Toll-like receptors （TLRs） are germline-encoded pattern-recognition receptors that initiate innate immune re- sponses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associ...Toll-like receptors （TLRs） are germline-encoded pattern-recognition receptors that initiate innate immune re- sponses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associated molecular patterns （PAMPs）. After tissue injury or cellular stress, TLRs also detect endogenous ligands known as danger-associated molecular patterns （DAMPs）. TLRs are expressed in both non-neuronal and neuronal cell types in the central nervous system （CNS） and contribute to both infectious and non-infectious disorders in the CNS. Following tissue insult and nerve injury, TLRs （such as TLR2, TLR3, and TLR4） induce the activation of microglia and astrocytes and the production of the proinflammatory cytokines in the spinal cord, leading to the development and maintenance of inflammatory pain and neu- ropathic pain. In particular, primary sensory neurons, such as nociceptors, express TLRs （e.g., TLR4 and TLR7） to sense exogenous PAMPs and endogenous DAMPs released after tissue injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of affected people, insights into TLR signaling in the nervous system will open a new avenue for the management of clinical pain and itch.展开更多
Objective To investigate the role of oxidative stress in itch-indicative scratching behavior in mice, and further- more, to define the cellular and molecular mechanisms underlying oxidative stress-mediated itch. Metho...Objective To investigate the role of oxidative stress in itch-indicative scratching behavior in mice, and further- more, to define the cellular and molecular mechanisms underlying oxidative stress-mediated itch. Methods Scratching behavior was induced by intradermal injection of the oxidants hydrogen peroxide （H202） or tert-butylhydroperoxide （tBHP） into the nape of the neck in mice. The mice were observed for 30 rain. Results Intradermal H202 （0.03%-1%） or tBHP （1-30 pmol） elicited robust scratching behavior, displaying an inverted U-shaped dose-response curve. Naloxone, an opioid receptor antagonist, but not morphine, largely suppressed the oxidant-induced scratching. Chlorpheniramine, a histamine H1 receptor antagonist, blocked histamine- but not oxidant-induced scratching, indicating the involvement of a histamine-independent mechanism in oxidant-evoked itch. Further, resiniferatoxin treatment abolished oxidant-induced scratching, suggesting an essential role of C-fibers. Notably, blockade of transient receptor potential subtype ankyrin 1 （TRPA1） with the selective TRPA1 antagonist HC-030031, or genetic deletion of Trpal but not Trpvl （subfamily V, mem- ber 1） resulted in a profound reduction in H202-evoked scratching. Finally, systemic administration of the antioxidant N- acetyl-L-cysteine or trolox （a water-soluble vitamin E analog） attenuated scratching induced by the oxidants. Conclusion Oxidative stress by different oxidants induces profound scratching behavior, which is largely histamine- and TRPV1- independent but TRPAl-dependent. Antioxidants and TRPA1 antagonists may be used to treat human itch conditions as- sociated with oxidative stress.展开更多
Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 （C-C motif chemokine ligand 2） has been shown ...Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 （C-C motif chemokine ligand 2） has been shown to enhance N-methyl-D-aspartate （NMDA）-induced currents in spinal outer lamina II （Iio） neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expres- sion in excitatory vesicular glutamate transporter subtype 2-positive （VGLUT2＋） neurons. CCL2 increased NMDA- induced currents in CCR2＋/VGLUT2＋ neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin- expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2- expressing excitatory neurons in spinal lamina Iio, and this underlies the generation of central sensitization in patho- logical pain.展开更多
