Background:The channel-forming protein Pannexin1(Panx1)has been implicated in both human studies and animal models of chronic pain,but the underlying mechanisms remain incompletely understood.Methods:Wild-type(WT,n=24...Background:The channel-forming protein Pannexin1(Panx1)has been implicated in both human studies and animal models of chronic pain,but the underlying mechanisms remain incompletely understood.Methods:Wild-type(WT,n=24),global Panx1 KO(n=24),neuron-specific Panx1 KO(n=20),and glia-specific Panx1 KO(n=20)mice were used in this study at Albert Einstein College of Medicine.The von Frey test was used to quantify pain sensitivity in these mice following complete Freund’s adjuvant(CFA)injection(7,14,and 21 d).The qRT-PCR was employed to measure mRNA levels of Panx1,Panx2,Panx3,Cx43,Calhm1,andβ-catenin.Laser scanning confocal microscopy imaging,Sholl analysis,and electrophysiology were utilized to evaluate the impact of Panx1 on neuronal excitability and morphology in Neuro2a and dorsal root ganglion neurons(DRGNs)in which Panx1 expression or function was manipulated.Ethidium bromide(EtBr)dye uptake assay and calcium imaging were employed to investigate the role of Panx1 in adenosine triphosphate(ATP)sensitivity.β-galactosidase(β-gal)staining was applied to determine the relative cellular expression levels of Panx1 in trigeminal ganglia(TG)and DRG of transgenic mice.Results:Global or neuron-specific Panx1 deletion markedly decreased pain thresholds after CFA stimuli(7,14,and 21 d;P<0.01 vs.WT group),indicating that Panx1 was positively correlated with pain sensitivity.In Neuro2a,global Panx1 deletion dramatically reduced neurite extension and inward currents compared to the WT group(P<0.05),revealing that Panx1 enhanced neurogenesis and excitability.Similarly,global Panx1 deletion significantly suppressed Wnt/β-catenin dependent DRG neurogenesis following 5 d of nerve growth factor(NGF)treatment(P<0.01 vs.WT group).Moreover,Panx1 channels enhanced DRG neuron response to ATP after CFA injection(P<0.01 vs.Panx1 KO group).Furthermore,ATP release increased Ca2+responses in DRGNs and satellite glial cells surrounding them following 7 d of CFA treatment(P<0.01 vs.Panx1 KO group),suggesting that Panx1 in glia also impacts exaggerated neuronal excitability.Interestingly,neuron-specific Panx1 deletion was found to markedly reduce differentiation in cultured DRGNs,as evidenced by stunted neurite outgrowth(P<0.05 vs.Panx1 KO group;P<0.01 vs.WT group or GFAP-Cre group),blunted activation of Wnt/β-catenin signaling(P<0.01 vs.WT,Panx1 KO and GFAP-Cre groups),and diminished cell excitability(P<0.01 vs.GFAP-Cre group)and response to ATP stimulation(P<0.01 vs.WT group).Analysis ofβ-gal staining showed that cellular expression levels of Panx1 in neurons are significantly higher(2.5-fold increase)in the DRG than in the TG.Conclusions:The present study revealed that neuronal Panx1 is a prominent driver of peripheral sensitivity in the setting of inflammatory pain through cell-autonomous effects on neuronal excitability.This hyperexcitability dependence on neuronal Panx1 contrasts with inflammatory orofacial pain,where similar studies revealed a prominent role for glial Panx1.The apparent differences in Panx1 expression in neuronal and non-neuronal TG and DRG cells are likely responsible for the distinct impact of these cell types in the two pain models.展开更多
Objective To investigate whether the kainate （KA） receptor subunit GluR6 is involved in the acute inflammatory pain. Methods Formalin was injected into the mucosa of rectum in Sprague-Dawley rats to induce visceral ...Objective To investigate whether the kainate （KA） receptor subunit GluR6 is involved in the acute inflammatory pain. Methods Formalin was injected into the mucosa of rectum in Sprague-Dawley rats to induce visceral pain. The antisense oligodeoxynucleotides （ODNs） of GluR6 were injected once per day for 3 d before formalin injection, after which GluR6 protein level was examined by immunoblotting method. The change of visceral pain was also investigated. Results The expression of GluR6 in the spinal cord of rats increased after the formalin injection. Moreover, pre-treatment of GluR6 antisense ODNs could suppress GluR6 expression in the spinal cord of rats and decrease the scores of visceral pain at 45 min following formalin injection. Conclusion Kainate receptor subunit GluR6 plays an important role in the visceral pain induced by injection of formalin into the wall of rectum. GluR6 may serve as a potential target for the treatment of acute inflammatory visceral pain.展开更多
Previous studies have confirmed the relationship between iron-dependent ferroptosis and a peripheral nerve injury-induced neuropathic pain model.However,the role of fe rroptosis in inflammatory pain remains inconclusi...Previous studies have confirmed the relationship between iron-dependent ferroptosis and a peripheral nerve injury-induced neuropathic pain model.However,the role of fe rroptosis in inflammatory pain remains inconclusive.Therefore,we aimed to explore whether ferroptosis in the spinal cord and do rsal root ganglion contributes to complete Freund's adjuvant(CFA)-induced painful behaviors in rats.Our results revealed that various biochemical and morphological changes were associated with ferroptosis in the spinal cord and dorsal root ganglion tissues of CFA rats.These changes included iron overload,enhanced lipid peroxidation,disorders of anti-acyl-coenzyme A synthetase long-chain family member 4 and glutathione peroxidase 4 levels,and abnormal morphological changes in mitochondria.Intrathecal treatment of liproxstatin-1(a ferroptosis inhibitor)reve rsed these ferroptosis-related changes and alleviated mechanical and thermal hype rsensitivities in CFA rats.Our study demonstrated the occurrence of fe rroptosis in the spinal cord and do rsal root ganglion tissues in a rodent model of inflammatory pain and indicated that intrathecal administration of fe rroptosis inhibitors,such as liproxstatin-1,is a potential therapeutic strategy for treating inflammatory pain.展开更多
