In a newborn affected by a non involuting congenital hemangioma we measured allodynia through the application of a standard tactile stimulus and hyperalgesia through the regular administration of the Comfort scale whi...In a newborn affected by a non involuting congenital hemangioma we measured allodynia through the application of a standard tactile stimulus and hyperalgesia through the regular administration of the Comfort scale which rates pain intensity. The baby presented signs of these pathological events over long periods of the disease. They may be attributed to the high amount of the nociceptive ligands in the hemangioma microenviroment and to the elevated concentration of TNF-alpha and IL-6 in the blood. For a long time, the pain was relieved by a combination of opioids, adjuvants and paracetamol, but also by thalidomide and unexpectedly by interferon alpha. A mechanism-based pain treatment needs to take into account the processes underlying pain and also the ongoing pathology.展开更多
Puerarin is a major active ingredient of the traditional Chinese plant medicine,Radix Puerariae,and commonly used in the treatment of myocardial and cerebral ischemia.However,the effects of puerarin on neuropathic pai...Puerarin is a major active ingredient of the traditional Chinese plant medicine,Radix Puerariae,and commonly used in the treatment of myocardial and cerebral ischemia.However,the effects of puerarin on neuropathic pain are still unclear.In this study,a neuropathic pain animal model was created by partial sciatic nerve ligation.Puerarin（30 or 60 mg/kg） was intraperitoneally injected once a day for 7 days.Mechanical allodynia and thermal hyperalgesia were examined at 1 day after model establishment.Mechanical threshold and paw withdrawal latency markedly increased in a dose-dependent manner in puerarin-treated rats,especially at 7 days after model establishment.At 7 days after model establishment,quantitative real-time reverse transcriptase-polymerase chain reaction results showed that puerarin administration reversed m RNA expression of transient receptor potential vanilloid 1（Trpv1） and transient receptor potential ankyrin 1（Trpa1） in a dose-dependent manner in dorsal root ganglion neurons after peripheral nerve injury.These results suggest that puerarin dose-dependently ameliorates neuropathic pain by suppressing Trpv1 and Trpa1 up-regulation in dorsal root ganglion of neuropathic pain rats.展开更多
The development of chronic pain after amputations is not an uncommon event. In some cases the most disabling problem is represented by the symptom called dynamic mechanical allodynia, characterized by the painful sens...The development of chronic pain after amputations is not an uncommon event. In some cases the most disabling problem is represented by the symptom called dynamic mechanical allodynia, characterized by the painful sensation evoked by gently stroking the skin. Despite the growing interest in understanding pain mechanisms, little is known about the mechanism sustaining this peculiar type of pain. We present here the case of a 53-year-old female patient who complained of severe tactile allodynia in the hand after amputation of her left second finger, resistant to several medical and surgical treatments. In order to gain information about the pain mechanism, two neurodiagnostic skin biopsies were obtained from the area of tactile allodynia and from the contralateral, normal skin area. Skin biopsies showed an unexpected increased innervation of the allodynic skin compared to the contralateral, normal skin area(+ 80.1%). Hyperinnervation has been proposed as a mechanism of pain following nerve lesions, but the increased innervation described here could be also attributed to neuronal plasticity occurring in chronic inflammatory conditions. Independently from the uncertain cause of the epidermal hyperinnervation, in this patient we tried to reduce the elevated number of epidermal nerve fibres by treating the skin with topical capsaicin(0.075%) three times a day, and obtained a persistent pain relief. In conclusion, neurodiagnostic skin biopsy might represent an useful tool for detecting derangements of epidermal innervation in patients with dynamic mechanical allodynia and can help to select an individually tailored therapeutic strategy in such difficult clinical conditions. Further studies are needed to clarify this issue and try to gain better understanding of chronic pain mechanisms in patients who underwent finger amputation.展开更多