Increasing evidence suggests that spinal micro- glia regulate pathological pain in males. In this study, we investigated the effects of several microglial and astroglial modulators on inflammatory and neuropathic pain...Increasing evidence suggests that spinal micro- glia regulate pathological pain in males. In this study, we investigated the effects of several microglial and astroglial modulators on inflammatory and neuropathic pain follow- ing intrathecal injection in male and female mice. These modulators were the microglial inhibitors minocycline and ZVEID （a caspase-6 inhibitor） and the astroglial inhibitors L-α-aminoadipate （L-AA, an astroglial toxin） and car- benoxolone （a connexin 43 inhibitor）, as well as U0126 （an ERK kinase inhibitor） and D-JNKI-1 （a c-Jun N-terminal kinase inhibitor）. We found that spinal administration of minocycline or ZVEID, or Caspase6 deletion, reduced formalin-induced inflammatory and nerve injury-induced neuropathic pain primarily in male mice. In contrast, intrathecal L-AA reduced neuropathic pain but not inflam- matory pain in both sexes. Intrathecal U0126 and D-JNKI- 1 reduced neuropathic pain in both sexes. Nerve injury caused spinal upregulation of the astroglial markers GFAP and Connexin 43 in both sexes. Collectively, our data confirmed male-dominant microglial signaling but also revealed sex-independent astroglial signaling in the spinal cord in inflammatory and neuropathic pain.展开更多
Programmed cell death protein 1(PD-1)is an immune checkpoint modulator and a major target of immunotherapy as anti-PD-1 monoclonal antibodies have demonstrated remarkable efficacy in cancer treatment.Accumulating evid...Programmed cell death protein 1(PD-1)is an immune checkpoint modulator and a major target of immunotherapy as anti-PD-1 monoclonal antibodies have demonstrated remarkable efficacy in cancer treatment.Accumulating evidence suggests an important role of PD-1 in the central nervous system(CNS).PD-1 has been implicated in CNS disorders such as brain tumors,Alzheimer’s disease,ischemic stroke,spinal cord injury,multiple sclerosis,cognitive function,and pain.PD-1 signaling suppresses the CNS immune response via resident microglia and infiltrating peripheral immune cells.Notably,PD-1 is also widely expressed in neurons and suppresses neuronal activity via downstream Src homology 2 domain-containing protein tyrosine phosphatase 1 and modulation of ion channel function.An improved understanding of PD-1 signaling in the cross-talk between glial cells,neurons,and peripheral immune cells in the CNS will shed light on immunomodulation,neuromodulation,and novel strategies for treating brain diseases.展开更多
Increasing evidence suggests that cytokines and chemokines play crucial roles in chronic itch. In the present study, we evaluated the roles of tumor necrosis factor-alpha （TNF-c0 and its receptors TNF receptor subtyp...Increasing evidence suggests that cytokines and chemokines play crucial roles in chronic itch. In the present study, we evaluated the roles of tumor necrosis factor-alpha （TNF-c0 and its receptors TNF receptor subtype-I （TNFR1） and TNFR2 in acute and chronic itch in mice. Compared to wild-type （WT） mice, TNFRl-knockout （TNFR1-KO） and TNFR1/R2 double-KO （DKO）, but not TNFR2-KO mice, exhibited reduced acute itch induced by compound 48/80 and chloroquine （CQ）. Application of the TNF-synthesis inhibitor thalidomide and the TNF-at antagonist etanercept dose-dependently suppressed acute itch. Intradermal injection of TNF-α was not sufficient to evoke scratching, but potentiated itch induced by compound 48/80, but not CQ. In addition, compound 48/80 induced TNF-α mRNA expression in the skin, while CQ induced its expression in the dorsal root ganglia （DRG） and spinal cord. Furthermore, chronic itch induced by dry skin was reduced by administration of thalidomide and etaner- cept and in TNFR1/R2 DKO mice. Dry skin induced TNF- expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-c^-fNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be benefi- cial for chronic itch treatment.展开更多
Voltage-gated sodium channels （Navs） play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained h...Voltage-gated sodium channels （Navs） play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained human dorsal root ganglion （hDRG） tissues from healthy donors. PCR analysis of seven DRG-expressed Nav subtypes revealed that the hDRG has higher expression of Navl.7 （,-~ 50% of total Nav expression） and lower expres- sion of Navl.8 （~ 12%）, whereas the mouse DRG has higher expression of Nav 1.8 （- 45%） and lower expression of Navl.7 （- 18%）. To mimic Nav regulation in chronic pain, we treated hDRG neurons in primary cultures with paclitaxel （0.1-1 μmol/L） for 24 h. Paclitaxel increased the Navl.7 but not Navl.8 expression and also increased the transient Na＋ currents and action potential firing frequency in small-diameter （〈50 ~tm） hDRG neurons. Thus, the hDRG provides a translational model in which to study ＂human pain in a dish＂ and test new pain therapeutics.展开更多