Functional changes in synaptic transmission from the lateral entorhinal cortex to the dentate gyrus(LEC-DG)are considered responsible for the chronification of pain.However,the underlying alterations in fan cells,whic...Functional changes in synaptic transmission from the lateral entorhinal cortex to the dentate gyrus(LEC-DG)are considered responsible for the chronification of pain.However,the underlying alterations in fan cells,which are the predominant neurons in the LEC that project to the DG,remain elusive.Here,we investigated possible mechanisms using a rat model of complete Freund’s adjuvant(CFA)-induced inflammatory pain.We found a substantial increase in hyperpolarization-activated/cyclic nucleotide-gated currents(Ih),which led to the hyperexcitability of LEC fan cells of CFA slices.This phenomenon was attenuated in CFA slices by activating dopamine D2,but not D1,receptors.Chemogenetic activation of the ventral tegmental area-LEC projection had a D2 receptor-dependent analgesic effect.Intra-LEC microinjection of a D2 receptor agonist also suppressed CFA-induced behavioral hypersensitivity,and this effect was attenuated by pre-activation of the Ih.Our findings suggest that down-regulating the excitability of LEC fan cells through activation of the dopamine D2 receptor may be a strategy for treating chronic inflammatory pain.展开更多
With the shifting role of placebos,there is a need to develop animal models of placebo analgesia and elucidate the mechanisms underlying the effect.In the present study,male Sprague-Dawley rats with chronic inflammato...With the shifting role of placebos,there is a need to develop animal models of placebo analgesia and elucidate the mechanisms underlying the effect.In the present study,male Sprague-Dawley rats with chronic inflammatory pain caused by complete Freund’s adjuvant(CFA)underwent a series of conditioning procedures,in which morphine was associated with different cues,but they failed to induce placebo analgesia.Then,conditioning with the conditioned place preference apparatus successfully induced analgesic expectancy and placebo analgesia in naive rats but only induced analgesic expectancy and no analgesic effect in CFA rats.Subsequently,we found enhanced c-fos expression in the nucleus accumbens and reduced expression in the anterior cingulate cortex in naive rats while c-fos expression in the anterior cingulate cortex in CFA rats was not altered.In summary,the behavioral conditioning model demonstrated the difficulty of establishing a placebo analgesia model in rats with a pathological condition.展开更多
Microtubule-associated protein Tau is responsible for the stabilization of neuronal microtubules under normal physiological conditions.Much attention has been focused on Tau’s contribution to cognition,but little res...Microtubule-associated protein Tau is responsible for the stabilization of neuronal microtubules under normal physiological conditions.Much attention has been focused on Tau’s contribution to cognition,but little research has explored its role in emotions such as pain,anxiety,and depression.In the current study,we found a significant increase in the levels of p-Tau(Thr231),total Tau,IL-1β,and brain-derived neurotrophic factor(BDNF)on day 7 after complete Freund's adjuvant(CFA)injection;they were present in the vast majority of neurons in the spinal dorsal horn.Microinjection of Mapt-shRNA recombinant adeno-associated virus into the spinal dorsal cord alleviated CFA-induced inflammatory pain and inhibited CFA-induced IL-1βand BDNF upregulation.Importantly,Tau overexpression was sufficient to induce hyperalgesia by increasing the expression of IL-1βand BDNF.Furthermore,the activation of glycogen synthase kinase 3 beta partly contributed to Tau accumulation.These findings suggest that Tau in the dorsal horn could be a promising target for chronic inflammatory pain therapy.展开更多
Nerve trauma commonly results in chronic neuropathic pain. This is by triggering the release of proinflammatory mediators from local and invading cells that induce inflammation and nociceptive neuron hyperexcitability...Nerve trauma commonly results in chronic neuropathic pain. This is by triggering the release of proinflammatory mediators from local and invading cells that induce inflammation and nociceptive neuron hyperexcitability. Even without apparent inflammation, injury sites are associated with increased inflammatory markers. This review focuses on how it might be possible to reduce neuropathic pain by reducing inflammation. Physiologically, pain is resolved by a combination of the out-migration of pro-inflammatory cells from the injury site, the down-regulation of the genes underlying the inflammation, up-regulating genes for anti-inflammatory mediators, and reducing nociceptive neuron hyperexcitability. While various techniques reduce chronic neuropathic pain, the best are effective on < 50% of patients, no technique reliably or permanently eliminates neuropathic pain. This is because most techniques are predominantly aimed at reducing pain, not inflammation. In addition, while single factors reduce pain, increasing evidence indicates significant and longer-lasting pain relief requires multiple factors acting simultaneously. Therefore, it is not surprising that extensive data indicate that the application of platelet-rich plasma provides more significant and longer-lasting pain suppression than other techniques, although its analgesia is neither complete nor permanent. However, several case reports indicate that platelet-rich plasma can induce permanent neuropathic pain elimination when the platelet concentration is significantly increased and is applied to longer nerve lengths. This review examines the primary triggers of the development and maintenance of neuropathic pain and techniques that reduce chronic neuropathic pain. The application of plateletrich plasma holds great promise for providing complete and permanent chronic neuropathic pain elimination.展开更多
