Publications by authors named "Stephen B McMahon"

158 Publications

The burden of musculoskeletal pain and the role of topical non-steroidal anti-inflammatory drugs (NSAIDs) in its treatment. Ten underpinning statements from a global pain faculty.

Curr Med Res Opin 2021 Feb 20;37(2):287-292. Epub 2020 Nov 20.

Department of Pharmacy and Pharmacology, University of Bath , Bath , UK.

This document presents the conclusions of a detailed discussion on the role of topical NSAIDs during a round table Global Pain Faculty meeting held in Amsterdam in 2019 and subsequent discussions online. The aim of this evidence-based document is to describe the impact of musculoskeletal pain both in terms of the large numbers of sufferers and its economic impact. The document considers the place of topical therapies alongside other pharmacological and non-pharmacological treatments and presents the evidence for the benefits and harms of topical NSAIDS including indicators of efficacy for three main topical NSAIDs- diclofenac, ibuprofen and ketoprofen - based on almost 15,000 participants in randomized controlled trials for acute and chronic musculoskeletal pain. These topical NSAIDs have the largest body of evidence. For acute pain, numbers needed to treat to achieve at least 50% reduction in pain are as follows with 95% confidence intervals in brackets: Diclofenac emulgel 1.8(1.5-2.1) (5170 participants), Ibuprofen gel 2.7 (1.7-4.2) (436 participants), Ketoprofen gel 2.2 (1.7-2.8) (683 participants). For chronic pain, the NNTs are Diclofenac any formulation 9.5(7-14) (5995 participants). Ketoprofen 6.9(5.5-9.3) (2573 participants). Randomized controlled trial evidence suggests that adverse events for active topical NSAIDs are similar to placebo. Finally the gaps in knowledge are considered with suggestions on how further research might help. The global pain faculty was brought together by GSK under an unrestricted educational grant.
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http://dx.doi.org/10.1080/03007995.2020.1847718DOI Listing
February 2021

The impact of paradigm and stringent analysis parameters on measuring a net conditioned pain modulation effect: A test, retest, control study.

Eur J Pain 2021 Feb 4;25(2):415-429. Epub 2020 Nov 4.

Central Modulation of Pain, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: Reporting in conditioned pain modulation (CPM) studies is not standardised. Here, two CPM protocols were performed in populations of healthy human subjects in order to investigate the influence of the CPM paradigm and stringent analyses parameters on the identification of a net CPM effect.

Methods: A standard thermal or mechanical CPM protocol was carried out on 25 and 17 subjects, respectively. The standard error of measurement (SEM) of the CPM effect was calculated in order to determine a change in pain thresholds greater than that due to measurement error or 'real' change in test scores. In addition, each individual underwent a minimum of two control CPM sessions, which were paired with the CPM test sessions. To quantify a net CPM effect, the intrasession difference between baseline and conditioning was subtracted from the difference calculated at the same time points during the control session.

Results: For both protocols, excellent reliability for intrasession repeats of the test stimulus at baseline was demonstrated for thermal and mechanical stimulation (ICC > 0.9). Test-retest subject responses (in terms of experimental Session 1 versus. Session 2) showed excellent reliability for mechanical (ICC > 0.8), compared to thermal stimulation, which ranged from poor to moderate (ICC < 0.4->0.75). However, calculating the net CPM effect using control session data demonstrated poor-fair reliability for both protocols (ICC < 0.4-0.59).

Conclusion: Calculating the net CPM effect should be optimised and standardised for comparison of CPM data collected from global research groups. Recommendation is made for the performance of a multicentre, test-retest study.
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http://dx.doi.org/10.1002/ejp.1681DOI Listing
February 2021

Linking Pain Sensation to the Autonomic Nervous System: The Role of the Anterior Cingulate and Periaqueductal Gray Resting-State Networks.

Front Neurosci 2020 27;14:147. Epub 2020 Feb 27.

Department of Neuroimaging, King's College London, London, United Kingdom.

There are bi-directional interactions between the autonomic nervous system (ANS) and pain. This is likely underpinned by a substantial overlap between brain areas of the central autonomic network and areas involved in pain processing and modulation. To date, however, relatively little is known about the neuronal substrates of the ANS-pain association. Here, we acquired resting state fMRI scans in 21 healthy subjects at rest and during tonic noxious cold stimulation. As indicators of autonomic function, we examined how heart rate variability (HRV) frequency measures were influenced by tonic noxious stimulation and how these variables related to participants' pain perception and to brain functional connectivity in regions known to play a role in both ANS regulation and pain perception, namely the right dorsal anterior cingulate cortex (dACC) and periaqueductal gray (PAG). Our findings support a role of the cardiac ANS in brain connectivity during pain, linking functional connections of the dACC and PAG with measurements of low frequency (LF)-HRV. In particular, we identified a three-way relationship between the ANS, cortical brain networks known to underpin pain processing, and participants' subjectively reported pain experiences. LF-HRV both at rest and during pain correlated with functional connectivity between the seed regions and other cortical areas including the right dorsolateral prefrontal cortex (dlPFC), left anterior insula (AI), and the precuneus. Our findings link cardiovascular autonomic parameters to brain activity changes involved in the elaboration of nociceptive information, thus beginning to elucidate underlying brain mechanisms associated with the reciprocal relationship between autonomic and pain-related systems.
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http://dx.doi.org/10.3389/fnins.2020.00147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527240PMC
February 2020

Noxious pressure stimulation demonstrates robust, reliable estimates of brain activity and self-reported pain.

Neuroimage 2020 11 22;221:117178. Epub 2020 Jul 22.

MRC Cognition and Brain Sciences Unit, University of Cambridge, UK.

