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| Open AccessEpigenetic regulation of beta-endorphin synthesis in hypothalamic arcuate nucleus neurons modulates neuropathic pain in a rodent pain model
Neuropathic pain is a complex and often disabling condition with unclear pathogenesis. Here, the authors elucidate an epigenetic regulatory pathway driven by microRNA regulation of betaendorphin (β-EP) synthesis in the hypothalamic arcuate nucleus (ARC) neurons to modulate neuropathic pain.
- Yu Tao
- , Yuan Zhang
- & Jin Tao
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Article
| Open AccessHuman OPRM1 and murine Oprm1 promoter driven viral constructs for genetic access to μ-opioidergic cell types
Tools for gaining long-term genetic access to mu-opioid receptor (MOR) neural cell types are limited. Here, the authors develop a suite of adeno-associated viral tools allowing selective genetic access to MOR cell types, and showcase their use across species.
- Gregory J. Salimando
- , Sébastien Tremblay
- & Gregory Corder
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| Open AccessA glutamatergic DRN–VTA pathway modulates neuropathic pain and comorbid anhedonia-like behavior in mice
The neural circuit mechanisms underlying chronic pain and comorbid anhedonia remain poorly understood. Here, the authors show the critical role of the DRN–VTA–NAcMed pathway in establishing and modulating chronic neuropathic pain and comorbid anhedonia.
- Xin-Yue Wang
- , Wen-Bin Jia
- & Yan Zhang
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| Open AccessA common neuronal ensemble in nucleus accumbens regulates pain-like behaviour and sleep
A comorbidity of chronic pain is sleep disturbance. Here, authors show the identification and characterization of a common neuronal ensemble in NAc that regulates pain-like behaviour and sleep through its divergent downstream circuit targets.
- Haiyan Sun
- , Zhilin Li
- & Jun-Li Cao
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Article
| Open AccessRole of TMEM100 in mechanically insensitive nociceptor un-silencing
Silent nociceptors remained enigmatic ever since they were first described decades ago. Here, Nees. et al. show that inflammation-induced upregulation of TMEM100 unsilences silent nociceptors, which triggers secondary mechanical pain hypersensitivity.
- Timo A. Nees
- , Na Wang
- & Stefan G. Lechner
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| Open AccessA photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals
Research on pain often relies on animals, and there is always a need for more precise and more ethical tools. Here, authors present a light-activatable molecule that induces pain in freely moving animal models in a reversible, non-invasive, and spatiotemporally defined way.
- Arnaud Landra-Willm
- , Ameya Karapurkar
- & Guillaume Sandoz
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Article
| Open AccessCross-species transcriptomic atlas of dorsal root ganglia reveals species-specific programs for sensory function
Sensory neurons are critical for maintaining tissue homeostasis. Here, the authors generated a single-nuclei cross-species atlas of the dorsal root ganglia, revealing conserved programs for sensory function that could inform therapeutic hypotheses.
- Min Jung
- , Michelle Dourado
- & Joshua S. Kaminker
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Article
| Open AccessComputational and neural mechanisms of statistical pain learning
Pain fluctuates over time in ways that are non-random. Here, the authors show that the human brain can learn to predict these changes in a manner consistent with optimal Bayesian inference by engaging sensorimotor, parietal, and premotor regions.
- Flavia Mancini
- , Suyi Zhang
- & Ben Seymour
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Article
| Open AccessTRPM8 contributes to sex dimorphism by promoting recovery of normal sensitivity in a mouse model of chronic migraine
A mouse model of chronic migraine reveals that males recover normal sensitivity before than females. This antinociception requires TRPM8 expression and presence of testosterone, which elicits currents and calcium transients via human and murine TRPM8.
- David Alarcón-Alarcón
- , David Cabañero
- & Antonio Ferrer-Montiel
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| Open AccessCell type-specific calcium imaging of central sensitization in mouse dorsal horn
Altered mechanosensation by application of capsaicin to the skin is thought to be spinally mediated. Here, the authors use Ca2+ imaging in spinal neurons and develop a cell profiling approach to identify populations involved in central sensitization.
- Charles Warwick
- , Joseph Salsovic
- & Sarah E. Ross
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Article
| Open AccessEarly life inflammation is associated with spinal cord excitability and nociceptive sensitivity in human infants
More than 1 in 10 babies born in the UK are suspected of having an infection. Here the authors show that newborn babies with signs of infection (raised C-Reactive Protein levels) have exaggerated leg reflexes and pain-related brain activity following a heel prick blood test, suggesting they may be more sensitive to pain.