Background: The primary motor cortex (M1) stimulation (MCS) is a useful tool for attenuation of the peripheral neuropathic pain in patients with pharmacologically refractory pain. Furthermore, that neurological proced...Background: The primary motor cortex (M1) stimulation (MCS) is a useful tool for attenuation of the peripheral neuropathic pain in patients with pharmacologically refractory pain. Furthermore, that neurological procedure may also cause antinociception in rodents with neuropathic pain. Cold allodynia is a frequent clinical finding in patients with neuropathic pain, then, we evaluated if an adapted model of neuropathy induced by chronic constriction injury (CCI) of the ischiadicus nervus (sciatic nerve) produces cold allodynia in an animal model of chronic pain. In addition, we also investigated the effect of the electrical stimulation of the M1 on chronic neuropathic pain condition in laboratory animals. Methods: Male Wistar rats were used. An adapted model of peripheral mononeuropathy induced by CCI was carried out by placing a single loose ligature around the right sciatic nerve. The acetone test was used to evaluate the cold allodynia in CCI or Sham (without ligature) rats. The MCS (M1) was performed at low-frequency (20 μA, 100 Hz) during 15 s by deep brain stimulation (DBS-Thomas Recording device) 21 days after CCI or Sham procedures. The cold allodynia was measured before and immediately after the neurostimulation of M1 in the following time-window: 0, 15 and 30 min after MCS. Results: Cold allodynia threshold increased in animals with chronic neuropathic pain submitted to the acetone test 21 days after the CCI surgery. The M1-stimulation by DBS procedure decreased the cold allodynia immediately and until 30 min after M1-stimulation in rats with chronic neuropathic pain. Conclusion: The current proposal for a CCI model by a single loose ligature of the sciatic nerve can be employed as an experimental model of chronic neuropathic pain in rats submitted to peripheral nervous system injury. The M1-stimulation produced antinociception in rats with chronic neuropathic pain. Thus, we reinforced that the MCS decreases cold allodynia in laboratory animals submitted to persistent sciatic nerve constriction and can be a more reasonable procedure for the treatment of chronic intractable neuropathic pain.展开更多
Background: Mechanical ventilation (hit one) during surgery (hit two) is often needed and both induce an inflammatory response. Dysregulation of the inflammatory response can cause chronic postoperative pain. Methods:...Background: Mechanical ventilation (hit one) during surgery (hit two) is often needed and both induce an inflammatory response. Dysregulation of the inflammatory response can cause chronic postoperative pain. Methods: Healthy C57BL6 mice (n = 56) were mechanically ventilated (MV) and allocated to receive sham (MV-sham) or mechanically ventilation with chronic constriction injury (MV-CCI) surgery in the left hind paw. Plasma interleukin (IL)-1β, IL-6, IL-10, keratinocyte derived chemokine (KC) and tumor necrosis factor (TNF)-α were determined on day 0 and 16. Sensory testing was performed on day 0, 3, 7 and 16 by cold plate test (number of lifts (NOL) and cumulative reaction time (CRT)) and von Frey test. The effect of lidocaine on cytokines and sensory testing was analyzed. Results: MV-Sham showed an increase in IL-1β and TNF-α, and MV- CCI-lido increased levels of KC compared with MV on day 0. No difference in cytokine levels was observed on day 16. NOL of the left paw versus the right was increased in MV-CCI on day 7, and in MV-CCI-lido on day 7 and 16. The NOL of the left paw was decreased in MV-sham and MV-CCI-lido compared with MV-CCI on day 16. The CRT of the left paw was increased for MV-CCI on day 3 and 7, and for MV-CCI-lido on day 7. On day 16, MV-sham and MV-CCI-lido showed a decreased CRT of the left paw compared with MV-CCI. Conclusion: Nerve injury and not systemic inflammatory response seems mandatory for development of neuropathic pain in this “two-hit” model. Lidocaine attenuates cold allodynia in mice.展开更多
The chronic use of morphine and other opioids is associated with opioid-induced hypersensitivity(OIH)and analgesic tolerance.Among the different forms of OIH and tolerance,the opioid receptors and cell types mediating...The chronic use of morphine and other opioids is associated with opioid-induced hypersensitivity(OIH)and analgesic tolerance.Among the different forms of OIH and tolerance,the opioid receptors and cell types mediating opioid-induced mechanical allodynia and anti-allodynic tolerance remain unresolved.Here we demonstrated that the loss of peripheralμ-opioid receptors(MORs)or MOR-expressing neurons attenuated thermal tolerance,but did not affect the expression and maintenance of morphine-induced mechanical allodynia and anti-allodynic tolerance.To confirm this result,we made dorsal root ganglia-dorsal roots-sagittal spinal cord slice preparations and recorded low-threshold Aβ-fiber stimulation-evoked inputs and outputs in superficial dorsal horn neurons.Consistent with the behavioral results,peripheral MOR loss did not prevent the opening of Aβmechanical allodynia pathways in the spinal dorsal horn.Therefore,the peripheral MOR signaling pathway may not be an optimal target for preventing mechanical OIH and analgesic tolerance.Future studies should focus more on central mechanisms.展开更多