Functional neuroimaging techniques have provided great insight in the field of pain. Utilising these techniques, we have characterised pain-induced responses in the brain and improved our understanding of key pain-related phenomena. Despite the utility of these methods, there remains a need to assess the test retest reliability of pain modulated blood-oxygen-level-dependant (BOLD) MR signal across repeated sessions. This is especially the case for more novel yet increasingly implemented stimulation modalities, such as noxious pressure, and it is acutely important for multi-session studies considering treatment efficacy. In the present investigation, BOLD signal responses were estimated for noxious-pressure stimulation in a group of healthy participants, across two separate sessions. Test retest reliability of functional magnetic resonance imaging (fMRI) data and self-reported visual analogue scale measures were determined by the intra-class correlation coefficient. High levels of reliability were observed in several key brain regions known to underpin the pain experience, including in the thalamus, insula, somatosensory cortices, and inferior frontal regions, alongside "excellent" reliability of self-reported pain measures. These data demonstrate that BOLD-fMRI derived signals are a valuable tool for quantifying noxious responses pertaining to pressure stimulation. We further recommend the implementation of pressure as a stimulation modality in experimental applications.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762811PMC
November 2020

The impact of bone cancer on the peripheral encoding of mechanical pressure stimuli.

Pain 2020 08 13;161(8):1894-1905. Epub 2020 Apr 13.

Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.

Skeletal metastases are frequently accompanied by chronic pain that is mechanoceptive in nature. Mechanistically, cancer-induced bone pain (CIBP) is mediated by peripheral sensory neurons innervating the cancerous site, the cell bodies of which are housed in the dorsal root ganglia (DRG). How these somatosensory neurons encode sensory information in CIBP remains only partly explained. Using a validated rat model, we first confirmed cortical bone destruction in CIBP but not sham-operated rats (day 14 after surgery, designated "late"-stage bone cancer). This occurred with behavioural mechanical hypersensitivity (Kruskal-Wallis H for independent samples; CIBP vs sham-operated, day 14; P < 0.0001). Next, hypothesising that the proportion and phenotype of primary afferents would be altered in the disease state, dorsal root ganglia in vivo imaging of genetically encoded calcium indicators and Markov Cluster Analysis were used to analyse 1748 late-stage CIBP (n = 10) and 757 sham-operated (n = 9), neurons. Distinct clusters of responses to peripheral stimuli were revealed. In CIBP rats, upon knee compression of the leg ipsilateral to the tumour, (1) 3 times as many sensory afferents responded (repeated-measures analysis of variance: P < 0.0001 [vs sham]); (2) there were significantly more small neurons responding (Kruskal-Wallis for independent samples (vs sham): P < 0.0001); and (3) approximately 13% of traced tibial cavity afferents responded (no difference observed between CIBP and sham-operated animals). We conclude that an increased sensory afferent response is present in CIBP rats, and this is likely to reflect afferent recruitment from outside of the bone rather than increased intraosseous afferent activity.
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http://dx.doi.org/10.1097/j.pain.0000000000001880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365668PMC
August 2020

Sustained perturbation in functional connectivity induced by cold pain.

Eur J Pain 2020 10 27;24(9):1850-1861. Epub 2020 Jul 27.

Department of Neuroimaging, King's College London, London, UK.

Background: Functional connectivity (FC) perturbations have been reported in multiple chronic pain phenotypes, but the nature of reported changes varies between cohorts and may relate to the consequences of living with chronic-pain related comorbidities, such as anxiety and depression. Healthy volunteer studies provide opportunities to study the effects of tonic noxious stimulation independently of these sequelae. Connectivity changes in task negative and positive networks, for example, the default mode and salience networks (DMN/SN), respectively, have been described, but how these and other connectivity networks, for example, those governing descending pain control are affected by the presence of tonic, noxious stimulation in healthy, pain-free individuals, remains unknown.

Method: In 20 healthy volunteers, we assessed FC prior to, during, and following tonic cold painful stimulation in the ventromedial prefrontal cortex (vmPFC), rostral anterior insula (rAI), subgenual anterior cingulate cortex (ACC) and periaqueductal grey (PAG). We also recorded subjectively reported pain using a computerised visual analogue scale.

Results: We saw DMN FC changes during painful stimulation and that inter-network connectivity between the rAI with the vmPFC increased during pain, whereas PAG-precuneus FC decreased. Pain-induced FC alterations persisted following noxious stimulation. FC changes related to the magnitude of individuals' subjectively reported pain.

Conclusions: We demonstrate FC changes during and following tonic cold-pain in healthy participants. Similarities between our findings and reports of patients with chronic pain suggest that some FC changes observed in these patients may relate to the presence of an ongoing afferent nociceptive drive.

Significance: How pain-related resting state networks are affected by tonic cold-pain remains unknown. We investigated functional connectivity alterations during and following tonic cold pain in healthy volunteers. Cold pain perturbed the functional connectivity of the ventro-medial prefrontal cortex, anterior insula, and the periacquaductal grey area. These connectivity changes were associated with the magnitude of individuals' reported pain. We suggest that some connectivity changes described in chronic pain patients may be due to an ongoing afferent peripheral drive.
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http://dx.doi.org/10.1002/ejp.1633DOI Listing
October 2020

Cortical Mechanisms of Single-Pulse Transcranial Magnetic Stimulation in Migraine.

Neurotherapeutics 2020 10;17(4):1973-1987

Headache Research-Wolfson CARD, Guy's Campus, King's College London, London, UK.