The 2021 Nobel Prize in Physiology or Medicine was awarded to two sensory neurobiologists and pain researchers,David.Julius at the University of California in San Francisco and Ardem Patapoutian at Scripps Research in...The 2021 Nobel Prize in Physiology or Medicine was awarded to two sensory neurobiologists and pain researchers,David.Julius at the University of California in San Francisco and Ardem Patapoutian at Scripps Research in San Diego,for their discoveries of thermal and mechanical transducers[1](https://www.nobelprize.org/prizes/medicine/2021/advanced-infor mation/).As the Nobel Committee stated,“the question of how we sense the physical world through somatic sensation has fascinated humankind for millennia,however,the identity of the molecular transducers responsible for detecting and converting heat.展开更多
Abstract The voltage-gated Na＋ channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody （SVmab） reduces Na＋ currents and pain an...Abstract The voltage-gated Na＋ channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody （SVmab） reduces Na＋ currents and pain and itch responses in mice. Here, we investigated whether recom- binant SVmab （rSVmab） binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltagesensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1.7 in these tests. Patch-clamp recordings showed that SVmab, but not rSVmab, markedly inhibited Na＋ currents in Nav1.7-expressing HEK293 cells. Notably, electrical field stimulation increased the blocking activity of SVmab and rSVmab in Nav1.7- expressing HEK293 cells. SVmab was more effective than rSVmab in inhibiting paclitaxel-induced mechanical allodynia. SVmab also bound to human DRG neurons and inhibited their Na＋ currents. Finally, potential reasons for the differential efficacy of SVmab and rSVmab and future directions are discussed.展开更多
In 2012, we published the first special issue on mechanisms of pain and itch in Neuroscience Bulletin, which covered the peripheral, central, and glial mechanisms of pain and itch [1-5]. In the last 5 years, the field...In 2012, we published the first special issue on mechanisms of pain and itch in Neuroscience Bulletin, which covered the peripheral, central, and glial mechanisms of pain and itch [1-5]. In the last 5 years, the field has seen tremendous progress in the molecular and functional characterization of primary sensory neurons [6, 7], neurocircuits of pain and itch [8-10], immune and glial modulation of pain and itch [11-15], molecular mechanisms of pain [16, 17], and identification of brain signatures of pain [18]. Thus, it is timely to highlight the recent progress in a second special issue. I invited the previous authors and new authors from China, the USA, and Japan, and they have contributed 20 mini-reviews and original articles to this special issue.展开更多
Chronic pain is a major health problem world-wide. According to a recent report in the New England Journal of Medicine , the prevalence of pain in the United States is striking： more than 116 million Americans have p...Chronic pain is a major health problem world-wide. According to a recent report in the New England Journal of Medicine , the prevalence of pain in the United States is striking： more than 116 million Americans have pain that persist for weeks to years. Chronic pain is characterized as inflammatory pain, cancer pain, and neuropathic pain, and can result from such conditions as arthritis, cancer, diabe- tes, low back injury, surgery, viral infection, spinal cord injury, and stroke.展开更多
We have published two special issues on pain and itch in Neuroscience Bulletin that cover their peripheral,central,and glial mechanisms[1,2],The first special was published in 2012[1],highlighting several topics such ...We have published two special issues on pain and itch in Neuroscience Bulletin that cover their peripheral,central,and glial mechanisms[1,2],The first special was published in 2012[1],highlighting several topics such as Toll-like receptors,capsaicin receptor TRPVI,interactionof u-and 8-opioid receptors,and population coding of somatic sensations.In 2018,we published the second special issue[2],which covered a wide breath of research,including molecular and functional characterization of primary sensory neurons,neurocircuits of pain and itch,Na+channel expression in human sensory neurons,modulation ofpainand itch byspinal glia,infection,sex dimorphisms inpain。展开更多