Pain is a subjective and unpleasant sensation that significantly impacts the daily lives of individuals.Chronic pain represents one of the most challenging public health issues,and ensuring effective pain management i...Pain is a subjective and unpleasant sensation that significantly impacts the daily lives of individuals.Chronic pain represents one of the most challenging public health issues,and ensuring effective pain management is a fundamental right of individuals and a sacred duty of healthcare providers.Cannabis,one of the earliest recognized medicinal plants,contains cannabinoids,which are non-opioid substances that modulate nociceptive responses.Electroacupuncture(EA),characterized by its low-risk and well-tolerated nature,is pivotal in pain management.The endocannabinoid system consists of endocannabinoids,cannabinoid receptors,and enzymes involved in endocannabinoid synthesis,degradation,and transport.Recently,the role of the endocannabinoid system in pain development and EA analgesia has attracted considerable research attention.Studies have highlighted the role of the endocannabinoid system in various types of pain,including inflammatory pain,neuropathic pain,and cancer-related pain,as well as in EA analgesia.This study aims to review the mechanisms of endocannabinoid system involvement in pain modulation and EA analgesia to provide insights to inform clinical approaches to pain management.展开更多
AIM To investigate the effects of herb-partitioned moxibustion(HPM) on phosphorylation of mitogen-activated extracellular signal-regulated kinase(MEK)1, extracellular signal-regulated kinase(ERK)1/2 and c AMP response...AIM To investigate the effects of herb-partitioned moxibustion(HPM) on phosphorylation of mitogen-activated extracellular signal-regulated kinase(MEK)1, extracellular signal-regulated kinase(ERK)1/2 and c AMP response element binding protein(CREB) in spinal cord of rats with chronic inflammatory visceral pain(CIVP), and to explore the central mechanism of HPM in treating CIVP.METHODS Male Sprague-Dawley rats were randomized into normal, model, HPM, sham-HPM, MEK-inhibitor and dimethyl sulfoxide(DMSO) groups. The CIVP model was established using an enema mixture of trinitrobenzene sulfonic acid and ethanol. HPM was applied at bilateral Tianshu(ST25) and Qihai(CV6) acupoints in the HPM group, while in the sham-HPM group, moxa cones and herb cakes were only placed on the same points but not ignited. The MEK-inhibitor and DMSO groups received L5-L6 intrathecal injection of U0126 and 30% DMSO, respectively. Abdominal withdrawal reflex(AWR), mechanical withdrawal threshold(MWT) and thermal withdrawal latency(TWL) were applied for the assessment of pain behavior. The colonic tissue was observed under an optical microscope after hematoxylin-eosin staining. Expression of phosphor(p)MEK1, p ERK1/2 and p CREB in rat spinal cord was detected using Western blotting. The levels of MEK, ERK and CREB m RNA in rat spinal cord were detected using real-time polymerase chain reaction. RESULTS Compared with the normal group, the AWR scores were increased significantly(P < 0.01) and the MWT and TWL scores were decreased significantly(P < 0.05) in the model, sham-HPM and DMSO groups. Compared with the model group, the AWR scores were decreased significantly(P < 0.01) and the MWT and TWL scores were increased significantly in the HPM and MEK-inhibitor groups(P < 0.05). Compared with the sham-HPM and DMSO groups, the AWR scores were decreased significantly(P < 0.01) and the MWT and TWL scores were increased significantly(P < 0.05) in the HPM and MEK-inhibitor groups. Compared with the normal group, the expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were increased significantly in the model, sham-HPM and DMSO groups(P < 0.01 or < 0.05). Compared with the model group, the expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were reduced significantly in the HPM and MEK-inhibitor groups(P < 0.01 or < 0.05). Compared with the sham-HPM and DMSO groups, expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were reduced significantly in the HPM and MEK-inhibitor groups(P < 0.01 or < 0.05). CONCLUSION HPM down-regulates protein phosphorylation of MEK1, ERK1/2 and CREB, and m RNA expression of MEK, ERK and CREB, inhibiting activation of the MEK/ERK/CREB signaling pathway in the spinal cord of CIVP rats, which is possibly a critical central mechanism of the analgesic effect of HPM.展开更多
Topical irritants such as capsaicin(CAP),peppermint oil(PO),and mustard oil(MO)are effective in relieving inflammatory muscle pain.We investigated the effects of topical irritants in a rat model of inflammatory muscle...Topical irritants such as capsaicin(CAP),peppermint oil(PO),and mustard oil(MO)are effective in relieving inflammatory muscle pain.We investigated the effects of topical irritants in a rat model of inflammatory muscle pain produced by injecting complete Freund's adjuvant(CFA)into the tibialis anterior muscle.CFAinduced mechanical hypersensitivity and the spontaneous activity of muscular nociceptive afferents,and decreased weight-bearing of the hindlimb were relieved by topical application of CAP,PO,or MO on the skin overlying the inflamed muscle.The effects of topical irritants were abolished when applied to the skin on the ipsilateral plantar region or on the contralateral leg,or when the relevant cutaneous nerve or dorsal root was transected.Our results demonstrated that topical irritants may alleviate inflammatory muscle pain via activating cutaneous nociceptors and subsequently inhibiting the abnormal activity of muscular nociceptive neurons.展开更多