Single-pulse transcranial magnetic stimulation (sTMS) of the occipital cortex is an effective migraine treatment. However, its mechanism of action and cortical effects of sTMS in migraine are yet to be elucidated. Using calcium imaging and GCaMP-expressing mice, sTMS did not depolarise neurons and had no effect on vascular tone. Pre-treatment with sTMS, however, significantly affected some characteristics of the cortical spreading depression (CSD) wave, the correlate of migraine aura. sTMS inhibited spontaneous neuronal firing in the visual cortex in a dose-dependent manner and attenuated L-glutamate-evoked firing, but not in the presence of GABA antagonists. In the CSD model, sTMS increased the CSD electrical threshold, but not in the presence of GABA antagonists. We first report here that sTMS at intensities similar to those used in the treatment of migraine, unlike traditional sTMS applied in other neurological fields, does not excite cortical neurons but it reduces spontaneous cortical neuronal activity and suppresses the migraine aura biological substrate, potentially by interacting with GABAergic circuits.
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http://dx.doi.org/10.1007/s13311-020-00879-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851313PMC
October 2020

Quantitative Proteomic Analysis of the Central Amygdala in Neuropathic Pain Model Rats.

J Proteome Res 2020 04 3;19(4):1592-1619. Epub 2020 Mar 3.

Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, U.K.

Pain and emotional distress have a reciprocal relation. The amygdala has been implicated in emotional processing. The central nucleus of the amygdala (CeA) receives nociceptive information from the dorsal horn of spinal cord and is responsible for the central plasticity in chronic pain. Neuropathic pain is a type of severe chronic pain and can be strongly influenced by emotional components. Plastic changes in the CeA may play a key role in the development or maintenance or both of neuropathic pain. We studied the expression levels of proteins in the CeA of spinal nerve transection (SNT) model rats. Total tissue lysate proteins were separated by two-dimensional-gel electrophoresis (2D-PAGE). Gels from different time points were compared using Progenesis SameSpot software, and the spots with Fold Change greater than 2 were excised for protein identification by mass spectrometry. We identified more than 50 cytosolic proteins as significantly altered in their expression levels in the CeA of SNT rats, and most of these changes have been validated at mRNA levels by qRT-PCR. We also identified more than 40 membrane proteins as notably up- or down-regulated in the CeA of SNT model rats relative to a control using stable isotope dimethyl labeling nano-LC-MS/MS based proteomics and found that one such protein, doublecortin (DCX), a microtubule-associated protein expressed by neuronal precursor cells during development, is specifically localized in the membrane fraction without changes in total amount of the protein. Immunohistochemistry showed that doublecortin is expressed in processes in the CeA of rats 7 and 21 days after SNT surgery, suggesting that doublecortin is one of the proteins that may contribute to the plastic changes, namely, redevelopment or rewiring of neural networks, in the CeA in the neuropathic pain model. These dysregulated proteins may play roles in reciprocal relationships between pain and psychological distress in the amygdala and contribute to central sensitization. Data are available via ProteomeXchange with identifier PXD017473.
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http://dx.doi.org/10.1021/acs.jproteome.9b00805DOI Listing
April 2020

Granulocyte-Macrophage Colony Stimulating Factor As an Indirect Mediator of Nociceptor Activation and Pain.

J Neurosci 2020 03 4;40(11):2189-2199. Epub 2020 Feb 4.

Neurorestoration group, Wolfson Centre for Age-Related Diseases, King's College London, London, SE1 1UL, United Kingdom.

The interaction between the immune system and the nervous system has been at the center of multiple research studies in recent years. Whereas the role played by cytokines as neuronal mediators is no longer contested, the mechanisms by which cytokines modulate pain processing remain to be elucidated. In this study, we have analyzed the involvement of granulocyte-macrophage colony stimulating factor (GM-CSF) in nociceptor activation in male and female mice. Previous studies have suggested GM-CSF might directly activate neurons. However, here we established the absence of a functional GM-CSF receptor in murine nociceptors, and suggest an indirect mechanism of action, via immune cells. We report that GM-CSF applied directly to magnetically purified nociceptors does not induce any transcriptional changes in nociceptive genes. In contrast, conditioned medium from GM-CSF-treated murine macrophages was able to drive nociceptor transcription. We also found that conditioned medium from nociceptors treated with the well established pain mediator, nerve growth factor, could also modify macrophage gene transcription, providing further evidence for a bidirectional crosstalk. The interaction of the immune system and the nervous system is known to play an important role in the development and maintenance of chronic pain disorders. Elucidating the mechanisms of these interactions is an important step toward understanding, and therefore treating, chronic pain disorders. This study provides evidence for a two-way crosstalk between macrophages and nociceptors in the peripheral nervous system, which may contribute to the sensitization of nociceptors by cytokines in pain development.
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http://dx.doi.org/10.1523/JNEUROSCI.2268-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083288PMC
March 2020

Methodology for quantifying excitability of identified projection neurons in the dorsal horn of the spinal cord, specifically to study spinal cord stimulation paradigms.

J Neurosci Methods 2020 01 6;330:108479. Epub 2019 Nov 6.

King's College London, Wolfson CARD, London, United Kingdom. Electronic address:

Background: Using in and ex vivo preparations, electrophysiological methods help understand the excitability of biological tissue, particularly neurons, by providing microsecond temporal resolution. However, for in vivo recordings, in the context of extracellular recordings, it is often unclear precisely which type of neuron the tip of the electrode is recording from. This is particularly true in the densely-populated central nervous system, such as the spinal cord dorsal horn at both superficial and deep levels.

New Method: Here, we present a detailed protocol for the identification of superficial dorsal horn spinal cord neurons that receive peripheral input and project to the brain, using multiple surgical laminectomies and the careful placement of electrodes. Once a superficial projection unit was found, quantification to electrical peripheral stimulation was performed using a Matlab algorithm to form a template of projection neuron response to controlled C2 stimulation and accurately match this to the responses from peripheral stimulation.