Mechanical allodynia(MA),including punctate and dynamic forms,is a common and debilitating symptom suffered by millions of chronic pain patients.Some peripheral injuries result in the development of bilateral MA,while...Mechanical allodynia(MA),including punctate and dynamic forms,is a common and debilitating symptom suffered by millions of chronic pain patients.Some peripheral injuries result in the development of bilateral MA,while most injuries usually led to unilateral MA.To date,the control of such laterality remains poorly understood.Here,to study the role of microglia in the control of MA laterality,we used genetic strategies to deplete microglia and tested both dynamic and punctate forms of MA in mice.Surprisingly,the depletion of central microglia did not prevent the induction of bilateral dynamic and punctate MA.Moreover,in dorsal root ganglion-dorsal root-sagittal spinal cord slice preparations we recorded the low-threshold Aβ-fiber stimulation-evoked inputs and outputs of superficial dorsal horn neurons.Consistent with behavioral results,microglial depletion did not prevent the opening of bilateral gates for Aβpathways in the superficial dorsal horn.This study challenges the role of microglia in the control of MA laterality in mice.Future studies are needed to further understand whether the role of microglia in the control of MA laterality is etiology-or species-specific.展开更多
Objective Low back pain is one of the most inextricable problems encountered in clinics. Animal models that imitate symptoms in humans are valuable tools for investigating low back pain mechanisms and the possible the...Objective Low back pain is one of the most inextricable problems encountered in clinics. Animal models that imitate symptoms in humans are valuable tools for investigating low back pain mechanisms and the possible therapeutic applications. With the development of genetic technology in pain field, the possibility of mutating specific genes in mice has provided a potent tool for investigating the specific mechanisms of pain. The aim of the present study was to develop a mouse model of chronic compression of dorsal root ganglion （CCD）, in which gene mutation can be applied to facilitate the studies of chronic pain. Methods Chronic compression of L4 and L5 dorsal root ganglia was conducted in mice by inserting fine stainless steel rods into the intervertebral foramina, one at L4 and the other at L5. Mechanical allodynia and thermal hyperalgesia were examined with von Frey filaments and radiating heat stimulator, respectively. Results The CCD mice displayed dramatic mechanical and thermal hyperalgesia as well as tactile allodynia in the hindpaw ipsilateral to CCD. In addition, this mechanical and thermal hyperalgesia as well as tactile allodynia was also found to spread to the contralateral hindpaw. Conclusion This model, combined with the possible genetic modification, will strengthen our knowledge of the underlying mechanisms of low back pain. It also favors the development of new treatment strategies for pain and hyperalgesia after spinal injury and other disorders which affect the dorsal root ganglion in humans.展开更多
Tetanic stimulation of the sciatic nerve （TSS） triggers long-term potentiation in the dorsal horn of the spinal cord and long-lasting pain hypersensitivity. CX3CL1- CX3CR1 signaling is an important pathway in neuron...Tetanic stimulation of the sciatic nerve （TSS） triggers long-term potentiation in the dorsal horn of the spinal cord and long-lasting pain hypersensitivity. CX3CL1- CX3CR1 signaling is an important pathway in neuronal- microglial activation. Nuclear factor nB （NF-KB） is a key signal transduction molecule that regulates neuroinflamma- tion and neuropathic pain. Here, we set out to determine whether and how NF-~B and CX3CR1 are involved in the mechanism underlying the pathological changes induced by TSS. After unilateral TSS, significant bilateral mechanical allodynia was induced, as assessed by the von Frey test. The expression of phosphorylated NF-nB （pNF-nB） and CX3CR1 was significantly up-regulated in the bilateral dorsal horn. Immunofluorescence staining demonstrated that pNF-κB and NeuN co-existed, implying that the NF-κB pathway is predominantly activated in neurons following TSS. Administration of either the NF-κB inhibitor ammo- nium pyrrolidine dithiocarbamate or a CX3CR1-neutralizing antibody blocked the development and maintenance of neuropathic pain. In addition, blockade of NF-κB down- regulated the expression of CX3CL1-CX3CR1 signaling,and conversely the CX3CRl-neutralizing antibody also down-regulated pNF-rd3. These findings suggest an involvement of NF-κB and the CX3CR1 signaling network in the development and maintenance of TSS-induced mechanical allodynia. Our work suggests the potential clinical application of NF-κB inhibitors or CX3CR 1-neutralizing antibodies in treating pathological pain.展开更多
Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brushevoked dynamic and filament-evoked punctate mechanical allodyn...Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brushevoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1(Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury(SNI).Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in na¨?ve but also in ML133-pretreated mice. In contrast, bicuculline, a GABAAreceptor antagonist, induced only punctate, but not dynamic,allodynia. These results indicated the involvement of glycinergic transmission in the development of dynamic allodynia. We further found that SNI significantly suppressed the frequency, but not the amplitude, of the glycinergic spontaneous inhibitory postsynaptic currents(gly-sIPSCs) in neurons on the lamina II-III border of the spinal dorsal horn, and pretreatment with ML133 prevented the SNI-induced gly-sIPSC reduction. Furthermore, 5 days after SNI, ML133, either by intrathecal administration oracute bath perfusion, and strychnine sensitively reversed the SNI-induced dynamic, but not punctate, allodynia and the gly-sIPSC reduction in lamina IIi neurons, respectively.In conclusion, our results suggest that blockade of Kir2.1 channels in the spinal dorsal horn selectively inhibits dynamic, but not punctate, mechanical allodynia by enhancing glycinergic inhibitory transmission.展开更多
Painful diabetic neuropathy(PDN)is a diabetes mellitus complication.Unfortunately,the mechanisms underlying PDN are still poorly understood.Adenosine triphosphate(ATP)-gated P2X7 receptor(P2X7R)plays a pivotal role in...Painful diabetic neuropathy(PDN)is a diabetes mellitus complication.Unfortunately,the mechanisms underlying PDN are still poorly understood.Adenosine triphosphate(ATP)-gated P2X7 receptor(P2X7R)plays a pivotal role in non-diabetic neuropathic pain,but little is known about its effects on streptozotocin(STZ)-induced peripheral neuropathy.Here,we explored whether spinal cord P2X7R was correlated with the generation of mechanical allodynia(MA)in STZ-induced type 1 diabetic neuropathy in mice.MA was assessed by measuring paw withdrawal thresholds and western blotting.Immunohistochemistry was applied to analyze the protein expression levels and localization of P2X7R.STZ-induced mice expressed increased P2X7R in the dorsal horn of the lumbar spinal cord during MA.Mice injected intrathecally with a selective antagonist of P2X7R and P2X7R knockout(KO)mice both presented attenuated progression of MA.Double-immunofluorescent labeling demonstrated that P2X7R-positive cells were mostly co-expressed with Iba1(a microglia marker).Our results suggest that P2X7R plays an important role in the development of MA and could be used as a cellular target for treating PDN.展开更多
Experimental studies have shown that exercise and human adipose-derived stem cells(ADSCs)play positive roles in spinal cord injury(SCI).However,whether ADSCs and/or exercise have a positive effect on SCI-induced neuro...Experimental studies have shown that exercise and human adipose-derived stem cells(ADSCs)play positive roles in spinal cord injury(SCI).However,whether ADSCs and/or exercise have a positive effect on SCI-induced neuropathic pain is still unclear.Thus,there is a need to explore the effects of exercise combined with administration of ADSCs on neuropathic pain after SCI.In this study,a thoracic 11(T11)SCI contusion model was established in adult C57BL/6 mice.Exercise was initiated from 7 days post-injury and continued to 28 days post-injury,and approximately 1×105 ADSCs were transplanted into the T11 spinal cord lesion site immediately after SCI.Motor function and neuropathic pain-related behaviors were assessed weekly using the Basso Mouse Scale,von Frey filament test,Hargreaves method,and cold plate test.Histological studies(Eriochrome cyanine staining and immunohistochemistry)were performed at the end of the experiment(28 days post-injury).Exercise combined with administration of ADSCs partially improved early motor function(7,14,and 21 days postinjury),mechanical allodynia,mechanical hypoalgesia,thermal hyperalgesia,and thermal hypoalgesia.Administration of ADSCs reduced white and gray matter loss at the lesion site.In addition,fewer microglia and astrocytes(as identified by expression of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein,respectively)were present in the lumbar dorsal horn in the SCI+ADSCs and SCI+exercise+ADSCs groups compared with the sham group.Our findings suggest that exercise combined with administration of ADSCs is beneficial for the early recovery of motor function and could partially ameliorate SCIinduced neuropathic pain.展开更多
文摘In a newborn affected by a non involuting congenital hemangioma we measured allodynia through the application of a standard tactile stimulus and hyperalgesia through the regular administration of the Comfort scale which rates pain intensity. The baby presented signs of these pathological events over long periods of the disease. They may be attributed to the high amount of the nociceptive ligands in the hemangioma microenviroment and to the elevated concentration of TNF-alpha and IL-6 in the blood. For a long time, the pain was relieved by a combination of opioids, adjuvants and paracetamol, but also by thalidomide and unexpectedly by interferon alpha. A mechanism-based pain treatment needs to take into account the processes underlying pain and also the ongoing pathology.