As the most common symptomatic reason to seek medical consultation,pain is a complex experience that has been classified into different categories and stages.In pain processing,noxious stimuli may activate the anterio...As the most common symptomatic reason to seek medical consultation,pain is a complex experience that has been classified into different categories and stages.In pain processing,noxious stimuli may activate the anterior cingulate cortex(ACC).But the function of ACC in the different pain conditions is not well discussed.In this review,we elaborate the commonalities and differences from accumulated evidence by a variety of pain assays for physiological pain and pathological pain including inflammatory pain,neuropathic pain,and cancer pain in the ACC,and discuss the cellular receptors and signaling molecules from animal studies.We further summarize the ACC as a new central neuromodulation target for invasive and non-invasive stimulation techniques in clinical pain management.The comprehensive understanding of pain processing in the ACC may lead to bridging the gap in translational research between basic and clinical studies and to develop new therapies.展开更多
Nitric oxide(NO)/cyclic guanosine 3′,5′-monophosphate(cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the ...Nitric oxide(NO)/cyclic guanosine 3′,5′-monophosphate(cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the NO/cGMP signaling pathway involved in chronic pain, including neuropathic pain, bone cancer pain, inflammatory pain, and morphine tolerance. The main process in the NO/cGMP signaling pathway in cells involves NO activating soluble guanylate cyclase, which leads to subsequent production of cGMP. cGMP then activates cGMP-dependent protein kinase(PKG), resulting in the activation of multiple targets such as the opening of ATP-sensitive K+ channels. The activation of NO/cGMP signaling in the spinal cord evidently induces upregulation of downstream molecules, as well as reactive astrogliosis and microglial polarization which participate in the process of chronic pain. In dorsal root ganglion neurons, natriuretic peptide binds to particulate guanylyl cyclase, generating and further activating the cGMP/PKG pathway, and it also contributes to the development of chronic pain. Upregulation of multiple receptors is involved in activation of the NO/cGMP signaling pathway in various pain models. Notably the NO/cGMP signaling pathway induces expression of downstream effectors, exerting both algesic and analgesic effects in neuropathic pain and inflammatory pain. These findings suggest that activation of NO/cGMP signaling plays a constituent role in the development of chronic pain, and this signaling pathway with dual effects is an interesting and promising target for chronic pain therapy.展开更多
Investigation of pain requires measurements of nociceptive sensitivity and other pain-related behaviors.Recent studies have indicated the superiority of gait analysis over traditional evaluations(e.g., skin sensitivit...Investigation of pain requires measurements of nociceptive sensitivity and other pain-related behaviors.Recent studies have indicated the superiority of gait analysis over traditional evaluations(e.g., skin sensitivity and sciatic function index [SFI]) in detecting subtle improvements and deteriorations in animal models. Here,pain-related gait parameters, whose criteria include(1)alteration in pain models,(2) correlation with nociceptive threshold, and(3) normalization by analgesics, were identified in representative models of neuropathic pain(spared nerve injury: coordination data) and inflammatory pain(intraplantar complete Freund’s adjuvant: both coordination and intensity data) in the DigiGait^TM and CatWalk^TM systems. DigiGait^TM had advantages in fixed speed(controlled by treadmill) and dynamic SFI, while CatWalk^TM excelled in intrinsic velocity, intensity data,and high-quality 3 D images. Insights into the applicability of each system may provide guidance for selecting the appropriate gait imaging system for different animal models and optimization for future pain research.展开更多
AIM: To provoke persistent/chronic multiorgan inflammatory response and to contribute to stones formation followed by fibrosis in hepatobiliary and pancreatic tissues.METHODS: Tumor necrosis factor receptors 1 and 2 (...AIM: To provoke persistent/chronic multiorgan inflammatory response and to contribute to stones formation followed by fibrosis in hepatobiliary and pancreatic tissues.METHODS: Tumor necrosis factor receptors 1 and 2 (TNFR1/R2) deficient mice reared in-house were given dibutyltin dichloride (DBTC) twice within 10 d by oral gavage delivery. Sham control animals received vehicle treatment and naïve animals remained untreated throughout the study. Animals were monitored daily for symptoms of pain and discomfort. The abdominal and hindpaw hypersensitivity were assessed with von Frey microfilaments. Exploratory behaviors were recorded at the baseline, after initiation of treatment, and before study termination. Histopathological changes were examined postmortem in tissues. Collagen accumulation and fibrosis were confirmed with Sirius Red staining.RESULTS: Animals lost weight after oral administration of DBTC and developed persistent inflammatory