Results: These superficial spinal projection neurons are normally activated by noxious peripheral stimuli, so we adopted a well-characterised wind-up protocol to obtain a neuronal excitability profile. Once achieved, this protocol allows for testing specific interventions, either pharmacological or neuromodulatory (e.g., spinal cord stimulation) to see how these affect the neuron's excitability. This preparation is robust and allows the accurate tracking of a projection neuron for over 3-h.

Comparison With Existing Method(s): Currently, most existing methods record from dorsal horn neurons that are often profiled based on their excitability to different peripherally-applied sensory modalities. While this is well-established, it fails to discriminate between interneurons and projection neurons, which is important as these two populations signal via distinctly different neuronal networks. Using the approach detailed here will result in studies with improved mechanistic understanding of the signal integration and processing that occurs in the superficial dorsal horn.

Conclusions: The refinements detailed in this protocol allow for more comprehensive studies to be carried out that will help understand spinal plasticity, in addition to many considerations for isolating the relevant neuronal population when performing in vivo electrophysiology.
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http://dx.doi.org/10.1016/j.jneumeth.2019.108479DOI Listing
January 2020

Noncanonical Ion Channel Behaviour in Pain.

Int J Mol Sci 2019 Sep 15;20(18). Epub 2019 Sep 15.

Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.

Ion channels contribute fundamental properties to cell membranes. Although highly diverse in conductivity, structure, location, and function, many of them can be regulated by common mechanisms, such as voltage or (de-)phosphorylation. Primarily considering ion channels involved in the nociceptive system, this review covers more novel and less known features. Accordingly, we outline noncanonical operation of voltage-gated sodium, potassium, transient receptor potential (TRP), and hyperpolarization-activated cyclic nucleotide (HCN)-gated channels. Noncanonical features discussed include properties as a memory for prior voltage and chemical exposure, alternative ion conduction pathways, cluster formation, and silent subunits. Complementary to this main focus, the intention is also to transfer knowledge between fields, which become inevitably more separate due to their size.
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http://dx.doi.org/10.3390/ijms20184572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770626PMC
September 2019

The role of Na channels in synaptic transmission after axotomy in a microfluidic culture platform.

Sci Rep 2019 09 9;9(1):12915. Epub 2019 Sep 9.

Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, SE1 1UL, United Kingdom.

Voltage gated sodium channels are key players in aberrant pain signaling and sensitization of nociceptors after peripheral nerve injury. The extent to which sodium channel activity after injury contributes to synaptic transmission at the first pain synapse however remains unclear. To investigate the effect of axotomy on synaptic transmission between dorsal root ganglia neurons and dorsal horn neurons, we reconstructed the first pain synapse in a novel microfluidic based compartmentalized cell culture system, which recapitulates the connectivity of peripheral pain signaling. We show that following axotomy of the distal axons, inhibition of Na1.7 and Na1.8 sodium channels in incoming presynaptic DRG axons is no longer sufficient to block activation of these axons and the resulting synaptic transmission to dorsal horn neurons. We found that blockade of Na1.6 activity is highly effective in reducing activation of incoming axons contributing to synaptic transmission after axotomy of DRG neurons. The microfluidic culture system described here offers an in vitro platform to recapitulate and study the first pain synapse.
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http://dx.doi.org/10.1038/s41598-019-49214-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733904PMC
September 2019

A refinement to the formalin test in mice.

F1000Res 2019 20;8:891. Epub 2019 Jun 20.

Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London SE1 1UL, London, UK.

The constant refinement of tests used in animal research is crucial for the scientific community. This is particularly true for the field of pain research, where ethical standards are notably sensitive. The formalin test is widely used in pain research and some of its mechanisms resemble those underlying clinical pain in humans. Immediately upon injection, formalin triggers two waves (an early and a late phase) of strong, nociceptive behaviour, characterised by licking, biting, lifting and shaking the injected paw of the animal. Although well characterised at the behaviour level, since its proposal over four decades ago, there has not been any significant refinement to the formalin test, especially those combining minimisation of animal distress and preservation of behavioural outcomes of the test.  Here, we propose a modified and improved method for the formalin test. We show that anaesthetising the animal with the inhalable anaesthetic sevoflurane at the time of the injection can produce reliable, robust and reproducible results whilst animal distress during the initial phase is reduced. Importantly, our results were validated by pharmacological suppression of the behaviour during the late phase of the test with gabapentin, the anaesthetic showing no interference with the drug. In addition, we demonstrate that this is also a useful method to screen for changes in pain behaviour in response to formalin in transgenic lines.
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http://dx.doi.org/10.12688/f1000research.18338.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707399PMC
June 2020

An ATF3-CreERT2 Knock-In Mouse for Axotomy-Induced Genetic Editing: Proof of Principle.

eNeuro 2019 Mar-Apr;6(2). Epub 2019 Apr 9.

International Collaboration on Repair Discoveries, the University of British Columbia, Vancouver, British Columbia, Canada V5Z 1M9.

