Defining the primary afferent circuitry that drives neuropathic pain

Lead Research Organisation: University of Oxford
Department Name: Clinical Neurosciences

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Dawes JM (2021) Addressing the gender pain gap. in Neuron

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Middleton SJ (2021) Studying human nociceptors: from fundamentals to clinic. in Brain : a journal of neurology

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Perez-Sanchez J (2022) Harnessing bacterial toxins to treat pain. in Nature neuroscience

 
Description MICA: Partnership for Assessment and Investigation of Neuropathic Pain: Studies Tracking Outcomes, Risks and Mechanisms (PAINSTORM).
Amount £3,620,191 (GBP)
Funding ID MR/W002388/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2021 
End 06/2025
 
Description The role of human ion channels and transporters in neuropathic pain
Amount £1,791,993 (GBP)
Funding ID 223149/Z/21/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2022 
End 04/2027
 
Description Colaboration with Hakan Olausson 
Organisation Linkoping University
Country Sweden 
Sector Academic/University 
PI Contribution We are interested in the role of C-low threshold mechanoreceptors in light touch but also in pathological conditions such as nerve injury. We have been collaborating on studying the contribution to human sensory perception using quantitative sensory testing and microneurography as well as animal models.
Collaborator Contribution Studying patients with loss of function mutations in Nav1.7 using QST as well as facial EMG.
Impact A paper accepted in Brain (PMID: 34957475) listed in the outputs section.
Start Year 2020
 
Description Faculty member for teh IASP/Heidelberg/Wellcome Pain consortium 'Pain School' 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact This was originally designed as a highly interactive summer school. Because of covid we delayed it until December and also we ultimately needed to deliver it online. I was lecturing on human pain channelopathies, I led a session on careers with R Kuner and N Finnerup and also chaired a session where the trainees presented. We discussed all aspects of pain and both preclinical and clinical approaches. This was well attended and feedback was positive despite the fact this was delivered online rather than in person.
Year(s) Of Engagement Activity 2021
 
Description New insights into neuropathic pain as part of the Brain conference, 5th March 2021 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact As part of 2021 Brain conference I presented data on the latest advances in neuropathic pain research especially pain channelopathies. This was followed by a question and answer session.
Year(s) Of Engagement Activity 2021
 
Description Plenary lecture to the annual meeting of the Canadian Pain Society 2021 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I gave a plenary lecture entitled 'Studying small neurons in the era of big data'. This was part of an online conference.
Year(s) Of Engagement Activity 2021
 
Description Presentation on the use of 'Big Data' to a pain workshop at the Academy of Medical Sciences aimed at improving development of new analgesics. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact This was a broad workshop organised by the Academy of Medical Sciences. The aim was to facilitate understanding of and develop new treatments for pain. It involved some lectures but also breakout session/workshop to discuss issues in the pain field. There were diverse participants which made for a very interactive discussion.
Year(s) Of Engagement Activity 2021