abdominal and hindpaw hypersensitivity compared to sham-treated controls (P < 0.0001). These pain related secondary mechanical hypersensitivity responses increased more than 2-fold in DBTC-treated animals. The drastically diminished rearing and grooming rates persisted after DBTC administration throughout the study. Gross as well as micropathology at one month confirmed that animals treated with DBTC developed chronic hepatobiliary injuries evidenced with activation of stellate cells, multifocal necrosis, fatty degeneration of hepatocytes, periportal infiltration of inflammatory cells, and prominent biliary ductal dilation. The severity of hepatitis was scored 3.7 ± 0.2 (severe) in DBTC-treated animals vs score 0 (normal) in sham-treated animals. Fibrotic thickening was extensive around portal ducts, in hepatic parenchyma as well as in lobular pancreatic structures and confirmed with Sirius Red histopathology. In addition, pancreatic microarchitecture was presented with distortion of islets, and parenchyma, infiltration of inflammatory cells, degeneration, vacuolization, and necrosis of acinar cells and distention of pancreatic ducts. Extent of pancreatic damage and pancreatitis were scored 3.6 ± 0.4 (severe) for DBTC-treated in contrast to score 0 (normal) in sham-treated animals. The gall bladder became expanded with ductal distention, and occasional bile stones were detected along with microscopic hepatic lesions. DBTC-treated animals developed splenic hypertrophy with increased weight and length (P < 0.01) along with thymic atrophy (P < 0.001). Finally, colitic lesions and colitis were prominent in DBTC-treated animals and scored 3.4 ± 0.3 (moderately severe) vs 0 (normal) for the sham-treated animals.CONCLUSION: This is the first report of chronic inflammatory multiorgan hepatobiliary pancreatitis, along with fibrosis and calculi formation induced reliably utilizing oral DBTC administration in TNFR1/R2 deficient mice.展开更多
The normal gastrointestinal interdigestive migrating motor complex cycle was interrupted, and paroxysmal contraction appeared after formaldehyde-induced stomach ache. Activities of nitric oxide synthase, acetylcholine...The normal gastrointestinal interdigestive migrating motor complex cycle was interrupted, and paroxysmal contraction appeared after formaldehyde-induced stomach ache. Activities of nitric oxide synthase, acetylcholinesterase and vasoactive intestinal peptide neurons were significantly reduced, whereas activities of calcitonin gene-related peptide neurons were significantly increased in the pyloric sphincter muscular layer, myenteric nerve plexus and submucous nerve plexus. Electroacupuncture at Zusanfi （ST36） suppressed paroxysmal contraction in rats with formaldehyde-induced stomach ache, and neurons in the enteric nervous system were normal. These results indicated that nitrergic neurons, cholinergic neurons, vasoactive intestinal peptide neurons and calcitonin gene-related peptide neurons in the enteric nervous system may be involved in changes to the gastrointestinal interdigestive migrating motor complex following stomach ache, and that electroacupuncture can regulate this process.展开更多
Objective： The present study aimed to evaluate the analgesic and anti-inflammatory effects of far infrared-emitting ceramics （cFIRs） in a model of persistent inflammatory hyperalgesia and to elucidate the possible ...Objective： The present study aimed to evaluate the analgesic and anti-inflammatory effects of far infrared-emitting ceramics （cFIRs） in a model of persistent inflammatory hyperalgesia and to elucidate the possible mechanisms of these effects. Methods： Mice were injected with complete Freund＇s adjuvant （CFA） and treated with cFIRs via place- ment on a pad impregnated with cFIRs on the bottom of the housing unit for different periods of time. Mice underwent mechanical hyperalgesia and edema assessments, and tumor necrosis factor-α （TNF-α）, interleukin-1β （IL-1β） and IL-10 levels were measured. Twenty-four hours after CFA injection and 30 min before cFIR treatment, mice were pretreated with a nonselective adenosinergic antagonist, caffeine, the selective adenosine receptor A antagonist, 1,3-dipropyl-8-cyclopentylxanthine （DPCPX）, the selective cannabinoid receptor type 1 antagonist, AM281, the selective cannabinoid receptor type 2 antagonist, AM630, or the nonselective opioid receptor antagonist, naloxone, and mechanical hyperalge- sia was assessed. Results： cFIRs statistically （P 〈 0.05） decreased CFA-induced mechanical hyperalgesia （82.86 ±5.21）% in control group vs （56.67±9.54）% in cFIR group） and edema （（1699.0 ± 77.8） gm in control group vs （988.7±107.6） gm in cFIR group）, cFIRs statistically （P 〈 0.05） reduced TNF-α （0.478± 0.072） pg/mg of protein in control group vs （0.273 ±0.055） pg/mg of protein in cFIR group） and IL-113 （（95.81 ± 3.95） pg/mg of protein in control group vs （80.61 ±4.71）pg/mg of protein in cFIR group） levels and statistically （P〈 0.05） increased IL-10 （（18.32 ±0.78） pg/mg of protein in control group vs （25.89 ±1.23） pg/mg of protein in cFIR group） levels in post-CFA-injected paws. Peripheral pre-administration of inhibitory neuroreceptor antagonists （caffeine, DPCPX, AM281, AM630 and naloxone） prevented the analgesic effects of cF1Rs （P 〈 0.05）.Conclusion： These data provide additional support for the use of cFIRs in the treatment of painful inflam- matory conditions and contribute to our understanding of the neurobiological mechanisms of the ther- apeutic effects of cFIRs.展开更多