Genome editing techniques have facilitated significant advances in our understanding of fundamental biological processes, and the Cre-Lox system has been instrumental in these achievements. Driving Cre expression specifically in injured neurons has not been previously possible: we sought to address this limitation in mice using a Cre-ERT2 construct driven by a reliable indicator of axotomy, activating transcription factor 3 (ATF3). When crossed with reporter mice, a significant amount of recombination was achieved (without tamoxifen treatment) in peripherally-projecting sensory, sympathetic, and motoneurons after peripheral nerve crush in hemizygotes (65-80% by 16 d) and was absent in uninjured neurons. Importantly, injury-induced recombination did not occur in Schwann cells distal to the injury, and with a knock-out-validated antibody we verified an absence of ATF3 expression. Functional recovery following sciatic nerve crush in ATF3-deficient mice (both hemizygotes and homozygotes) was delayed, indicating previously unreported haploinsufficiency. In a proof-of-principle experiment, we crossed the ATF3-CreERT2 line with a floxed phosphatase and tensin homolog (PTEN) line and show significantly improved axonal regeneration, as well as more complete recovery of neuromuscular function. We also demonstrate the utility of the ATF3-CreERT2 hemizygous line by characterizing recombination after lateral spinal hemisection (C8/T1), which identified specific populations of ascending spinal cord neurons (including putative spinothalamic and spinocerebellar) and descending supraspinal neurons (rubrospinal, vestibulospinal, reticulospinal and hypothalamic). We anticipate these mice will be valuable in distinguishing axotomized from uninjured neurons of several different classes (e.g., via reporter expression), and in probing the function of any number of genes as they relate to neuronal injury and regeneration.
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http://dx.doi.org/10.1523/ENEURO.0025-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464513PMC
February 2020

Disruption of the Sensory System Affects Sterile Cutaneous Inflammation In Vivo.

J Invest Dermatol 2019 09 8;139(9):1936-1945.e3. Epub 2019 Apr 8.

Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.

Increasing evidence suggests that nerve fibers responding to noxious stimuli (nociceptors) modulate immunity in a variety of tissues, including the skin. Yet, the role of nociceptors in regulating sterile cutaneous inflammation remains unexplored. To address this question, we have developed a detailed description of the sterile inflammation caused by overexposure to UVB irradiation (i.e., sunburn) in the mouse plantar skin. Using this model, we observed that chemical depletion of nociceptor terminals did not alter the early phase of the inflammatory response to UVB, but it caused a significant increase in the number of dendritic cells and αβ T cells as well as enhanced extravasation during the later stages of inflammation. Finally, we showed that such regulation was driven by the nociceptive neuropeptide calcitonin gene-related peptide. In conclusion, we propose that nociceptors not only play a crucial role in inflammation through avoidance reflexes and behaviors, but can also regulate sterile cutaneous immunity in vivo.
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http://dx.doi.org/10.1016/j.jid.2019.01.037DOI Listing
September 2019

Prospective comparative study of the effects of lidocaine on urodynamic and sensory parameters in bladder pain syndrome.

Int Urogynecol J 2019 08 14;30(8):1293-1301. Epub 2019 Mar 14.

Department of Urogynaecology, Cork University Maternity Hospital, Wilton, Co. Cork, Ireland.

Introduction And Hypothesis: Intravesically administered lidocaine is used in patients with bladder pain syndrome (BPS) to test the hypothesis that symptoms have a peripheral versus central mechanism.

Methods: A cross-sectional study of 24 female patients with BPS was performed. The Central Sensitisation Inventory (CSI) and Kings Health Questionnaire (KHQ) were completed. Urodynamic assessment was undertaken. Women were asked to report their pain using a numeric rating scale at cystometric capacity and post void. Participants then received an intravesical instillation of either 20 ml of 2% alkalinised lidocaine (n = 16) or 20 ml of normal saline (n = 8). These solutions were allowed to remain in situ for 20 min and pain score repeated. Urodynamics was repeated.

Results: There was a statistically significant volume increase following lidocaine treatment: maximal cystometric capacity (MCC) 192-261 ml post lidocaine (p = 0.005.) In contrast, there was no significant difference in the saline controls: MCC 190-183 ml (p = 0.879.) Individual analysis revealed five of 16 lidocaine participants did not respond to lidocaine. These five reported a significantly worse quality of life (QoL) than lidocaine responders and had a tendency towards central sensitivity syndromes.

Conclusion: Lidocaine significantly improved MCC in 11/16 participants in this study. These patients appear to have peripherally mediated disease. However, the failure of response to treatment in five participants, as well as their tendency towards central sensitivity syndromes, implies that in this subgroup, a peripheral drive from the bladder is not critical to their pain, suggesting central nervous system (CNS) pathology. This simple and safe test could be used to stratify patients for research or therapeutic trials.
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http://dx.doi.org/10.1007/s00192-019-03892-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647211PMC
August 2019

On-target and off-target effects of novel orthosteric and allosteric activators of GPR84.

Sci Rep 2019 02 12;9(1):1861. Epub 2019 Feb 12.

Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, University of Glasgow, Glasgow, G12 8QQ, United Kingdom.

Many members of the G protein-coupled receptor family, including examples with clear therapeutic potential, remain poorly characterised. This often reflects limited availability of suitable tool ligands with which to interrogate receptor function. In the case of GPR84, currently a target for the treatment of idiopathic pulmonary fibrosis, recent times have seen the description of novel orthosteric and allosteric agonists. Using 2-(hexylthiol)pyrimidine-4,6 diol (2-HTP) and di(5,7-difluoro-1H-indole-3-yl)methane (PSB-16671) as exemplars of each class, in cell lines transfected to express either human or mouse GPR84, both ligands acted as effective on-target activators and with high co-operativity in their interactions. This was also the case in lipopolysaccharide-activated model human and mouse immune cell lines. However in mouse bone-marrow-derived neutrophils, where expression of GPR84 is particularly high, the capacity of PSB-16671 but not of 2-HTP to promote G protein activation was predominantly off-target because it was not blocked by an antagonist of GPR84 and was preserved in neutrophils isolated from GPR84 deficient mice. These results illustrate the challenges of attempting to study and define functions of poorly characterised receptors using ligands that have been developed via medicinal chemistry programmes, but where assessed activity has been limited largely to the initially identified target.
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http://dx.doi.org/10.1038/s41598-019-38539-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372602PMC
February 2019

Stroke Recovery in Rats after 24-Hour-Delayed Intramuscular Neurotrophin-3 Infusion.