It is widely accepted that microglia are present in the central nervous system(CNS)but not in the peripheral nervous system(PNS).1,2 However,this notion is challenged by a recent study published in Cell.3 Wu et al.dis...It is widely accepted that microglia are present in the central nervous system(CNS)but not in the peripheral nervous system(PNS).1,2 However,this notion is challenged by a recent study published in Cell.3 Wu et al.discovered microglia-like cells that envelop the neuronal soma in the PNS,specifically in the dorsal root ganglion(DRG)and sympathetic ganglion(SG).These microglia-like cells share transcriptomic and epigenetic profiles with CNS microglia and play a key role in regulating the neuronal soma sizes in the DRG and SG.Notably,PNS microglia-like cells have been identified in primates(humans and macaques)and large-body-sized animals(e.g.,pigs)but are absent in small-body-sized animals,such as rodents(mice and rats).3 This absence underscores the limitations of using rodent models to study human diseases.展开更多
In 2012,we published the first special issue on the mechanisms of pain and itch in Neuroscience Bulletin[1],covering peripheral[2,3],central[4],and glial[5]mechanisms.In 2018,the second special issue expanded on these...In 2012,we published the first special issue on the mechanisms of pain and itch in Neuroscience Bulletin[1],covering peripheral[2,3],central[4],and glial[5]mechanisms.In 2018,the second special issue expanded on these topics[6],featuring single-cell profiling and in vivo Ca2+imaging of primary sensory neurons[7,8],and illustrating how nociceptors regulate pain,itch,and infection[9].It also highlighted spinal neurocircuits of pain[10]and itch[11],glial contributions[12],sex differences[13],and supraspinal mechanisms underlying pain and empathy[14,15].Over the past seven years,significant advances have been made in neuroglial and neuroimmune interactions and supraspinal circuits.Thus,this third special issue—comprising one review,eleven original articles,and one research highlight[16,17,18,19,20,21,22,23,24,25,26,27,28]—timely summarizes recent progress in pain and itch research.展开更多
Pain is a main symptom in inflammation,and inflammation induces pain via inflammatory mediators acting on nociceptive neurons.Macrophages and microglia are distinct cell types,representing immune cells and glial cells...Pain is a main symptom in inflammation,and inflammation induces pain via inflammatory mediators acting on nociceptive neurons.Macrophages and microglia are distinct cell types,representing immune cells and glial cells,respectively,but they share similar roles in pain regulation.Macrophages are key regulators of inflammation and pain.Macrophage polarization plays different roles in inducing and resolving pain.Notably,macrophage polarization and phagocytosis can be induced by specialized pro-resolution mediators(SPMs).SPMs also potently inhibit inflammatory and neuropathic pain via immunomodulation and neuromodulation.In this review,we discuss macrophage signaling involved in pain induction and resolution,as well as in maintaining physiological pain.Microglia are macrophage-like cells in the central nervous system(CNS)and drive neuroinflammation and pathological pain in various inflammatory and neurological disorders.Microglia-produced inflammatory cytokines can potently regulate excitatory and inhibitory synaptic transmission as neuromodulators.We also highlight sex differences in macrophage and microglial signaling in inflammatory and neuropathic pain.Thus,targeting macrophage and microglial signaling in distinct locations via pharmacological approaches,including immunotherapies,and non-pharmacological approaches will help to control chronic inflammation and chronic pain.展开更多
基金supported by the US National Institutes of Health (R01-DE17794, R01-NS54362 and R01-NS67686)
文摘Toll-like receptors （TLRs） are germline-encoded pattern-recognition receptors that initiate innate immune re- sponses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associated molecular patterns （PAMPs）. After tissue injury or cellular stress, TLRs also detect endogenous ligands known as danger-associated molecular patterns （DAMPs）. TLRs are expressed in both non-neuronal and neuronal cell types in the central nervous system （CNS） and contribute to both infectious and non-infectious disorders in the CNS. Following tissue insult and nerve injury, TLRs （such as TLR2, TLR3, and TLR4） induce the activation of microglia and astrocytes and the production of the proinflammatory cytokines in the spinal cord, leading to the development and maintenance of inflammatory pain and neu- ropathic pain. In particular, primary sensory neurons, such as nociceptors, express TLRs （e.g., TLR4 and TLR7） to sense exogenous PAMPs and endogenous DAMPs released after tissue injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of affected people, insights into TLR signaling in the nervous system will open a new avenue for the management of clinical pain and itch.