- Maria M. Cobo
- , Gabrielle Green
- & Rebeccah Slater
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Article
| Open AccessDistinct nociception processing in the dysgranular and barrel regions of the mouse somatosensory cortex
The processing of nociception in the somatosensory cortex (S1) has yet to be fully understood. Here, the authors demonstrate that the dysgranular region in S1 has an affinity for nociception and is critically involved in pain-like behavior.
- Hironobu Osaki
- , Moeko Kanaya
- & Mariko Miyata
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Article
| Open AccessDissociation between individual differences in self-reported pain intensity and underlying fMRI brain activation
Previous work had suggested that fMRI measures can be used as a marker of pain experience. Here the authors find no evidence for a link between perceived pain intensity and fMRI activation.
- M. E. Hoeppli
- , H. Nahman-Averbuch
- & R. C. Coghill
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Article
| Open AccessPresynaptic NMDARs on spinal nociceptor terminals state-dependently modulate synaptic transmission and pain
Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. Here, the authors show that also presynaptic NMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner.
- Rou-Gang Xie
- , Wen-Guang Chu
- & Ceng Luo
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Article
| Open AccessRare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology
Little is known about the biology of back pain, a leading cause of disability. Here the authors report 30 new back pain loci, implicating genes involved in cartilage/bone biology, as well as neurological and inflammatory processes.
- Gyda Bjornsdottir
- , Lilja Stefansdottir
- & Kari Stefansson
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| Open AccessFunctional and diffusion MRI reveal the neurophysiological basis of neonates’ noxious-stimulus evoked brain activity
The neurophysiological basis of neonatal responses to noxious stimulation is poorly understood. Using MRI, the authors observe that neonates’ noxious-stimulus evoked brain activity is coupled to both their resting-state network activity and white matter microstructure.
- Luke Baxter
- , Fiona Moultrie
- & Rebeccah Slater
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Article
| Open AccessSingle cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain
The contribution of distinct types of dorsal root ganglion neurons to chronic pain is unclear. Here, the authors molecularly profile non-human primate sensory neurons and show that genome-wide associations converge on two neuronal types with different genetic susceptibilities for chronic pain.
- Jussi Kupari
- , Dmitry Usoskin
- & Patrik Ernfors
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Article
| Open AccessATF4 selectively regulates heat nociception and contributes to kinesin-mediated TRPM3 trafficking
The molecular mechanisms mediating nociception are unclear. Here, the authors show that the Activating Transcription Factor 4 (ATF4) is important for the response to heat nociception in mice and ATF4 role in mediating protein trafficking in dorsal root ganglion neurons.
- Man-Xiu Xie
- , Xian-Ying Cao
- & Xiao-Long Zhang
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Article
| Open AccessMeta-analysis of neural systems underlying placebo analgesia from individual participant fMRI data
The neural mechanisms of placebo analgesia are not fully understood. Here the authors conducted a large scale meta-analysis of individual data from fMRI studies of pain and placebo conditions.
- Matthias Zunhammer
- , Tamás Spisák
- & Fadel Zeidan
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| Open AccessParabrachial nucleus circuit governs neuropathic pain-like behavior
The parabrachial nucleus (PBN) projects to the amygdala, and contributes to affective aspects of neuropathic pain. Here the authors demonstrate that the lateral parabrachial nucleus (LPBN) contributes to hypersensitivity in a mouse model of neuropathic pain.
- Li Sun
- , Rui Liu
- & Shumin Duan
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Article
| Open AccessCommon and distinct neural representations of aversive somatic and visceral stimulation in healthy individuals
Whether the brain processes different types of pain similarly or differently remains unknown. The authors show that an established neurologic pain signature responds to five different types of visceral and somatic pain; they also develop a new classifier that reliably discriminates between both pain modalities.
- Lukas Van Oudenhove
- , Philip A. Kragel
- & Tor D. Wager
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| Open AccessDistinct thalamocortical network dynamics are associated with the pathophysiology of chronic low back pain
Thalamocortical dysrhythmia is a key pathology of chronic pain. Here, the authors propose an analytical pipeline to study dynamic fMRI brain networks and demonstrate that chronic low back pain pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics.
- Yiheng Tu
- , Zening Fu
- & Jian Kong
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Article
| Open AccessDifferential chloride homeostasis in the spinal dorsal horn locally shapes synaptic metaplasticity and modality-specific sensitization
Inhibition in spinal nociceptive pathways is weaker and more labile in lamina I —where thermal input is primarily processed— than in lamina II that encodes predominantly high threshold mechanical input. This explains why noxious thermal input makes spinal circuits prone to catastrophic sensitization.
- Francesco Ferrini
- , Jimena Perez-Sanchez
- & Yves De Koninck
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Article
| Open AccessIntestinal microbiome composition and its relation to joint pain and inflammation
Alterations to the microbiome are now associated with various diseases. Here the authors analyze microbiomes from a large population based cohort and show positive correlations between abundance of Streptococcus spp. and osteoarthritis-related knee pain.
