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The endocannabinoid N-arachidonoyl dopamine is critical for hyperalgesia induced by chronic sleep disruption
Generalized body pain and headaches are common experience after sleep disruption. How does sleep disruption lead to generalized pain is unknown. Here, authors reveal that N-arachidonoyl dopamine, an endocannabinoid, is critically implicated in pain perception after sleep disruption.
- Weihua Ding
- , Liuyue Yang
- & Shiqian Shen
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| Open Access
A 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 Access
Galectin-3 activates spinal microglia to induce inflammatory nociception in wild type but not in mice modelling Alzheimer’s disease
In inflammatory arthritis, pain neurons communicate with spinal cord microglia to establish nociception. Here, the authors show that this communication is mediated by pain neurons releasing galectin-3, which activates microglia through TLR4. In a mouse model of Alzheimer’s disease, pain is attenuated because microglia lack expression of TLR4.
- George Sideris-Lampretsas
- , Silvia Oggero
- & Marzia Malcangio
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The basolateral amygdala-anterior cingulate pathway contributes to depression-like behaviors and comorbidity with chronic pain behaviors in male mice
While depression and chronic pain are frequently comorbid, underlying neuronal circuits and their psychopathological relevance remain poorly defined. Here, authors show the critical role of the BLA-ACC pathway in pain and emotional processing, and their comorbidity.
- Léa J. Becker
- , Clémentine Fillinger
- & Ipek Yalcin
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Piezo2 regulates colonic mechanical sensitivity in a sex specific manner in mice
Piezo2 in mucosa and primary afferents mediates colonic mechanical sensation. Here the authors show that activation of Piezo2 regulates colonic mechanical sensitivity in a sex dependent manner.
- Jonathan Madar
- , Namrata Tiwari
- & Liya Y. Qiao
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Role 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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Synchronized activity of sensory neurons initiates cortical synchrony in a model of neuropathic pain
Increased low frequency cortical oscillations are observed in neuropathic pain. Here the authors perform Ca2+ imaging of DRG sensory neurons in a mouse model of neuropathic pain, and show that synchronized activity of DRG neurons occurs within hours after injury and 1-2 days before increased cortical oscillations are observed.
- Chao Chen
- , Linlin Sun
- & Peifu Tang
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TRPM8 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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Cell 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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| Open Access
Cholinergic basal forebrain nucleus of Meynert regulates chronic pain-like behavior via modulation of the prelimbic cortex
The basal nucleus of Meynert (NBM) plays a role in cognition by modulating cortical circuits. Here, the authors demonstrate plasticity of the NBM upon tissue injury, and that activating NBM cholinergic-GABAergic projections to the prefrontal cortex alleviates chronic pain-like behaviour in mice.
- Manfred J. Oswald
- , Yechao Han
- & Rohini Kuner
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| Open Access
Organic anion transporter 1 is an HDAC4-regulated mediator of nociceptive hypersensitivity in mice
Chronic pain is sustained by alterations in gene transcription. Here, the authors show that increased expression of Organic Anionic Transporter 1 in the spinal cord is epigenetically controlled and key to hypersensitivity in pathological pain.
- Christian Litke
- , Anna M. Hagenston
- & Daniela Mauceri
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| Open Access
A diencephalic circuit in rats for opioid analgesia but not positive reinforcement
Opioids are potent analgesics but also have addiction risk. Here a lateral preoptic area to lateral habenula connection is identified by which opioids relieve ongoing pain but do not produce reward in animals that do not have ongoing pain.
- Maggie W. Waung
- , Kayla A. Maanum
- & Elyssa B. Margolis
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| Open Access
Presynaptic 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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Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission
Lack of expression and function of chloride ion-extruding transporter KCC2 in central neurons, a consequence of various forms of neural injury, is strongly suggested to contribute to chronic pain. Here the authors identify from a screen of cancer drugs a kinase-inhibitor, kenpaullone, as an enhancer of Kcc2/KCC2 gene expression and show that it (i) alleviates pain like behaviour in animal models, (ii) repairs neural-circuit disrupting elevated chloride in pain relay neurons in the dorsal spinal cord.
- Michele Yeo
- , Yong Chen
- & Wolfgang Liedtke
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Inhibiting endocytosis in CGRP+ nociceptors attenuates inflammatory pain-like behavior
The authors show the endocytotic adaptor subunit called AP2A2 is differentially expressed in CGRP+ nociceptors. Locally inhibiting nociceptor endocytosis with a lipidated AP2 inhibitor peptide reduces acute and chronic pain-like behaviour in mice and rats, indicating prolonged analgesia.
