Identifying novel therapeutic targets for chronic neck pain: RNA-sequencing in human painful atlanto-axial arthropathy

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PROJECT SUMMARY / ABSTRACT Background. Chronic neck pain is one of leading determinants of disability worldwide, a major contributor to the current opioid epidemic, and the cause of enormous health care expenditures. We currently do not understand which molecular mechanisms in the diseased tissues of the neck generate the painful signals that cause this disease burden. This gap in knowledge impedes development of effective, mechanism-specific therapeutics. Aim. We plan to use RNA sequencing on tissues taken from chronic neck pain patients undergoing surgery and then use computational biology and patient phenotyping techniques to gain better insight into molecular drivers that cause chronic neck pain. Approach. We will recruit patients undergoing surgery for chronic neck pain stemming from the atlanto-axial joint. This joint is located between the 1st and 2nd cervical vertebrae on both sides of the spine and is a common site of arthritis. We will also recruit patients undergoing the same surgery for acute pain due to fractures. During surgery, we will sample tissues from the joint and the dorsal root ganglion (DRG), in which the nerves supplying the joint are located. These tissues would be removed during surgery in chronic pain patients, independent of the study. For acute pain patients we will use our existing dorsal root ganglion database of people with no pain. We will perform RNA sequencing on samples from both sides, in order to compare tissues from painful and non- painful side of the same individual. We will record clinical pain characteristics, measure pain sensitivity and assess nerve function using pinprick, pressure and cold stimuli. We will also use computational biology methods to assess how diseased tissue interacts with the nervous system to drive pain. These methods will allow us to identify targets that are related to pain outcomes. Aim 1: To determine the RNA expression profile of the joint tissues and DRG from acute and chronic pain patients to determine genes that are differentially expressed in chronic neck pain tissues. Aim 2: To use computational biology techniques to determine how pathological molecules originating in the joint tissues interact with specific receptors on neurons of the DRG to generate the pain signal. Aim 3: To determine the association of RNA sequencing findings in the joint and nerves with clinical manifestations of neck pain, pain sensitivity and nerve function. This will provide information on which molecular changes at the joint and nerves are of specific importance to pain. Impact. The project will enable unprecedented identification of molecular pathways specifically associated with chronic neck pain. Our work will create a unique map of molecular targets for the future treatment of chronic neck pain based entirely on human molecular neuroscience.