基金supported by grants from the US National Institutes of Health (R01-DE17794,R01-NS54362 and R01-NS67686)
文摘Objective To investigate the role of oxidative stress in itch-indicative scratching behavior in mice, and further- more, to define the cellular and molecular mechanisms underlying oxidative stress-mediated itch. Methods Scratching behavior was induced by intradermal injection of the oxidants hydrogen peroxide （H202） or tert-butylhydroperoxide （tBHP） into the nape of the neck in mice. The mice were observed for 30 rain. Results Intradermal H202 （0.03%-1%） or tBHP （1-30 pmol） elicited robust scratching behavior, displaying an inverted U-shaped dose-response curve. Naloxone, an opioid receptor antagonist, but not morphine, largely suppressed the oxidant-induced scratching. Chlorpheniramine, a histamine H1 receptor antagonist, blocked histamine- but not oxidant-induced scratching, indicating the involvement of a histamine-independent mechanism in oxidant-evoked itch. Further, resiniferatoxin treatment abolished oxidant-induced scratching, suggesting an essential role of C-fibers. Notably, blockade of transient receptor potential subtype ankyrin 1 （TRPA1） with the selective TRPA1 antagonist HC-030031, or genetic deletion of Trpal but not Trpvl （subfamily V, mem- ber 1） resulted in a profound reduction in H202-evoked scratching. Finally, systemic administration of the antioxidant N- acetyl-L-cysteine or trolox （a water-soluble vitamin E analog） attenuated scratching induced by the oxidants. Conclusion Oxidative stress by different oxidants induces profound scratching behavior, which is largely histamine- and TRPV1- independent but TRPAl-dependent. Antioxidants and TRPA1 antagonists may be used to treat human itch conditions as- sociated with oxidative stress.
基金supported by grants from the National Natural Science Foundation of China(31400949,81502102,31471059,81371498,and 31371121)NIH R01,USA Grants(DE17794,DE22743,and NS87988)
文摘Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 （C-C motif chemokine ligand 2） has been shown to enhance N-methyl-D-aspartate （NMDA）-induced currents in spinal outer lamina II （Iio） neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expres- sion in excitatory vesicular glutamate transporter subtype 2-positive （VGLUT2＋） neurons. CCL2 increased NMDA- induced currents in CCR2＋/VGLUT2＋ neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin- expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2- expressing excitatory neurons in spinal lamina Iio, and this underlies the generation of central sensitization in patho- logical pain.
基金supported by NIH R01 grants DE17794,DE22743,and NS87988 to RRJsupported by NIH T32 2T32GM008600a Foundation of Anesthesia Education and Research Fellowship
文摘Increasing evidence suggests that spinal micro- glia regulate pathological pain in males. In this study, we investigated the effects of several microglial and astroglial modulators on inflammatory and neuropathic pain follow- ing intrathecal injection in male and female mice. These modulators were the microglial inhibitors minocycline and ZVEID （a caspase-6 inhibitor） and the astroglial inhibitors L-α-aminoadipate （L-AA, an astroglial toxin） and car- benoxolone （a connexin 43 inhibitor）, as well as U0126 （an ERK kinase inhibitor） and D-JNKI-1 （a c-Jun N-terminal kinase inhibitor）. We found that spinal administration of minocycline or ZVEID, or Caspase6 deletion, reduced formalin-induced inflammatory and nerve injury-induced neuropathic pain primarily in male mice. In contrast, intrathecal L-AA reduced neuropathic pain but not inflam- matory pain in both sexes. Intrathecal U0126 and D-JNKI- 1 reduced neuropathic pain in both sexes. Nerve injury caused spinal upregulation of the astroglial markers GFAP and Connexin 43 in both sexes. Collectively, our data confirmed male-dominant microglial signaling but also revealed sex-independent astroglial signaling in the spinal cord in inflammatory and neuropathic pain.
基金The work related to this review was partially supported by Duke University Fund.
文摘Programmed cell death protein 1(PD-1)is an immune checkpoint modulator and a major target of immunotherapy as anti-PD-1 monoclonal antibodies have demonstrated remarkable efficacy in cancer treatment.Accumulating evidence suggests an important role of PD-1 in the central nervous system(CNS).PD-1 has been implicated in CNS disorders such as brain tumors,Alzheimer’s disease,ischemic stroke,spinal cord injury,multiple sclerosis,cognitive function,and pain.PD-1 signaling suppresses the CNS immune response via resident microglia and infiltrating peripheral immune cells.Notably,PD-1 is also widely expressed in neurons and suppresses neuronal activity via downstream Src homology 2 domain-containing protein tyrosine phosphatase 1 and modulation of ion channel function.An improved understanding of PD-1 signaling in the cross-talk between glial cells,neurons,and peripheral immune cells in the CNS will shed light on immunomodulation,neuromodulation,and novel strategies for treating brain diseases.