Tweety-homolog 1(Ttyh1)is expressed in neural tissue and has been implicated in the generation of several brain diseases.However,its functional significance in pain processing is not understood.By disrupting the gene ...Tweety-homolog 1(Ttyh1)is expressed in neural tissue and has been implicated in the generation of several brain diseases.However,its functional significance in pain processing is not understood.By disrupting the gene encoding Ttyh1,we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice,along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey(PAG)in the basal state.More importantly,the peripheral inflammationevoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice.Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release.Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief.Thus,in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.展开更多
<strong>Background: </strong>Pre-clinical and clinical studies have shown that inflammatory pain intensity is increased under diabetes condition. Open cholecystectomy (OC) is a surgical procedure with pred...<strong>Background: </strong>Pre-clinical and clinical studies have shown that inflammatory pain intensity is increased under diabetes condition. Open cholecystectomy (OC) is a surgical procedure with predictable postoperative pain. However, the comparison of postoperative pain due to open cholecystectomy in diabetic and non-diabetic patients remains unknown. The research question to answer was whether diabetic patients undergoing OC development greater intensity of postoperative pain than non-diabetic patients. <strong>Methods: </strong>The study was conducted between June 2016 and February 2018 at the Regional Hospital of High Specialty “Dr. Juan Graham Casasús” of Villahermosa, Tabasco, Mexico. Seventy patients in two groups of 35 patients each scheduled for OC under general anesthesia were studied. Pain was assessed using the 11-point numerical rating scale (NRS). The primary endpoint was to know NRS pain scores after awaking of general anesthesia. Secondary outcomes included the time of onset of pain and comparing NRS scores between diabetic and non-diabetic patients undergoing OC. <strong>Results:</strong> Diabetic patients reported significantly greater intensity pain than non-diabetic patients. The mean overall pain score in the diabetic and non-diabetic patients was 7.2 ± 0.3 and 5.3 ± 0.3 (P = 0.0002), respectively. Furthermore, 60% of diabetic patients had severe pain (NRS ≥ 8) compared to 20% of non-diabetics (P = 0.006). The time to onset postoperative pain was about 35 minutes in both groups (P = 0.876). <strong>Conclusions:</strong> Diabetic patients undergoing OC have greater intensity postoperative pain and also more frequency of patients with severe pain scores compared with non-diabetic patients. Therefore, analgesic treatment in those patients should consider this point in order to provide a satisfactory postoperative analgesia.展开更多
In this review,we explored the dose-effect relationship of electroacupuncture(EA)analgesia and its stimulus parameters by searching articles on clinical and experimental research of EA analgesia in the past30 years.Th...In this review,we explored the dose-effect relationship of electroacupuncture(EA)analgesia and its stimulus parameters by searching articles on clinical and experimental research of EA analgesia in the past30 years.The impacts on the analgesic effects are discussed in terms of the pulse waveform,frequency,amplitude,wave width,and time effect,as well as parameter combinations,and the optimization of the EA parameters are summarized for the treatment of neuropathic,inflammatory,and cancer pains.It was initially discovered that the distant-dense(D-D)wave(2/15 Hz or 2/100 Hz)and stimulus for 30-45 min were appropriate in the treatment of chronic inflammatory pain,the strong stimulus was applicable to the acute stage of pain(twice a week),while the weak stimulus was for the stable stage(once weekly).The continuous(2 Hz)/D-D wave(2/100 Hz)and moderate/low intensity of stimulus for 30-45 min are preferred in the treatment of neuropathic pain with EA,once daily or every 2 days.Regarding the treatment of cancer pain,EA with continuous(2 Hz or 100 Hz)or D-D wave(2/100 Hz),moderate and low intensity of stimulus for 30-45 min is adopted,once every 2 days.There is a certain rule for the correlation of each parameter and the combination of parameters to ensure an analgesic effect of EA,which should be further explored in future studies.展开更多
BACKGROUND:Central sensitization,a state of increased excitability of nociceptive neurons in the spinal dorsal horn following peripheral tissue injury and/or inflammation,is an important mechanism underlying hyperalge...BACKGROUND:Central sensitization,a state of increased excitability of nociceptive neurons in the spinal dorsal horn following peripheral tissue injury and/or inflammation,is an important mechanism underlying hyperalgesia and neuropathic pain.Participation of the glutamate-glutamine cycle in central sensitization of the spinal cord remains poorly understood.OBJECTIVE:To determine whether the astrocyte-neuronal glutamate-glutamine cycle is involved in formalin-induced central sensitization in the spinal cord.DESIGN,TIME AND SETTING:A randomized,controlled,animal experiment was performed at the Institute of Orthopedics,Second Hospital,Lanzhou University,China from September 2007 to August 2008.MATERIALS:Methionine sulfoximine(MSO,0.1 mmol/L),glutamine(0.25 mmol/L),and formalin were used for this study.METHODS:A total of 43 male,Sprague Dawley rats,aged 4 months,were randomly assigned to a sham operation group(n=6)and a model group(n=37).Rats in the model group received intrathecal infusion in the spinal cord.7 days later,37 model rats were randomly divided into PBS,MSO,glutamine,MSO+glutamine and formalin subcutaneous injection alone groups.The PBS,MSO,glutamine,MSO+glutamine groups were respectively intrathecally