Ann Neurol 2019 01 28;85(1):32-46. Epub 2018 Dec 28.

Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.

Objective: Neurotrophin-3 (NT3) plays a key role in the development and function of locomotor circuits including descending serotonergic and corticospinal tract axons and afferents from muscle and skin. We have previously shown that gene therapy delivery of human NT3 into affected forelimb muscles improves sensorimotor recovery after stroke in adult and elderly rats. Here, to move toward the clinic, we tested the hypothesis that intramuscular infusion of NT3 protein could improve sensorimotor recovery after stroke.

Methods: Rats received unilateral ischemic stroke in sensorimotor cortex. To simulate a clinically feasible time to treatment, 24 hours later rats were randomized to receive NT3 or vehicle by infusion into affected triceps brachii for 4 weeks using implanted catheters and minipumps.

Results: Radiolabeled NT3 crossed from the bloodstream into the brain and spinal cord in rodents with or without strokes. NT3 increased the accuracy of forelimb placement during walking on a horizontal ladder and increased use of the affected arm for lateral support during rearing. NT3 also reversed sensory impairment of the affected wrist. Functional magnetic resonance imaging during stimulation of the affected wrist showed spontaneous recovery of peri-infarct blood oxygenation level-dependent signal that NT3 did not further enhance. Rather, NT3 induced neuroplasticity of the spared corticospinal and serotonergic pathways.

Interpretation: Our results show that delayed, peripheral infusion of NT3 can improve sensorimotor function after ischemic stroke. Phase I and II clinical trials of NT3 (for constipation and neuropathy) have shown that peripheral high doses are safe and well tolerated, which paves the way for NT3 as a therapy for stroke. ANN NEUROL 2019;85:32-46.
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http://dx.doi.org/10.1002/ana.25386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492080PMC
January 2019

Comprehensive analysis of long noncoding RNA expression in dorsal root ganglion reveals cell-type specificity and dysregulation after nerve injury.

Pain 2019 Feb;160(2):463-485

Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.

Dorsal root ganglion (DRG) neurons provide connectivity between peripheral tissues and the spinal cord. Transcriptional plasticity within DRG sensory neurons after peripheral nerve injury contributes to nerve repair but also leads to maladaptive plasticity, including the development of neuropathic pain. This study presents tissue and neuron-specific expression profiling of both known and novel long noncoding RNAs (LncRNAs) in the rodent DRG after nerve injury. We have identified a large number of novel LncRNAs expressed within the rodent DRG, a minority of which were syntenically conserved between the mouse, rat, and human, and including, both intergenic and antisense LncRNAs. We have also identified neuron type-specific LncRNAs in the mouse DRG and LncRNAs that are expressed in human IPS cell-derived sensory neurons. We show significant plasticity in LncRNA expression after nerve injury, which in mice is strain and gender dependent. This resource is publicly available and will aid future studies of DRG neuron identity and the transcriptional landscape in both the naive and injured DRG. We present our work regarding novel antisense and intergenic LncRNAs as an online searchable database, accessible from PainNetworks (http://www.painnetworks.org/). We have also integrated all annotated gene expression data in PainNetworks, so they can be examined in the context of their protein interactions.
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http://dx.doi.org/10.1097/j.pain.0000000000001416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343954PMC
February 2019

Neuromodulation in the restoration of function after spinal cord injury.

Lancet Neurol 2018 10 18;17(10):905-917. Epub 2018 Sep 18.

Regeneration Group, Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, Guy's Campus, King's College London, London, UK. Electronic address:

Neuromodulation, the use of electrical interfaces to alter neuronal activity, has been successful as a treatment approach in several neurological disorders, including deep brain stimulation for Parkinson's disease and epidural spinal stimulation for chronic pain. Neuromodulation can also be beneficial for spinal cord injury, from assisting basic functions such as respiratory pacing and bladder control, through to restoring volitional movements and skilled hand function. Approaches range from electrical stimulation of peripheral muscles, either directly or via brain-controlled bypass devices, to stimulation of the spinal cord and brain. Limitations to widespread clinical application include durability of neuromodulation devices, affordability and accessibility of some approaches, and poor understanding of the underlying mechanisms. Efforts to overcome these challenges through advances in technology, together with pragmatic knowledge gained from clinical trials and basic research, could lead to personalised neuromodulatory interventions to meet the specific needs of individuals with spinal cord injury.
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http://dx.doi.org/10.1016/S1474-4422(18)30287-4DOI Listing
October 2018

Mice lacking Kcns1 in peripheral neurons show increased basal and neuropathic pain sensitivity.

Pain 2018 Aug;159(8):1641-1651

Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.

Voltage-gated potassium (Kv) channels are increasingly recognised as key regulators of nociceptive excitability. Kcns1 is one of the first potassium channels to be associated with neuronal hyperexcitability and mechanical sensitivity in the rat, as well as pain intensity and risk of developing chronic pain in humans. Here, we show that in mice, Kcns1 is predominantly expressed in the cell body and axons of myelinated sensory neurons positive for neurofilament-200, including Aδ-fiber nociceptors and low-threshold Aβ mechanoreceptors. In the spinal cord, Kcns1 was detected in laminae III to V of the dorsal horn where most sensory A fibers terminate, as well as large motoneurons of the ventral horn. To investigate Kcns1 function specifically in the periphery, we generated transgenic mice in which the gene is deleted in all sensory neurons but retained in the central nervous system. Kcns1 ablation resulted in a modest increase in basal mechanical pain, with no change in thermal pain processing. After neuropathic injury, Kcns1 KO mice exhibited exaggerated mechanical pain responses and hypersensitivity to both noxious and innocuous cold, consistent with increased A-fiber activity. Interestingly, Kcns1 deletion also improved locomotor performance in the rotarod test, indicative of augmented proprioceptive signalling. Our results suggest that restoring Kcns1 function in the periphery may be of some use in ameliorating mechanical and cold pain in chronic states.
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http://dx.doi.org/10.1097/j.pain.0000000000001255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053330PMC
August 2018

Large Scale Recording of Sensory Neuron Activity with GCaMP6.

eNeuro 2018 Jan-Feb;5(1). Epub 2018 Apr 6.

Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, United Kingdom.

Greater emphasis on the study of intact cellular networks in their physiological environment has led to rapid advances in intravital imaging of the central nervous system (CNS), while the peripheral system remains largely unexplored. To assess large networks of sensory neurons, we selectively label primary afferents with GCaMP6s in male and female C57bl/6 mice and visualize their functional responses to peripheral stimulation . We show that we are able to monitor the activity of hundreds of sensory neurons simultaneously, with sufficient sensitivity to detect, in most cases, single action potentials with a typical rise time of around 200 ms, and an exponential decay with a time constant of approximately 700 ms. With this technique we are able to characterize the responses of large populations of sensory neurons to innocuous and noxious mechanical and thermal stimuli under normal and inflammatory conditions. We demonstrate that the majority of primary afferents are polymodal with between 50-80% of thermally sensitive DRG neurons responding also to noxious mechanical stimulation. We also specifically assess the small population of peripheral cold neurons and demonstrate significant sensitization to cooling after a model of sterile and persistent inflammation, with significantly increased sensitivity already at decreases of 5°C when compared to uninflamed responses. This not only reveals interesting new insights into the (patho)physiology of the peripheral nervous system but also demonstrates the sensitivity of this imaging technique to physiological changes in primary afferents.
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http://dx.doi.org/10.1523/ENEURO.0417-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898788PMC
January 2019

Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability.

Neuron 2018 02 8;97(4):806-822.e10. Epub 2018 Feb 8.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK. Electronic address:

Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2 mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability.
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http://dx.doi.org/10.1016/j.neuron.2018.01.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011627PMC
February 2018

Immune Cytokines and Their Receptors in Inflammatory Pain.

Trends Immunol 2018 03 12;39(3):240-255. Epub 2018 Jan 12.

University of Melbourne, Department of Medicine at Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. Electronic address:

There is burgeoning interest in the interaction between the immune and nervous systems. Pain is mediated by primary sensory neurons (nociceptors) that can respond to a variety of thermal, mechanical and chemical signals. Cytokines are now recognized as important mediators of inflammatory pain. They can induce nociceptor sensitization indirectly via mediators, wherein neurons become primed and thus become more responsive to stimulation; alternatively, there is also evidence that cytokines can directly activate neurons via their specific receptors present on the neuronal cells. We review here the evidence for and against these respective mechanisms, focusing on arthritis and inflammatory skin models. A number of striking inconsistencies amongst the conclusions made in the literature are highlighted and discussed.
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http://dx.doi.org/10.1016/j.it.2017.12.003DOI Listing
March 2018

Sex differences in peripheral not central immune responses to pain-inducing injury.

Sci Rep 2017 11 28;7(1):16460. Epub 2017 Nov 28.

King's College London, London, United Kingdom.

Women suffer chronic pain more frequently than men. It is not clear whether this is due to differences in higher level cognitive processes or basic nociceptive responses. In this study we used a mouse model of neuropathic pain to dissociate these factors. We performed RNA-seq on purified peripheral afferent neurons, but found no striking differences in gene expression between male and female mice, neither before nor after nerve injury. Similarly, spinal cord immune responses between the sexes appeared to be indistinguishable when studied by flow cytometry or qRT-PCR. Differences emerged only upon studying peripheral immune cell infiltration into the dorsal root ganglion, suggesting that adaptive immune responses in neuropathic pain could be sexually dimorphic.
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http://dx.doi.org/10.1038/s41598-017-16664-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705679PMC
November 2017

The Molecular Fingerprint of Dorsal Root and Trigeminal Ganglion Neurons.

Front Mol Neurosci 2017 26;10:304. Epub 2017 Sep 26.

Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.

The dorsal root ganglia (DRG) and trigeminal ganglia (TG) are clusters of cell bodies of highly specialized sensory neurons which are responsible for relaying information about our environment to the central nervous system. Despite previous efforts to characterize sensory neurons at the molecular level, it is still unknown whether those present in DRG and TG have distinct expression profiles and therefore a unique molecular fingerprint. To address this question, we isolated lumbar DRG and TG neurons using fluorescence-activated cell sorting from Advillin-GFP transgenic mice and performed RNA sequencing. Our transcriptome analyses showed that, despite being overwhelmingly similar, a number of genes are differentially expressed in DRG and TG neurons. Importantly, we identified 24 genes which were uniquely expressed in either ganglia, including an arginine vasopressin receptor and several homeobox genes, giving each population a distinct molecular fingerprint. We compared our findings with published studies to reveal that many genes previously reported to be present in neurons are in fact likely to originate from other cell types in the ganglia. Additionally, our neuron-specific results aligned well with a dataset examining whole human TG and DRG. We propose that the data can both improve our understanding of primary afferent biology and help contribute to the development of drug treatments and gene therapies which seek targets with unique or restricted expression patterns.
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http://dx.doi.org/10.3389/fnmol.2017.00304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623188PMC
September 2017

Using an engineered glutamate-gated chloride channel to silence sensory neurons and treat neuropathic pain at the source.