基金supported by grants from the National Natural Science Foundation of China(31371179 and 81300968)the Natural Science Foundation of Jiangsu Province,China(BK20140372)+2 种基金the Scientific Funding from Jiangsu Province,China(2015-JY-029)the Second Affiliated Hospital of Soochow University Preponderant Clinic Discipline Group Project Funding(XKQ2015007)a Project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions,Jiangsu Province,China
文摘Increasing evidence suggests that cytokines and chemokines play crucial roles in chronic itch. In the present study, we evaluated the roles of tumor necrosis factor-alpha （TNF-c0 and its receptors TNF receptor subtype-I （TNFR1） and TNFR2 in acute and chronic itch in mice. Compared to wild-type （WT） mice, TNFRl-knockout （TNFR1-KO） and TNFR1/R2 double-KO （DKO）, but not TNFR2-KO mice, exhibited reduced acute itch induced by compound 48/80 and chloroquine （CQ）. Application of the TNF-synthesis inhibitor thalidomide and the TNF-at antagonist etanercept dose-dependently suppressed acute itch. Intradermal injection of TNF-α was not sufficient to evoke scratching, but potentiated itch induced by compound 48/80, but not CQ. In addition, compound 48/80 induced TNF-α mRNA expression in the skin, while CQ induced its expression in the dorsal root ganglia （DRG） and spinal cord. Furthermore, chronic itch induced by dry skin was reduced by administration of thalidomide and etaner- cept and in TNFR1/R2 DKO mice. Dry skin induced TNF- expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-c^-fNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be benefi- cial for chronic itch treatment.
基金supported in part by NIH RO1Grants NS87988,DE17794,and DE22743 to R.R.J and NS89479 to S.Y.L and R.R.J
文摘Voltage-gated sodium channels （Navs） play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained human dorsal root ganglion （hDRG） tissues from healthy donors. PCR analysis of seven DRG-expressed Nav subtypes revealed that the hDRG has higher expression of Navl.7 （,-~ 50% of total Nav expression） and lower expres- sion of Navl.8 （~ 12%）, whereas the mouse DRG has higher expression of Nav 1.8 （- 45%） and lower expression of Navl.7 （- 18%）. To mimic Nav regulation in chronic pain, we treated hDRG neurons in primary cultures with paclitaxel （0.1-1 μmol/L） for 24 h. Paclitaxel increased the Navl.7 but not Navl.8 expression and also increased the transient Na＋ currents and action potential firing frequency in small-diameter （〈50 ~tm） hDRG neurons. Thus, the hDRG provides a translational model in which to study ＂human pain in a dish＂ and test new pain therapeutics.
文摘The 2021 Nobel Prize in Physiology or Medicine was awarded to two sensory neurobiologists and pain researchers,David.Julius at the University of California in San Francisco and Ardem Patapoutian at Scripps Research in San Diego,for their discoveries of thermal and mechanical transducers[1](https://www.nobelprize.org/prizes/medicine/2021/advanced-infor mation/).As the Nobel Committee stated,“the question of how we sense the physical world through somatic sensation has fascinated humankind for millennia,however,the identity of the molecular transducers responsible for detecting and converting heat.
基金supported by National Institutes of Health Grants R01NS89479,R01NS045594 and ROINS055860
文摘Abstract The voltage-gated Na＋ channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody （SVmab） reduces Na＋ currents and pain and itch responses in mice. Here, we investigated whether recom- binant SVmab （rSVmab） binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltagesensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1.7 in these tests. Patch-clamp recordings showed that SVmab, but not rSVmab, markedly inhibited Na＋ currents in Nav1.7-expressing HEK293 cells. Notably, electrical field stimulation increased the blocking activity of SVmab and rSVmab in Nav1.7- expressing HEK293 cells. SVmab was more effective than rSVmab in inhibiting paclitaxel-induced mechanical allodynia. SVmab also bound to human DRG neurons and inhibited their Na＋ currents. Finally, potential reasons for the differential efficacy of SVmab and rSVmab and future directions are discussed.
文摘In 2012, we published the first special issue on mechanisms of pain and itch in Neuroscience Bulletin, which covered the peripheral, central, and glial mechanisms of pain and itch [1-5]. In the last 5 years, the field has seen tremendous progress in the molecular and functional characterization of primary sensory neurons [6, 7], neurocircuits of pain and itch [8-10], immune and glial modulation of pain and itch [11-15], molecular mechanisms of pain [16, 17], and identification of brain signatures of pain [18]. Thus, it is timely to highlight the recent progress in a second special issue. I invited the previous authors and new authors from China, the USA, and Japan, and they have contributed 20 mini-reviews and original articles to this special issue.