- Cindy G. Boer
- , Djawad Radjabzadeh
- & Joyce B. J. van Meurs
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Article
| Open AccessDifferent brain networks mediate the effects of social and conditioned expectations on pain
Our experience of pain can be affected by our expectations about how much pain we will feel. Here, the authors show that both social information-driven expectations, and those based on personal experience, are both able to modulate pain, but by different neural pathways.
- Leonie Koban
- , Marieke Jepma
- & Tor D. Wager
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| Open AccessDistinct patterns of brain activity mediate perceptual and motor and autonomic responses to noxious stimuli
Pain is a complex phenomenon involving not just the perception of pain, but also autonomic and motor responses. Here, the authors show that these different dimensions of pain are associated with distinct patterns of neural responses to noxious stimuli as measured using EEG.
- Laura Tiemann
- , Vanessa D. Hohn
- & Markus Ploner
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| Open AccessBrain and psychological determinants of placebo pill response in chronic pain patients
People vary in the extent to which they feel better after taking an inert, placebo, treatment, but the basis for individual placebo response is unclear. Here, the authors show how brain structural and functional variables, as well as personality traits, predict placebo response in those with chronic back pain.
- Etienne Vachon-Presseau
- , Sara E. Berger
- & A. Vania Apkarian
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Article
| Open AccessStaphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314
Bacterial infection can cause pain but the underlying mechanism is unclear. This study shows pain induced in mice by methicillin-resistant Staphylococcus aureus infection is mediated by bacterial pore-forming toxins, and a sodium channel blocker QX-314 can alleviate infection-associated pain.
- Kimbria J. Blake
- , Pankaj Baral
- & Isaac M. Chiu
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| Open AccessSchwann cell TRPA1 mediates neuroinflammation that sustains macrophage-dependent neuropathic pain in mice
Following peripheral nerve injury, influx of immune cells to the site may contribute to the development of chronic pain. Here the authors show that TRPA1 is expressed on Schwann cells and contributes to immune cell influx in a mouse model of neuropathic pain.
- Francesco De Logu
- , Romina Nassini
- & Pierangelo Geppetti
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| Open AccessSemaphorin 4C Plexin-B2 signaling in peripheral sensory neurons is pronociceptive in a model of inflammatory pain
Semaphorins and their receptors are involved in neurodevelopment, but their functions in the adult nervous system are not fully understood. This study finds that semaphorin 4C and its receptor Plexin B are expressed in sensory neurons and are pronociceptive in a mouse model of inflammatory pain.
- Eszter Paldy
- , Manuela Simonetti
- & Rohini Kuner
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| Open AccessInhibition of TRPV1 channels by a naturally occurring omega-9 fatty acid reduces pain and itch
TRPV1 channels are known to mediate pathological pain and itch. Here, the authors find a naturally occurring fatty acid, oleic acid, acts as a TRPV1 antagonist and can modulate capsaicin and histamine-mediated pain and itch response in mouse models.
- Sara L. Morales-Lázaro
- , Itzel Llorente
- & Tamara Rosenbaum
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| Open AccessBK channels in microglia are required for morphine-induced hyperalgesia
Long-term use of opioids can lead to a paradoxical increase in pain sensitivity. Here, Hayashi et al. link activation of potassium channels on microglia with morphine-induced hyperalgesia and anti-nociceptive tolerance in mice.
- Yoshinori Hayashi
- , Saori Morinaga
- & Hiroshi Nakanishi
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| Open AccessCross-modal representations of first-hand and vicarious pain, disgust and fairness in insular and cingulate cortex
Anterior insula (AI) and medial anterior cingulate cortex (mACC) are activated by self and vicarious pain, disgust and fairness, yet the overlap of these representations are not known. Here the authors provide evidence for shared neural codes in the left AI and mACC and distinct codes in the right AI.
- Corrado Corradi-Dell’Acqua
- , Anita Tusche
- & Tania Singer
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| Open AccessCold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant
A mutation in the sodium channel Nav1.9 has been identified in a family and shown to associate with cold-aggravated pain. Here, the authors characterize the electrophysiological consequences of this mutation and propose a mechanism for the pain that the individuals experience.
- Enrico Leipold
- , Andrea Hanson-Kahn
- & Ingo Kurth
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| Open AccessA pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1
The venom of the Chinese red-headed centipede causes excruciating pain. Here, Yanget al. identify a novel toxin protein from the centipede venom and find that it can activate the nociceptive TRPV1 ion channel by binding to the channel’s outer pore to potentiate the heat activation machinery.