基金supported by the National Natural Science Foundation of China,No.81671891
文摘Puerarin is a major active ingredient of the traditional Chinese plant medicine,Radix Puerariae,and commonly used in the treatment of myocardial and cerebral ischemia.However,the effects of puerarin on neuropathic pain are still unclear.In this study,a neuropathic pain animal model was created by partial sciatic nerve ligation.Puerarin（30 or 60 mg/kg） was intraperitoneally injected once a day for 7 days.Mechanical allodynia and thermal hyperalgesia were examined at 1 day after model establishment.Mechanical threshold and paw withdrawal latency markedly increased in a dose-dependent manner in puerarin-treated rats,especially at 7 days after model establishment.At 7 days after model establishment,quantitative real-time reverse transcriptase-polymerase chain reaction results showed that puerarin administration reversed m RNA expression of transient receptor potential vanilloid 1（Trpv1） and transient receptor potential ankyrin 1（Trpa1） in a dose-dependent manner in dorsal root ganglion neurons after peripheral nerve injury.These results suggest that puerarin dose-dependently ameliorates neuropathic pain by suppressing Trpv1 and Trpa1 up-regulation in dorsal root ganglion of neuropathic pain rats.
文摘The development of chronic pain after amputations is not an uncommon event. In some cases the most disabling problem is represented by the symptom called dynamic mechanical allodynia, characterized by the painful sensation evoked by gently stroking the skin. Despite the growing interest in understanding pain mechanisms, little is known about the mechanism sustaining this peculiar type of pain. We present here the case of a 53-year-old female patient who complained of severe tactile allodynia in the hand after amputation of her left second finger, resistant to several medical and surgical treatments. In order to gain information about the pain mechanism, two neurodiagnostic skin biopsies were obtained from the area of tactile allodynia and from the contralateral, normal skin area. Skin biopsies showed an unexpected increased innervation of the allodynic skin compared to the contralateral, normal skin area(+ 80.1%). Hyperinnervation has been proposed as a mechanism of pain following nerve lesions, but the increased innervation described here could be also attributed to neuronal plasticity occurring in chronic inflammatory conditions. Independently from the uncertain cause of the epidermal hyperinnervation, in this patient we tried to reduce the elevated number of epidermal nerve fibres by treating the skin with topical capsaicin(0.075%) three times a day, and obtained a persistent pain relief. In conclusion, neurodiagnostic skin biopsy might represent an useful tool for detecting derangements of epidermal innervation in patients with dynamic mechanical allodynia and can help to select an individually tailored therapeutic strategy in such difficult clinical conditions. Further studies are needed to clarify this issue and try to gain better understanding of chronic pain mechanisms in patients who underwent finger amputation.
文摘Background: The primary motor cortex (M1) stimulation (MCS) is a useful tool for attenuation of the peripheral neuropathic pain in patients with pharmacologically refractory pain. Furthermore, that neurological procedure may also cause antinociception in rodents with neuropathic pain. Cold allodynia is a frequent clinical finding in patients with neuropathic pain, then, we evaluated if an adapted model of neuropathy induced by chronic constriction injury (CCI) of the ischiadicus nervus (sciatic nerve) produces cold allodynia in an animal model of chronic pain. In addition, we also investigated the effect of the electrical stimulation of the M1 on chronic neuropathic pain condition in laboratory animals. Methods: Male Wistar rats were used. An adapted model of peripheral mononeuropathy induced by CCI was carried out by placing a single loose ligature around the right sciatic nerve. The acetone test was used to evaluate the cold allodynia in CCI or Sham (without ligature) rats. The MCS (M1) was performed at low-frequency (20 μA, 100 Hz) during 15 s by deep brain stimulation (DBS-Thomas Recording device) 21 days after CCI or Sham procedures. The cold allodynia was measured before and immediately after the neurostimulation of M1 in the following time-window: 0, 15 and 30 min after MCS. Results: Cold allodynia threshold increased in animals with chronic neuropathic pain submitted to the acetone test 21 days after the CCI surgery. The M1-stimulation by DBS procedure decreased the cold allodynia immediately and until 30 min after M1-stimulation in rats with chronic neuropathic pain. Conclusion: The current proposal for a CCI model by a single loose ligature of the sciatic nerve can be employed as an experimental model of chronic neuropathic pain in rats submitted to peripheral nervous system injury. The M1-stimulation produced antinociception in rats with chronic neuropathic pain. Thus, we reinforced that the MCS decreases cold allodynia in laboratory animals submitted to persistent sciatic nerve constriction and can be a more reasonable procedure for the treatment of chronic intractable neuropathic pain.