- Rasheen Powell
- , Violet A. Young
- & Arin Bhattacharjee
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Single 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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| Open Access
Parabrachial 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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| Open Access
Distinct 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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| Open Access
Enhancing neuronal chloride extrusion rescues α2/α3 GABAA-mediated analgesia in neuropathic pain
Disinhibition in the dorsal horn of the spinal cord may contribute to chronic pain. Here the authors show that, despite a paradoxical increase in α2/α3 subunits of the GABAA receptor in a neuropathic pain model, inhibition eventually fails due to KCC2 hypofunction.
- Louis-Etienne Lorenzo
- , Antoine G. Godin
- & Yves De Koninck
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Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain
Interactions among spinal dorsal horn neurons and microglia contribute to the induction and maintenance of neuropathic pain after peripheral nerve injury. The authors show that depletion of macrophages in the dorsal root ganglia prevents and reverses ongoing nerve injury-induced hypersensitivity.
- Xiaobing Yu
- , Hongju Liu
- & Allan I. Basbaum
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Sensory innervation in porous endplates by Netrin-1 from osteoclasts mediates PGE2-induced spinal hypersensitivity in mice
Spinal pain is a major clinical problem. Here the authors show that osteoclasts create porous area of endplates of the vertebrae and sensory innervation of porous endplates by Netrin-1 release from osteoclasts mediates PGE2-induced spinal hypersensitivity in mice.
- Shuangfei Ni
- , Zemin Ling
- & Xu Cao
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| Open Access
CircAnks1a in the spinal cord regulates hypersensitivity in a rodent model of neuropathic pain
Circular RNAs are non-coding RNAs that are enriched in the CNS, but their role in chronic pain is not known. Here the authors show that CircAnks1a in dorsal horn neurons contributes to pain-like hypersensitivity in a rodent model of neuropathic pain, via a VEGF mechanism.
- Su-Bo Zhang
- , Su-Yan Lin
- & Wen-Jun Xin
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Gamma oscillations in somatosensory cortex recruit prefrontal and descending serotonergic pathways in aversion and nociception
Gamma oscillations in somatosensory areas in humans correlate with pain perception and pain stimulus intensity, but could also reflect cognitive processes such as attention. Here the authors provide evidence in mice that these oscillations causally contribute to pain perception.
- Linette Liqi Tan
- , Manfred Josef Oswald
- & Rohini Kuner
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| Open Access
Ketamine reduces aversion in rodent pain models by suppressing hyperactivity of the anterior cingulate cortex
Ketamine is a short-acting analgesic that also has anti-depressant effects. Here the authors show in rat models of chronic pain that low-dose ketamine can induce an anti-aversive state that persists after the initial short term analgesia has ended.
- Haocheng Zhou
- , Qiaosheng Zhang
- & Jing Wang
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| Open Access
Top-down descending facilitation of spinal sensory excitatory transmission from the anterior cingulate cortex
It is known that descending facilitation of spinal responses may contribute to chronic pain, however many studies have focussed on brainstem mechanisms. Here the authors show that stimulation of the anterior cingulate cortex increases excitatory transmission in the dorsal horn, and that this may be via a direct pathway independent of the brainstem.
- Tao Chen
- , Wataru Taniguchi
- & Min Zhuo
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Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons
There are several classes of sensory neuron that contribute to pain states. Here, the authors demonstrate that TrkB+ sensory neurons detect light touch under normal conditions in mice but contribute to hypersensitivity in models of chronic pain, and that ligand-guided laser ablation of TrkB+ sensory neurons in the mouse skin attenuates this hypersensitivity.
- Rahul Dhandapani
- , Cynthia Mary Arokiaraj
- & Paul A. Heppenstall
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| Open Access
TRPV1 SUMOylation regulates nociceptive signaling in models of inflammatory pain
SUMOylation is a post translational modification. Here the authors show that TRPV1, which conveys thermal nociception, is SUMOylated in DRGs in inflammatory conditions and contributes to pain behavior in mice.
