Defining the primary afferent circuitry that drives neuropathic pain

Neuropathic pain occurs as a consequence of damage to the nervous system and is characterise by both loss of sensation such as numbness as well as unpleasant positive sensory features such as spontaneous pain and 'allodynia' whereby stimuli which are not normally painful such as brushing the skin become painful. Neuropathic pain is common, affecting almost 1 in 10 people and causes include neuropathy due to diabetes or chemotherapy treatment and traumatic injury to the nerves for instance phantom limb pain. Unfortunately, current treatments are ineffective and can have significant side effects for instance the addictive potential of strong opioids. Our over-arching aim is to understand the neural circuits driving neuropathic pain and to develop means to suppress aberrant activity in these circuits in order to inform new treatment approaches in neuropathic pain.

Our focus will be the primary sensory neurons which are those neurons designed to detect sensory stimuli applied to the body (such as the skin) and transmit this information to the spinal cord. These neurons can be broadly classified into low threshold mechanoreceptors which respond to brushing the skin or skin indentation/stretch, thermoceptors responding to warmth or cooling and nociceptors which respond to stimuli which could cause injury such as extremes of temperature/mechanical pressure or chemicals such as acid. These neurons have distinct termination patterns (within their innervation targets and spinal cord) and gene expression profiles. After injury sensory neurons develop hyper-excitability including enhanced responses to stimulation and the development of spontaneous activity (action potentials generated in the absence of a stimulus). This represents an important treatment target however we need to understand exactly which sensory neurons are driving specific features of neuropathic pain. We can then target them selectively in order to treat neuropathic pain whilst not impairing other important aspects of neural function such as movement or useful sensations such as thermoception or pleasant touch.

In order to understand which sensory neuron sub-types drive neuropathic pain we will use new technologies to control their activity and in particular 'chemogenetics' in which we express a modified receptor gene in a desired specific sensory neuron sub-type in mice using viruses or transgenic techniques. This receptor can then be activated by a non-toxic chemical to reversibly silence these neurons. We will use this to 'switch off' specific sensory neuron sub-populations and determine how these neurons contribute to specific aspects of neuropathic pain related behaviour such as brush evoked allodynia or assays of spontaneous pain. Once we have identified the key sensory neuron populations driving neuropathic pain we will investigate the pathophysiological changes specifically within these neurons for instance: defining the gene expression changes evoked by nerve injury that result in neuronal hyper-excitability and understanding how activity in these neurons impacts on spinal cord circuits. We hope to identify molecules/pathophysiological changes specific to these sub-populations in order to enhance the precision of treatment. Finally we will explore the translational potential of using this chemogenetic approach as a treatment for neuropathic pain. We will compare the sensory neuron sub-populations that we have identified in mouse to human DRG, information that would be needed in the future to target these neurons. We will also test a newly developed fully humanised chemogenetic system in both animal models and also human cellular models of neuropathic pain. This will therefore not only be informative regarding the critical circuit changes which drive neuropathic pain but also provide proof of concept that a chemogenetic gene therapy approach could be applied to neuropathic pain patients.

Neuropathic pain arises as a consequence of a lesion or disease of the somatosensory nervous system. It is common, affecting circa 8% of the general population. Unfortunately, current treatments are inadequate due to both poor efficacy and tolerability. We will focus on hyper-excitability in primary sensory neurons as a target because this has been shown to be critical in the maintenance of neuropathic pain. Indiscriminate nerve fibre conduction blockade (for instance with local anaesthetic) is not clinically viable due to its non-specific nature and other safety concerns. Importantly, sensory neurons consist of heterogenous sub-populations categorised by molecular profile, connectivity and stimulus-response function. We will determine which sensory neuron sub-populations are critical in the development and maintenance of neuropathic pain in order to develop means to suppress aberrant activity in these circuits. We will use chemogenetic technologies to reversibly silence specific sensory neuron sub-populations following induction of traumatic or chemotherapy induced painful neuropathy in mice. We will determine how these sub-populations contribute to specific aspects of neuropathic pain related behaviour such as brush evoked allodynia versus assays of spontaneous pain. We will investigate the pathophysiological changes such as transcriptional dysregulation and altered connectivity to dorsal horn neurons within these sub-populations in order to enhance the precision of treatment. To assess the translational potential of this chemogenetic approach we will compare the sensory neuron sub-populations that we have identified in mouse to human DRG and use a newly developed fully humanised chemogenetic system in both animal models and human iPSC derived sensory neurons. As an outcome we hope to have defined the critical circuit changes which drive neuropathic pain but also provide proof of concept that a chemogenetic approach could be applied to neuropathic pain patients.

Impact for patients, healthcare and society: Patients and wider society may benefit from these outputs. Chronic pain affects 1 in 5 Europeans with a major negative effect on quality of life and function at work. In the USA the total costs associated with persistent pain in adults, is now estimated at $560-635 billion. These costs are reported to exceed those estimated for heart disease, cancer and diabetes. Unfortunately, in the majority of patients chronic pain remains inadequately treated due to both poor efficacy and tolerability of current analgesics. Poor treatment response is especially true of neuropathic pain (which affects 8% of the general population). The current opioid crisis in which excessive prescribing in the context of chronic pain has led to substance misuse and lasting harm illustrating these problems. Understanding the pathological processes underlying pain is the first step in developing new therapeutics and we will provide proof of concept that gene therapy based on chemogenetics could be an effective non-addictive treatment for neuropathic pain. These advances would not only ameliorate suffering at an individual patient level but would benefit health services and the economy.

Impact for the pharmaceutical industry and biotechnology: Chronic pain is a very large drug market given the prevalence of the condition (which is increasing). Astra Zeneca, Biogen, Lilly, Pfizer and GSK have ongoing programmes relating to chronic pain. Many smaller biotechnology companies and SMEs also have interests in pain and neurobiology and are exploring the use of new therapeutic avenues including gene therapy. Identification of the sensory neuron sub-populations driving neuropathic pain will define exactly what neural circuits should be targeted therapeutically. Furthermore we will make transcriptional changes in these sub-sets publicly available so that if that is a molecule is identified as a drug target a searchable database will be used to determine which sensory neurons express the gene and how this changes after injury. We will also be developing methodologies that can facilitate the practice of analgesia development such as optimizing the latest outcome measures in animal models of pain as well as human cellular platforms for studying sensory neurons.

Impact for research scientists: Academic beneficiaries will include pain scientists, clinical scientists and neurobiologists. Understanding how different populations of sensory neurons respond to injury and identifying those that are critical drivers of neuropathic pain will provide fundamental insight into pain pathophysiology but will also act as a framework for the therapeutic targeting of these neurons. Our focus is pain but this research could generate knowledge which will be transferable to many other domains of neuroscience and especially disorders of hyper-excitability such as epilepsy. For instance we will be optimizing methodologies to reversible silence neurons as well as new human cellular models. We will make data such as gene expression changes publicly available (in an accessible format) in order to encourage its adoption by other researchers. We will also be providing post-doctoral research scientists with an excellent training environment which we hope will further their future careers in neuroscience.