文摘Background: Mechanical ventilation (hit one) during surgery (hit two) is often needed and both induce an inflammatory response. Dysregulation of the inflammatory response can cause chronic postoperative pain. Methods: Healthy C57BL6 mice (n = 56) were mechanically ventilated (MV) and allocated to receive sham (MV-sham) or mechanically ventilation with chronic constriction injury (MV-CCI) surgery in the left hind paw. Plasma interleukin (IL)-1β, IL-6, IL-10, keratinocyte derived chemokine (KC) and tumor necrosis factor (TNF)-α were determined on day 0 and 16. Sensory testing was performed on day 0, 3, 7 and 16 by cold plate test (number of lifts (NOL) and cumulative reaction time (CRT)) and von Frey test. The effect of lidocaine on cytokines and sensory testing was analyzed. Results: MV-Sham showed an increase in IL-1β and TNF-α, and MV- CCI-lido increased levels of KC compared with MV on day 0. No difference in cytokine levels was observed on day 16. NOL of the left paw versus the right was increased in MV-CCI on day 7, and in MV-CCI-lido on day 7 and 16. The NOL of the left paw was decreased in MV-sham and MV-CCI-lido compared with MV-CCI on day 16. The CRT of the left paw was increased for MV-CCI on day 3 and 7, and for MV-CCI-lido on day 7. On day 16, MV-sham and MV-CCI-lido showed a decreased CRT of the left paw compared with MV-CCI. Conclusion: Nerve injury and not systemic inflammatory response seems mandatory for development of neuropathic pain in this “two-hit” model. Lidocaine attenuates cold allodynia in mice.
基金supported by grants from the Ministry of Science and Technology of China(2021ZD0203302)the National Natural Science Foundation of China(32170996)+4 种基金Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(2021SHIBS0002)the Guangdong Science and Technology Committee(2019A1515010041,A2021319)the Shenzhen Innovation Committee of Science and Technology(ZDSYS20200811144002008)the Natural Science Foundation of Shenzhen University General Hospital(SUGH2018QD024)the Basic Research Project of Shenzhen Science and Technology Innovation Commission(JCYJ20210324100206017).
文摘The chronic use of morphine and other opioids is associated with opioid-induced hypersensitivity(OIH)and analgesic tolerance.Among the different forms of OIH and tolerance,the opioid receptors and cell types mediating opioid-induced mechanical allodynia and anti-allodynic tolerance remain unresolved.Here we demonstrated that the loss of peripheralμ-opioid receptors(MORs)or MOR-expressing neurons attenuated thermal tolerance,but did not affect the expression and maintenance of morphine-induced mechanical allodynia and anti-allodynic tolerance.To confirm this result,we made dorsal root ganglia-dorsal roots-sagittal spinal cord slice preparations and recorded low-threshold Aβ-fiber stimulation-evoked inputs and outputs in superficial dorsal horn neurons.Consistent with the behavioral results,peripheral MOR loss did not prevent the opening of Aβmechanical allodynia pathways in the spinal dorsal horn.Therefore,the peripheral MOR signaling pathway may not be an optimal target for preventing mechanical OIH and analgesic tolerance.Future studies should focus more on central mechanisms.
基金supported by grants from the Ministry of Science and Technology of China(2021ZD0203302)the National Natural Science Foundation of China(32170996,32060199)+3 种基金the Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(2021SHIBS0002)the Guangdong Science and Technology Committee(2019A1515010041,A2021319)the Shenzhen Innovation Committee of Science and Technology(ZDSYS20200811144002008)the Shenzhen Science and Technology Innovation Committee(JCYJ20180302174233348).