- Yan Wang
- , Yingwei Gao
- & Yong Li
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| Open Access
Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice
Sensitisation of dorsal root ganglia neurons contributes to neuropathic pain. Here the authors demonstrate the cytokine FL contributes to sensitisation of DRGs via its receptor FLT3 expressed on neurons, and identify a novel FLT3 inhibitor that attenuates neuropathic pain in mice.
- Cyril Rivat
- , Chamroeun Sar
- & Jean Valmier
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| Open Access
Schwann 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 Access
Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma
Exosomes are known to contain microRNAs (miRs). Here the authors show that dorsal root ganglion neurons release exosomes containing miR-21-5p, which contributes to inflammatory cell recruitment following peripheral nerve injury.
- Raffaele Simeoli
- , Karli Montague
- & Marzia Malcangio
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| Open Access
Cardioprotection induced in a mouse model of neuropathic pain via anterior nucleus of paraventricular thalamus
Various forms of preconditioning can prevent ischemic-reperfusion injury after myocardial infarction. Here, the authors show that in mice, the presence of chronic neuropathic pain can have a cardioprotective effect, and that this is dependent on neural activation in the paraventricular thalamus.
- Yi-Fen Cheng
- , Ya-Ting Chang
- & Chien-Chang Chen
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| Open Access
Semaphorin 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 Access
Quantifying cerebral contributions to pain beyond nociception
Pain is affected by cerebral processes in addition to afferent nociceptive input. Here the authors develop an fMRI-based signature that predicts pain independent of the intensity of nociceptive signals and mediates the pain-modulating effects of several cognitive interventions.
- Choong-Wan Woo
- , Liane Schmidt
- & Tor D. Wager
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| Open Access
Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain
Purinergic receptor activation by extracellular ATP in the dorsal horn contributes to neuropathic pain, but which cell types release ATP in this context is not known. The authors show in a mouse model of neuropathic pain that ATP is released by dorsal horn neurons, a process requiring the vesicular nucleotide transporter, VNUT.
- Takahiro Masuda
- , Yui Ozono
- & Kazuhide Inoue
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Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury
Microglia and monocytes contribute to neuropathic pain states, but the precise role of the two cell types is not clear. Here Peng et al.use temporally controlled ablation of monocytes and microglia in mice to show that these cells work together to initiate neuropathic-pain like behaviour, but are less important in the maintenance phase.
- Jiyun Peng
- , Nan Gu
- & Long-Jun Wu
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| Open Access
Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7
Nav1.7 channels are known to regulate pain perception in humans and mice. Here, the authors provide evidence that Nav1.7 deletion leads to transcriptional upregulation of opioid peptides in sensory neurons, and that treatment with the opioid blocker naloxone helps reverse analgesia in mice and human Nav1.7 nulls.
- Michael S. Minett
- , Vanessa Pereira
- & John N. Wood
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| Open Access
Membrane stiffening by STOML3 facilitates mechanosensation in sensory neurons
To maintain viability, cells must be able to sense and respond to mechanical stimuli. Here, Qi et al. show that the STOML3 protein acts in mechanosensation by binding cholesterol and regulating membrane stiffness which can in turn regulate ion flux through mechanosensitive channels.
- Yanmei Qi
- , Laura Andolfi
- & Jing Hu
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| Open Access
Differential methylation of the TRPA1 promoter in pain sensitivity
Genetically identical twins provide a valuable resource to identify epigenetic factors associated with complex traits. Here the authors adopt this approach and find that differential methylation of the pain gene TRPA1is associated with pain sensitivity in humans.
- J.T. Bell
- , A.K. Loomis
- & T.D. Spector
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Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain
Peptide drugs are attractive as therapeutics for gut-based applications, although they may be susceptible to reduction and degradation. Here, the authors develop seleno-oxytocin analogues, with enhanced stability at no cost to potency, and demonstrate their efficacy at colonic nociceptor inhibition in a mouse model.
- Aline Dantas de Araujo
- , Mehdi Mobli
- & Paul F. Alewood
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Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Nav1.7 mutant channel
Mutations of the NaV1.7 voltage-gated sodium channel are implicated in abnormal pain signal transduction. Yang and colleagues perform structural modeling, mutant cycle analysis and electrophysiology on specific mutants and find that they can accurately predict their response profiles to channel blockers.
- Yang Yang
- , Sulayman D. Dib-Hajj
- & Stephen G. Waxman
A mesocortical glutamatergic pathway modulates neuropathic pain independent of dopamine co-release