow of pain information to the brain. Thus the pain experience is determined by the interplay between descending control of spinal pain processing, the resultant ascending pain information, and pain processing in the brain. In chronic pain the relationship between the magnitude of peripheral pain input and the pain experience is lost, such that pain is maintained beyond the period of tissue damage. We postulate that, in these circumstances, changes in central nervous system networks that process pain information alter the DPMS control of spinal pain processing and, in so doing, contribute to enhanced pain perception and negative emotion. Specifically, recent findings have placed particular importance on the medial prefrontal cortex (mPFC), an area of the brain involved in higher processing such as the generation and regulation of emotion, and the integration of emotional with sensory information that then feeds into conscious awareness. However, understanding of the mechanisms that underlie the role of the mPFC in pain are not fully understood and there is little information about its interactions with other brain regions that mediate effects on pain sensation and/or emotion. It is these questions our proposed investigations will address.
Direct connections exist between the mPFC and the midbrain periaqueductal grey (PAG); the latter being a key orchestrator of the DPMS. We propose that mPFC-PAG connections are important pathways that mediate effects of high order PFC function on lower order pain processing in the spinal cord, and thus contribute to altered pain sensation and emotion in chronic pain. In an established animal model of chronic pain we will manipulate, and characterise, the communication within the mPFC-PAG-SC network in anaesthetised and behaving animals during the development of chronic pain. This will enable us to relate underlying mechanisms to disease symptomology. Critically, selective inactivation of mPFC-PAG connections at a number of time points will enable identification of their dynamic contributions to sensory and emotional aspects of the pain state as it progresses.
The study will generate novel data about the causal relationship between alterations to high-order pain processing in the brain, its interplay with the DPMS and the enhanced experience of pain sensation and negative emotion. The findings will further our understanding of brain mechanisms that contribute to chronic pain and will support and inform studies in human patients. The long-term benefits include the identification of potential targets for effective therapeutic strategies.

Progressive alterations in the functional connectivity of the medial prefrontal cortex (mPFC) are thought critical to the development of chronic pain in humans but how they relate to sensory and affective disturbances or disease progression is not understood. The mPFC is directly connected with the periaqueductal grey (PAG) and their functional connectivity is altered in chronic pain patients. The PAG is an important component of emotional networks and a key orchestrator of the descending control of spinal nociception; both of which are major determinants of the pain experience. We propose that progressive alterations in mPFC-PAG communication alter the cortical control of the PAG and, in so doing, contribute to sensory and affective aspects of the pain phenotype.
Our pilot data show that, in naïve rats, mPFC effects on spinal nociception are dependent, at least in part, on the integrity of direct projections to the PAG. We now wish to use combined anatomical, electrophysiological and behavioural approaches in neuropathic rats to (i) characterise communication between the mPFC and the PAG, and how it engages with nociceptive processing in the spinal dorsal horn, (ii) chart progressive changes to mPFC-PAG network dynamics during neuropathic pain development and (iii) determine functional contributions of PFC-PAG projections to sensory and affective disturbances using chemogenetic approaches.
Our overall aim is to interrogate the causal relationships between, and provide mechanistic insights into, progressive alterations in mPFC-PAG-SC networks and the development of the neuropathic pain phenotype. Specifically, to provide novel details on (i) functionally identified mPFC-PAG pathways that will serve as an important reference for other pain researchers and reveal potential therapeutic targets, (ii) the relationship between network alterations and pain symptoms that, together with human imaging data, will help develop biomarkers for components of chronic pain.

The research will be of benefit to:
(i) Patients, their families and the wider public
(ii) The medical community
(iii) Pharmaceutical industry
(iv) The research staff employed on the grant
(v) Academia
How will they benefit from this research?
(i) 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. Chronic pain often dramatically effects normal work and social life, leading to negative impacts on friends, family and employers. 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) Treatment strategies for chronic pain patients are often misaligned between front-line doctors (e.g. GP) and pain specialists, and largely based on pharmacological interventions that are often ineffective and counter-productive. As a result, the cost to the NHS is huge and the patient's general health often deteriorates (e.g. opioid dependence). Through correct and effective dissemination of findings within the medical community our research will help to (i) align treatment strategies within the medical community by increasing appreciation for the role of central pain control circuits in the development of chronic pain and (ii) strengthen the scientific underpinnings for non-pharmacological treatment strategies such as exercise, mindfulness or cognitive behavioural therapy; and potentially reveal means to augment their treatment effects.
(iii) Despite urgent need, there have been very few approved drugs with novel targets in the last 10 years for the treatment of chronic pain. Alarmingly, available treatments are only effective in around a third of chronic pain patents and opioids remain widely used despite serious known issues with addiction and overdose. Our research will directly benefit the pharmaceutical industry by (i) identifying disease relevant brain circuitry and neurophysiological alterations within this circuitry that may lead to the identification of more efficacious therapeutic targets and (ii) 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) The named post-doc will develop highly novel and state-of-the-art research techniques. As indicated in the Academic Beneficiaries section, there is worldwide shortage of researchers with experimental animal in vivo research expertise. Additionally, the named post-doc is at a key point is his career and the project will allow him to generate data for publications and fellowship applications that will greatly benefit career progression.
(v) International academia in the fields of pain, psychiatry and cognition, as well as basic scientists in fields of sensory and behavioural neuroscience, and prefrontal cortical function are likely to benefit from the progress made by this research (see 'Academic Beneficiaries').