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.