- Shilong Yang
- , Fan Yang
- & Ren Lai
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| Open AccessHyaluronan modulates TRPV1 channel opening, reducing peripheral nociceptor activity and pain
Hyaluronan is a major component of the extracellular matrix, and is used to treat joint pain in osteoarthritis. In this study, Caires et al.show hyaluronan achieves its analgesic effects by targeting TRPV1 and stabilising the channel in its closed state.
- Rebeca Caires
- , Enoch Luis
- & Elvira de la Peña
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| Open AccessAnalgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype
Benzodiazepines (BDZs) target GABAA receptors to alleviate pain but these also cause side effects. Here the authors use mice in which only one GABAA receptor is BDZ-sensitive at a time to identify α2GABAAas the receptor that provides maximal analgesic activity but minimal side-effects in response to BDZs.
- William T. Ralvenius
- , Dietmar Benke
- & Hanns Ulrich Zeilhofer
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Article
| Open AccessSteroidal and non-steroidal third-generation aromatase inhibitors induce pain-like symptoms via TRPA1
Use of aromatase inhibitors for breast cancer therapy is associated with severe pain symptoms, the underlying mechanism of which is unknown. Here the authors show that in mice, TRPA1 is a major mediator of the proinflammatory and proalgesic actions of aromatase inhibitors.
- Camilla Fusi
- , Serena Materazzi
- & Romina Nassini
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ZBTB20 regulates nociception and pain sensation by modulating TRP channel expression in nociceptive sensory neurons
The upregulation of TRP ion channels is implicated in pain processing. In this study, the authors show that the zinc-finger protein ZBTB20 is responsible for TRP channel upregulation, and eliminating ZBTB20 from pain-sensing neurons in mouse models of pain results in the reduction of pain-like sensation.
- An-Jing Ren
- , Kai Wang
- & Weiping J. Zhang
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Article
| Open AccessTRPV channel-mediated calcium transients in nociceptor neurons are dispensable for avoidance behaviour
TRPs are calcium-permeable channels involved in the sensing of damaging stimuli but the relationship between calcium influx and pain behaviour has been elusive. Here the authors find that the TRP channel OSM-9 functions as an ion channel in vivo in C. elegans, and establish residues that are critical for worm pain-like behaviour.
- Amanda S. Lindy
- , Puja K. Parekh
- & Wolfgang B. Liedtke
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Three functionally distinct classes of C-fibre nociceptors in primates
C-fibre polymodal nociceptors in primates have been classified into two groups based on their sensitivity to mechanical stimuli. Here, Wooten et al.describe how the differences in the response speed of the receptors to stimuli suggest that these should be considered as three separate groups.
- Matthew Wooten
- , Hao-Jui Weng
- & Matthias Ringkamp
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| Open AccessTRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins
Gram-negative bacterial infections can often cause inflammation and pain. Meseguer et al. show that the inflammation and pain result from the direct activation of nociceptor TRPA1 channels by lipopolysaccharide, a major component of the outer membrane of Gram-negative bacteria.
- Victor Meseguer
- , Yeranddy A. Alpizar
- & Félix Viana
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Activation of TREK-1 by morphine results in analgesia without adverse side effects
Opioid analgesic drugs act at opioid receptors to exert analgesic effects, but they also exert adverse side effects. In this study, the authors show that the TREK-1 potassium channel is responsible for mediating the analgesic effects of morphine but not the adverse side effects.
- Maïly Devilliers
- , Jérôme Busserolles
- & Alain Eschalier
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Article
| Open AccessA role for Piezo2 in EPAC1-dependent mechanical allodynia
Mechanical allodynia describes the process whereby innocuous stimuli is perceived as being noxious and is a common symptom of neuropathic pain. Using mice deficient in the cAMP sensor Epac1, the authors in this study find that Epac1 regulates mechanical allodynia by sensitizing the mechanotransducer Piezo2.
- N Eijkelkamp
- , J.E. Linley
- & J.N. Wood
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Article
| Open AccessPhantom pain is associated with preserved structure and function in the former hand area
Reorganization of the sensorimotor cortex due to loss of sensory input is implicated in phantom pain. Makin and colleagues use functional MRI to show that phantom pain experience is instead associated with maintained local functional and structural cortical representations but disrupted inter-regional connectivity.
- Tamar R. Makin
- , Jan Scholz
- & Heidi Johansen-Berg
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TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol
TRPA1 is a key ion channel in pain signalling. This study shows that activation of TRPA1 in the spinal cord by acetaminophen metabolites and a non-electrophilic cannabinoid produces antinociception that is lost in mice lacking TRPA1, providing an explanation for the analgesic activity of acetaminophen.
- David A Andersson
- , Clive Gentry
- & Peter M Zygmunt