injected with PBS,MSO,glutamine,MSO+glutamine(50μL each),and then infused with 10μL of saline.Rats from the sham operation group were not subjected to intrathecal infusion in the spinal cord.At 15 minutes after intrathecal injection,a rat model of formalin-induced inflammatory pain was established by subcutaneous injection of 5%formalin(50μL)in the left hindpaw.MAIN OUTCOME MEASURES:Changes in spontaneous nociceptive behavior(licking/biting or flinching)were observed following formalin injection into the rat hindpaw.RESULTS:Compared with the PBS group,duration of licking/biting was significantly shortened,and flinching frequency was significantly diminished in the MSO group(P〈0.05).Compared with the MSO group,duration of licking/biting was significantly prolonged,and flinching frequency was significantly increased in the MSO+glutamine group(P〈0.05).There was no significant difference in inflammatory pain behaviors among the sham operation,PBS,glutamine,MSO+glutamine,and formalin subcutaneous injection alone groups(P〉0.05).CONCLUSION:The astrocyte-neuronal glutamate-glutamine cycle in the spinal cord was shown to be involved in central sensitization induced by formalin subcutaneous injection into the hindpaw.展开更多
基金This work was NIH(R01NS092466),NSFC(U2004201)Central Plains Thousand People Plan of Henan Province(204200510013)+1 种基金Henan Overseas Expertise Introduction Center for Discipline Innovation(CXJD2021002)Key Special Project of Zhengzhou University Disciplinary Construction(XKZDJC202001)。
文摘Background:The channel-forming protein Pannexin1(Panx1)has been implicated in both human studies and animal models of chronic pain,but the underlying mechanisms remain incompletely understood.Methods:Wild-type(WT,n=24),global Panx1 KO(n=24),neuron-specific Panx1 KO(n=20),and glia-specific Panx1 KO(n=20)mice were used in this study at Albert Einstein College of Medicine.The von Frey test was used to quantify pain sensitivity in these mice following complete Freund’s adjuvant(CFA)injection(7,14,and 21 d).The qRT-PCR was employed to measure mRNA levels of Panx1,Panx2,Panx3,Cx43,Calhm1,andβ-catenin.Laser scanning confocal microscopy imaging,Sholl analysis,and electrophysiology were utilized to evaluate the impact of Panx1 on neuronal excitability and morphology in Neuro2a and dorsal root ganglion neurons(DRGNs)in which Panx1 expression or function was manipulated.Ethidium bromide(EtBr)dye uptake assay and calcium imaging were employed to investigate the role of Panx1 in adenosine triphosphate(ATP)sensitivity.β-galactosidase(β-gal)staining was applied to determine the relative cellular expression levels of Panx1 in trigeminal ganglia(TG)and DRG of transgenic mice.Results:Global or neuron-specific Panx1 deletion markedly decreased pain thresholds after CFA stimuli(7,14,and 21 d;P<0.01 vs.WT group),indicating that Panx1 was positively correlated with pain sensitivity.In Neuro2a,global Panx1 deletion dramatically reduced neurite extension and inward currents compared to the WT group(P<0.05),revealing that Panx1 enhanced neurogenesis and excitability.Similarly,global Panx1 deletion significantly suppressed Wnt/β-catenin dependent DRG neurogenesis following 5 d of nerve growth factor(NGF)treatment(P<0.01 vs.WT group).Moreover,Panx1 channels enhanced DRG neuron response to ATP after CFA injection(P<0.01 vs.Panx1 KO group).Furthermore,ATP release increased Ca2+responses in DRGNs and satellite glial cells surrounding them following 7 d of CFA treatment(P<0.01 vs.Panx1 KO group),suggesting that Panx1 in glia also impacts exaggerated neuronal excitability.Interestingly,neuron-specific Panx1 deletion was found to markedly reduce differentiation in cultured DRGNs,as evidenced by stunted neurite outgrowth(P<0.05 vs.Panx1 KO group;P<0.01 vs.WT group or GFAP-Cre group),blunted activation of Wnt/β-catenin signaling(P<0.01 vs.WT,Panx1 KO and GFAP-Cre groups),and diminished cell excitability(P<0.01 vs.GFAP-Cre group)and response to ATP stimulation(P<0.01 vs.WT group).Analysis ofβ-gal staining showed that cellular expression levels of Panx1 in neurons are significantly higher(2.5-fold increase)in the DRG than in the TG.Conclusions:The present study revealed that neuronal Panx1 is a prominent driver of peripheral sensitivity in the setting of inflammatory pain through cell-autonomous effects on neuronal excitability.This hyperexcitability dependence on neuronal Panx1 contrasts with inflammatory orofacial pain,where similar studies revealed a prominent role for glial Panx1.The apparent differences in Panx1 expression in neuronal and non-neuronal TG and DRG cells are likely responsible for the distinct impact of these cell types in the two pain models.
基金supported by the Natural Science Foundation of Jiangsu Province,China(No:BK2004028)
文摘Objective To investigate whether the kainate （KA） receptor subunit GluR6 is involved in the acute inflammatory pain. Methods Formalin was injected into the mucosa of rectum in Sprague-Dawley rats to induce visceral pain. The antisense oligodeoxynucleotides （ODNs） of GluR6 were injected once per day for 3 d before formalin injection, after which GluR6 protein level was examined by immunoblotting method. The change of visceral pain was also investigated. Results The expression of GluR6 in the spinal cord of rats increased after the formalin injection. Moreover, pre-treatment of GluR6 antisense ODNs could suppress GluR6 expression in the spinal cord of rats and decrease the scores of visceral pain at 45 min following formalin injection. Conclusion Kainate receptor subunit GluR6 plays an important role in the visceral pain induced by injection of formalin into the wall of rectum. GluR6 may serve as a potential target for the treatment of acute inflammatory visceral pain.