Brain 2017 10;140(10):2570-2585

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

See Basbaum (doi:10.1093/brain/awx227) for a scientific commentary on this article. Peripheral neuropathic pain arises as a consequence of injury to sensory neurons; the development of ectopic activity in these neurons is thought to be critical for the induction and maintenance of such pain. Local anaesthetics and anti-epileptic drugs can suppress hyperexcitability; however, these drugs are complicated by unwanted effects on motor, central nervous system and cardiac function, and alternative more selective treatments to suppress hyperexcitability are therefore required. Here we show that a glutamate-gated chloride channel modified to be activated by low doses of ivermectin (but not glutamate) is highly effective in silencing sensory neurons and reversing neuropathic pain-related hypersensitivity. Activation of the glutamate-gated chloride channel expressed in either rodent or human induced pluripotent stem cell-derived sensory neurons in vitro potently inhibited their response to both electrical and algogenic stimuli. We have shown that silencing is achieved both at nerve terminals and the soma and is independent of membrane hyperpolarization and instead likely mediated by lowering of the membrane resistance. Using intrathecal adeno-associated virus serotype 9-based delivery, the glutamate-gated chloride channel was successfully targeted to mouse sensory neurons in vivo, resulting in high level and long-lasting expression of the channel selectively in sensory neurons. This enabled reproducible and reversible modulation of thermal and mechanical pain thresholds in vivo; analgesia was observed for 3 days after a single systemic dose of ivermectin. We did not observe any motor or proprioceptive deficits and noted no reduction in cutaneous afferent innervation or upregulation of the injury marker ATF3 following prolonged glutamate-gated chloride channel expression. Established mechanical and cold pain-related hypersensitivity generated by the spared nerve injury model of neuropathic pain was reversed by ivermectin treatment. The efficacy of ivermectin in ameliorating behavioural hypersensitivity was mirrored at the cellular level by a cessation of ectopic activity in sensory neurons. These findings demonstrate the importance of aberrant afferent input in the maintenance of neuropathic pain and the potential for targeted chemogenetic silencing as a new treatment modality in neuropathic pain.
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http://dx.doi.org/10.1093/brain/awx201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841150PMC
October 2017

Structural and Functional Substitution of Deleted Primary Sensory Neurons by New Growth from Intrinsic Spinal Cord Nerve Cells: An Alternative Concept in Reconstruction of Spinal Cord Circuits.

Front Neurol 2017 24;8:358. Epub 2017 Jul 24.

The Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.

In a recent clinical report, return of the tendon stretch reflex was demonstrated after spinal cord surgery in a case of total traumatic brachial plexus avulsion injury. Peripheral nerve grafts had been implanted into the spinal cord to reconnect to the peripheral nerves for motor and sensory function. The dorsal root ganglia (DRG) containing the primary sensory nerve cells had been surgically removed in order for secondary or spinal cord sensory neurons to extend into the periphery and replace the deleted DRG neurons. The present experimental study uses a rat injury model first to corroborate the clinical finding of a re-established spinal reflex arch, and second, to elucidate some of the potential mechanisms underlying these findings by means of morphological, immunohistochemical, and electrophysiological assessments. Our findings indicate that, after spinal cord surgery, the central nervous system sensory system could replace the traumatically detached original peripheral sensory connections through new neurite growth from dendrites.
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http://dx.doi.org/10.3389/fneur.2017.00358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523078PMC
July 2017

Sensory processing of deep tissue nociception in the rat spinal cord and thalamic ventrobasal complex.

Physiol Rep 2017 Jul;5(14)

Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.

Sensory processing of deep somatic tissue constitutes an important component of the nociceptive system, yet associated central processing pathways remain poorly understood. Here, we provide a novel electrophysiological characterization and immunohistochemical analysis of neural activation in the lateral spinal nucleus (LSN). These neurons show evoked activity to deep, but not cutaneous, stimulation. The evoked responses of neurons in the LSN can be sensitized to somatosensory stimulation following intramuscular hypertonic saline, an acute model of muscle pain, suggesting this is an important spinal relay site for the processing of deep tissue nociceptive inputs. Neurons of the thalamic ventrobasal complex (VBC) mediate both cutaneous and deep tissue sensory processing, but in contrast to the lateral spinal nucleus our electrophysiological studies do not suggest the existence of a subgroup of cells that selectively process deep tissue inputs. The sensitization of polymodal and thermospecific VBC neurons to mechanical somatosensory stimulation following acute muscle stimulation with hypertonic saline suggests differential roles of thalamic subpopulations in mediating cutaneous and deep tissue nociception in pathological states. Overall, our studies at both the spinal (lateral spinal nucleus) and supraspinal (thalamic ventrobasal complex) levels suggest a convergence of cutaneous and deep somatosensory inputs onto spinothalamic pathways, which are unmasked by activation of muscle nociceptive afferents to produce consequent phenotypic alterations in spinal and thalamic neural coding of somatosensory stimulation. A better understanding of the sensory pathways involved in deep tissue nociception, as well as the degree of labeled line and convergent pathways for cutaneous and deep somatosensory inputs, is fundamental to developing targeted analgesic therapies for deep pain syndromes.
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http://dx.doi.org/10.14814/phy2.13323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532477PMC
July 2017

Nerve Growth Factor and Pain Mechanisms.

Annu Rev Neurosci 2017 07 24;40:307-325. Epub 2017 Apr 24.

Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, United Kingdom; email:

Nerve growth factor (NGF) antagonism is on the verge of becoming a powerful analgesic treatment for numerous conditions, including osteoarthritis and lower back pain. This review summarizes the historical research, both fundamental and clinical, that led to our current understanding of NGF biology. We also discuss the surprising number of questions that remain about NGF expression patterns and NGF's various functions and interaction partners in relation to persistent pain and the potential side effects of anti-NGF therapy.
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http://dx.doi.org/10.1146/annurev-neuro-072116-031121DOI Listing
July 2017