文摘Mechanical allodynia(MA),including punctate and dynamic forms,is a common and debilitating symptom suffered by millions of chronic pain patients.Some peripheral injuries result in the development of bilateral MA,while most injuries usually led to unilateral MA.To date,the control of such laterality remains poorly understood.Here,to study the role of microglia in the control of MA laterality,we used genetic strategies to deplete microglia and tested both dynamic and punctate forms of MA in mice.Surprisingly,the depletion of central microglia did not prevent the induction of bilateral dynamic and punctate MA.Moreover,in dorsal root ganglion-dorsal root-sagittal spinal cord slice preparations we recorded the low-threshold Aβ-fiber stimulation-evoked inputs and outputs of superficial dorsal horn neurons.Consistent with behavioral results,microglial depletion did not prevent the opening of bilateral gates for Aβpathways in the superficial dorsal horn.This study challenges the role of microglia in the control of MA laterality in mice.Future studies are needed to further understand whether the role of microglia in the control of MA laterality is etiology-or species-specific.
基金supported by the National Natural Science Foundation of China(No.30970971)Fourth Military Medical University Grant(No.00002215)
文摘Objective Low back pain is one of the most inextricable problems encountered in clinics. Animal models that imitate symptoms in humans are valuable tools for investigating low back pain mechanisms and the possible therapeutic applications. With the development of genetic technology in pain field, the possibility of mutating specific genes in mice has provided a potent tool for investigating the specific mechanisms of pain. The aim of the present study was to develop a mouse model of chronic compression of dorsal root ganglion （CCD）, in which gene mutation can be applied to facilitate the studies of chronic pain. Methods Chronic compression of L4 and L5 dorsal root ganglia was conducted in mice by inserting fine stainless steel rods into the intervertebral foramina, one at L4 and the other at L5. Mechanical allodynia and thermal hyperalgesia were examined with von Frey filaments and radiating heat stimulator, respectively. Results The CCD mice displayed dramatic mechanical and thermal hyperalgesia as well as tactile allodynia in the hindpaw ipsilateral to CCD. In addition, this mechanical and thermal hyperalgesia as well as tactile allodynia was also found to spread to the contralateral hindpaw. Conclusion This model, combined with the possible genetic modification, will strengthen our knowledge of the underlying mechanisms of low back pain. It also favors the development of new treatment strategies for pain and hyperalgesia after spinal injury and other disorders which affect the dorsal root ganglion in humans.
基金supported by the National Natural Science Foundation of China(81471130,31420103903,and 31421091)a Development Project of Shanghai Peak Disciplines Integrated Chinese and Western Medicine
文摘Tetanic stimulation of the sciatic nerve （TSS） triggers long-term potentiation in the dorsal horn of the spinal cord and long-lasting pain hypersensitivity. CX3CL1- CX3CR1 signaling is an important pathway in neuronal- microglial activation. Nuclear factor nB （NF-KB） is a key signal transduction molecule that regulates neuroinflamma- tion and neuropathic pain. Here, we set out to determine whether and how NF-~B and CX3CR1 are involved in the mechanism underlying the pathological changes induced by TSS. After unilateral TSS, significant bilateral mechanical allodynia was induced, as assessed by the von Frey test. The expression of phosphorylated NF-nB （pNF-nB） and CX3CR1 was significantly up-regulated in the bilateral dorsal horn. Immunofluorescence staining demonstrated that pNF-κB and NeuN co-existed, implying that the NF-κB pathway is predominantly activated in neurons following TSS. Administration of either the NF-κB inhibitor ammo- nium pyrrolidine dithiocarbamate or a CX3CR1-neutralizing antibody blocked the development and maintenance of neuropathic pain. In addition, blockade of NF-κB down- regulated the expression of CX3CL1-CX3CR1 signaling,and conversely the CX3CRl-neutralizing antibody also down-regulated pNF-rd3. These findings suggest an involvement of NF-κB and the CX3CR1 signaling network in the development and maintenance of TSS-induced mechanical allodynia. Our work suggests the potential clinical application of NF-κB inhibitors or CX3CR 1-neutralizing antibodies in treating pathological pain.