文摘Chronic pain is a major health problem world-wide. According to a recent report in the New England Journal of Medicine , the prevalence of pain in the United States is striking： more than 116 million Americans have pain that persist for weeks to years. Chronic pain is characterized as inflammatory pain, cancer pain, and neuropathic pain, and can result from such conditions as arthritis, cancer, diabe- tes, low back injury, surgery, viral infection, spinal cord injury, and stroke.
基金supported by the National Natural Science Foundations of China(81620108008 and 31971112)the Innovation Capability Support Program of Shaanxi Province,China(2021TD-57).
文摘We have published two special issues on pain and itch in Neuroscience Bulletin that cover their peripheral,central,and glial mechanisms[1,2],The first special was published in 2012[1],highlighting several topics such as Toll-like receptors,capsaicin receptor TRPVI,interactionof u-and 8-opioid receptors,and population coding of somatic sensations.In 2018,we published the second special issue[2],which covered a wide breath of research,including molecular and functional characterization of primary sensory neurons,neurocircuits of pain and itch,Na+channel expression in human sensory neurons,modulation ofpainand itch byspinal glia,infection,sex dimorphisms inpain。
基金supported by a research fund from Duke University.R.R.J.is partially supported by the NIH grant R01NS13181201.
文摘It is widely accepted that microglia are present in the central nervous system(CNS)but not in the peripheral nervous system(PNS).1,2 However,this notion is challenged by a recent study published in Cell.3 Wu et al.discovered microglia-like cells that envelop the neuronal soma in the PNS,specifically in the dorsal root ganglion(DRG)and sympathetic ganglion(SG).These microglia-like cells share transcriptomic and epigenetic profiles with CNS microglia and play a key role in regulating the neuronal soma sizes in the DRG and SG.Notably,PNS microglia-like cells have been identified in primates(humans and macaques)and large-body-sized animals(e.g.,pigs)but are absent in small-body-sized animals,such as rodents(mice and rats).3 This absence underscores the limitations of using rodent models to study human diseases.
文摘In 2012,we published the first special issue on the mechanisms of pain and itch in Neuroscience Bulletin[1],covering peripheral[2,3],central[4],and glial[5]mechanisms.In 2018,the second special issue expanded on these topics[6],featuring single-cell profiling and in vivo Ca2+imaging of primary sensory neurons[7,8],and illustrating how nociceptors regulate pain,itch,and infection[9].It also highlighted spinal neurocircuits of pain[10]and itch[11],glial contributions[12],sex differences[13],and supraspinal mechanisms underlying pain and empathy[14,15].Over the past seven years,significant advances have been made in neuroglial and neuroimmune interactions and supraspinal circuits.Thus,this third special issue—comprising one review,eleven original articles,and one research highlight[16,17,18,19,20,21,22,23,24,25,26,27,28]—timely summarizes recent progress in pain and itch research.
文摘Pain is a main symptom in inflammation,and inflammation induces pain via inflammatory mediators acting on nociceptive neurons.Macrophages and microglia are distinct cell types,representing immune cells and glial cells,respectively,but they share similar roles in pain regulation.Macrophages are key regulators of inflammation and pain.Macrophage polarization plays different roles in inducing and resolving pain.Notably,macrophage polarization and phagocytosis can be induced by specialized pro-resolution mediators(SPMs).SPMs also potently inhibit inflammatory and neuropathic pain via immunomodulation and neuromodulation.In this review,we discuss macrophage signaling involved in pain induction and resolution,as well as in maintaining physiological pain.Microglia are macrophage-like cells in the central nervous system(CNS)and drive neuroinflammation and pathological pain in various inflammatory and neurological disorders.Microglia-produced inflammatory cytokines can potently regulate excitatory and inhibitory synaptic transmission as neuromodulators.We also highlight sex differences in macrophage and microglial signaling in inflammatory and neuropathic pain.Thus,targeting macrophage and microglial signaling in distinct locations via pharmacological approaches,including immunotherapies,and non-pharmacological approaches will help to control chronic inflammation and chronic pain.
