Defining descending inhibitory pathway functionality in health and disease

When we break an ankle, further damage is prevented through the protective sensation of pain; we avoid weight bearing. Unfortunately on occasion, after damaged body parts have healed, pain persists. This kind of pain, termed chronic pain, has no protective function. Current pain relieving drugs do not always work and as such chronic pain affects up to 20% of the adult population. This results in a significant economic strain on the healthcare system as well as a huge socioeconomic burden on the individual. To identify new drugs that make chronic pain patients feel less pain we must identify new therapeutic targets based on novel mechanistic insight. My research ultimately aims to provide such insight.
The process of pain perception is highly complex. It involves many different nerve signals travelling from the brain to the spinal cord. These nerve signals comprise regulatory pathways that, in the normal situation, make us feel less pain. However, in chronic pain, the function of these regulatory pathways can go wrong leading us to feel more pain. This grant seeks to investigate the functionality of these pathways a) in health and b) in a rodent model of chronic pain.
Chronic pain can manifest in patients suffering from cancer; the growth of secondary cancer tumours in the bone may lead to cancer induced bone pain (CIBP). Due to improvements in cancer treatments coupled with largely ineffective pain relieving options, the prevalence of CIBP is high. In my laboratory I have developed a rodent model of CIBP that encompasses early and late stages of the disease. I have collected preliminary data showing that regulatory pathways, from the brain to the spinal cord, do not function in the proper manner in these rodents in the early stage of disease. I wish to use NIRG MRC funding to prove whether or not the nerve signals that comprise the regulatory pathways have gone wrong in a manner that is specific to the stage of disease progression. My hypotheses are that multiple distinct regulatory pathways exist and that regulatory pathways are impacted negatively in a stage-specific way. I propose that this negative impact on regulatory pathways is an underlying cause of the pain associated with this disease, and if true it would mean that directed therapies, intended to relieve suffering in, for example, cancer pain patients, could be more easily formulated according to, for example, the stage of disease.
To this end I will study the influencing factors and function of brain to spinal cord inhibitory pain pathways in health and in CIBP rats. Through comparison it will be possible to pinpoint where regulatory pain pathway connections have gone wrong. Ultimately, pain-relieving agents could be prescribed more effectively if we understand what regulatory pain pathway we should target for chronic pain relief.

Descending modulatory controls project from the brainstem to the spinal cord to inhibit or facilitate pain sensations. In health the descending pain modulatory system (DPMS), which encompasses a unique form of descending control termed diffuse noxious inhibitory controls (DNIC), may act endogenously to inhibit spinal neuronal processing and thus reduce the final percept of pain. However maladaptive activity in the DPMS has been reported in rodent models of chronic pain and I have published evidence that DNIC pathway expression, quantifiable as a reduction in spinal nociceptive processing upon application of a noxious conditioning stimulus, is dysfunctional in rodent models of chronic pain.
For this NIRG application I have collected pilot data to evidence that the DNIC pathway originates in the A5 nucleus and that DNIC expression is negatively impacted by excitation of the locus coeruleus (LC). My working hypothesis is that while the DPMS (LC projection) and DNIC (A5 projection) pathways influence one another in health, they are functionally separate and evolutionarily distinct and that they influence one another differentially in a disease state. If correct, the DPMS and DNIC pathways offer 2 separate therapeutic targets in disease. I have shown that in early stage cancer induced bone pain rats DNIC is dysfunctional. I want to know does the functional relationship between the A5 and LC nuclei change in these animals? I will investigate brainstem reciprocal crosstalk and spinal pharmacological functionality in healthy and early stage CIBP rats in order to potentially reveal a novel underlying mechanism of pain.
Altogether, the research proposed in this application will enable me to gain mechanistic insight of pain inhibition pathway malfunction in disease. This insight is crucial for the eventual development of targeted therapeutic strategies that act to boost endogenous descending inhibitory pathway activity.