基金supported by grants from the National Natural Science Foundation of China (31771188 and 31471027)the Science and Technology Commission of Shanghai Municipality, China (13DJ1400302)
文摘Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brushevoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1(Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury(SNI).Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in na¨?ve but also in ML133-pretreated mice. In contrast, bicuculline, a GABAAreceptor antagonist, induced only punctate, but not dynamic,allodynia. These results indicated the involvement of glycinergic transmission in the development of dynamic allodynia. We further found that SNI significantly suppressed the frequency, but not the amplitude, of the glycinergic spontaneous inhibitory postsynaptic currents(gly-sIPSCs) in neurons on the lamina II-III border of the spinal dorsal horn, and pretreatment with ML133 prevented the SNI-induced gly-sIPSC reduction. Furthermore, 5 days after SNI, ML133, either by intrathecal administration oracute bath perfusion, and strychnine sensitively reversed the SNI-induced dynamic, but not punctate, allodynia and the gly-sIPSC reduction in lamina IIi neurons, respectively.In conclusion, our results suggest that blockade of Kir2.1 channels in the spinal dorsal horn selectively inhibits dynamic, but not punctate, mechanical allodynia by enhancing glycinergic inhibitory transmission.
基金Project supported by the National Natural Science Foundation of China(Nos.81771208 and 81971043)the Health and Family Planning Commission of Wuxi(No.YGZXM1406)+3 种基金the Wuxi Municipal Bureau on Science and Technology(No.CSE31N1614)the Fundamental Research Fund of Wuxi People’s Hospital(No.RKA201720)the Technology for Social Development Project of Kunshan(No.KS1539)China.
文摘Painful diabetic neuropathy(PDN)is a diabetes mellitus complication.Unfortunately,the mechanisms underlying PDN are still poorly understood.Adenosine triphosphate(ATP)-gated P2X7 receptor(P2X7R)plays a pivotal role in non-diabetic neuropathic pain,but little is known about its effects on streptozotocin(STZ)-induced peripheral neuropathy.Here,we explored whether spinal cord P2X7R was correlated with the generation of mechanical allodynia(MA)in STZ-induced type 1 diabetic neuropathy in mice.MA was assessed by measuring paw withdrawal thresholds and western blotting.Immunohistochemistry was applied to analyze the protein expression levels and localization of P2X7R.STZ-induced mice expressed increased P2X7R in the dorsal horn of the lumbar spinal cord during MA.Mice injected intrathecally with a selective antagonist of P2X7R and P2X7R knockout(KO)mice both presented attenuated progression of MA.Double-immunofluorescent labeling demonstrated that P2X7R-positive cells were mostly co-expressed with Iba1(a microglia marker).Our results suggest that P2X7R plays an important role in the development of MA and could be used as a cellular target for treating PDN.
基金supported in part by the National Natural Science Foundation of China,Nos.81971151(to YW),82201360(to XC),82102583(to LW),and 82202739(to GPM)China Postdoctoral Science Foundation,Nos.YJ20210208 and 2022M713592+2 种基金Guangdong Basic and Applied Basic Research Foundation,China,No.2021A1515110188(to XC)the Natural Science Foundation of Guangdong Province,China,No.2020A1515010306(to LW)the Science and Technology Program of Guangzhou,China,No.202102020040(to LW)。
文摘Experimental studies have shown that exercise and human adipose-derived stem cells(ADSCs)play positive roles in spinal cord injury(SCI).However,whether ADSCs and/or exercise have a positive effect on SCI-induced neuropathic pain is still unclear.Thus,there is a need to explore the effects of exercise combined with administration of ADSCs on neuropathic pain after SCI.In this study,a thoracic 11(T11)SCI contusion model was established in adult C57BL/6 mice.Exercise was initiated from 7 days post-injury and continued to 28 days post-injury,and approximately 1×105 ADSCs were transplanted into the T11 spinal cord lesion site immediately after SCI.Motor function and neuropathic pain-related behaviors were assessed weekly using the Basso Mouse Scale,von Frey filament test,Hargreaves method,and cold plate test.Histological studies(Eriochrome cyanine staining and immunohistochemistry)were performed at the end of the experiment(28 days post-injury).Exercise combined with administration of ADSCs partially improved early motor function(7,14,and 21 days postinjury),mechanical allodynia,mechanical hypoalgesia,thermal hyperalgesia,and thermal hypoalgesia.Administration of ADSCs reduced white and gray matter loss at the lesion site.In addition,fewer microglia and astrocytes(as identified by expression of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein,respectively)were present in the lumbar dorsal horn in the SCI+ADSCs and SCI+exercise+ADSCs groups compared with the sham group.Our findings suggest that exercise combined with administration of ADSCs is beneficial for the early recovery of motor function and could partially ameliorate SCIinduced neuropathic pain.