基金supported by the Basic and Applied Basic Research Foundation of Guangdong Province,No.2021A1515220081(to XL)。
文摘Previous studies have confirmed the relationship between iron-dependent ferroptosis and a peripheral nerve injury-induced neuropathic pain model.However,the role of fe rroptosis in inflammatory pain remains inconclusive.Therefore,we aimed to explore whether ferroptosis in the spinal cord and do rsal root ganglion contributes to complete Freund's adjuvant(CFA)-induced painful behaviors in rats.Our results revealed that various biochemical and morphological changes were associated with ferroptosis in the spinal cord and dorsal root ganglion tissues of CFA rats.These changes included iron overload,enhanced lipid peroxidation,disorders of anti-acyl-coenzyme A synthetase long-chain family member 4 and glutathione peroxidase 4 levels,and abnormal morphological changes in mitochondria.Intrathecal treatment of liproxstatin-1(a ferroptosis inhibitor)reve rsed these ferroptosis-related changes and alleviated mechanical and thermal hype rsensitivities in CFA rats.Our study demonstrated the occurrence of fe rroptosis in the spinal cord and do rsal root ganglion tissues in a rodent model of inflammatory pain and indicated that intrathecal administration of fe rroptosis inhibitors,such as liproxstatin-1,is a potential therapeutic strategy for treating inflammatory pain.
基金supported by the National Natural Science Foundation of China(81901119 and 81901142)Special Project on Innovation and Generation of Medical Support Capacity,and the Natural Science Foundation of Tibet(XZ2019ZRG-119),China.
文摘Functional changes in synaptic transmission from the lateral entorhinal cortex to the dentate gyrus(LEC-DG)are considered responsible for the chronification of pain.However,the underlying alterations in fan cells,which are the predominant neurons in the LEC that project to the DG,remain elusive.Here,we investigated possible mechanisms using a rat model of complete Freund’s adjuvant(CFA)-induced inflammatory pain.We found a substantial increase in hyperpolarization-activated/cyclic nucleotide-gated currents(Ih),which led to the hyperexcitability of LEC fan cells of CFA slices.This phenomenon was attenuated in CFA slices by activating dopamine D2,but not D1,receptors.Chemogenetic activation of the ventral tegmental area-LEC projection had a D2 receptor-dependent analgesic effect.Intra-LEC microinjection of a D2 receptor agonist also suppressed CFA-induced behavioral hypersensitivity,and this effect was attenuated by pre-activation of the Ih.Our findings suggest that down-regulating the excitability of LEC fan cells through activation of the dopamine D2 receptor may be a strategy for treating chronic inflammatory pain.
基金supported by grants from the National Natural Science Foundation of China(31720103908,31530028,and 81821092)the National Basic Research Development Program of the Ministry of Science and Technology of China(2017YFA0701300).
文摘With the shifting role of placebos,there is a need to develop animal models of placebo analgesia and elucidate the mechanisms underlying the effect.In the present study,male Sprague-Dawley rats with chronic inflammatory pain caused by complete Freund’s adjuvant(CFA)underwent a series of conditioning procedures,in which morphine was associated with different cues,but they failed to induce placebo analgesia.Then,conditioning with the conditioned place preference apparatus successfully induced analgesic expectancy and placebo analgesia in naive rats but only induced analgesic expectancy and no analgesic effect in CFA rats.Subsequently,we found enhanced c-fos expression in the nucleus accumbens and reduced expression in the anterior cingulate cortex in naive rats while c-fos expression in the anterior cingulate cortex in CFA rats was not altered.In summary,the behavioral conditioning model demonstrated the difficulty of establishing a placebo analgesia model in rats with a pathological condition.
基金supported by the National Natural Science Foundation of China(82171176 and 82001424)the Key Program of the Natural Science Foundation of Zhejiang,China(LZ19H090003)the Health Innovation Talent Program of Zhejiang,China(wscx202306).
文摘Microtubule-associated protein Tau is responsible for the stabilization of neuronal microtubules under normal physiological conditions.Much attention has been focused on Tau’s contribution to cognition,but little research has explored its role in emotions such as pain,anxiety,and depression.In the current study,we found a significant increase in the levels of p-Tau(Thr231),total Tau,IL-1β,and brain-derived neurotrophic factor(BDNF)on day 7 after complete Freund's adjuvant(CFA)injection;they were present in the vast majority of neurons in the spinal dorsal horn.Microinjection of Mapt-shRNA recombinant adeno-associated virus into the spinal dorsal cord alleviated CFA-induced inflammatory pain and inhibited CFA-induced IL-1βand BDNF upregulation.Importantly,Tau overexpression was sufficient to induce hyperalgesia by increasing the expression of IL-1βand BDNF.Furthermore,the activation of glycogen synthase kinase 3 beta partly contributed to Tau accumulation.These findings suggest that Tau in the dorsal horn could be a promising target for chronic inflammatory pain therapy.
文摘Nerve trauma commonly results in chronic neuropathic pain. This is by triggering the release of proinflammatory mediators from local and invading cells that induce inflammation and nociceptive neuron hyperexcitability. Even without apparent inflammation, injury sites are associated with increased inflammatory markers. This review focuses on how it might be possible to reduce neuropathic pain by reducing inflammation. Physiologically, pain is resolved by a combination of the out-migration of pro-inflammatory cells from the injury site, the down-regulation of the genes underlying the inflammation, up-regulating genes for anti-inflammatory mediators, and reducing nociceptive neuron hyperexcitability. While various techniques reduce chronic neuropathic pain, the best are effective on < 50% of patients, no technique reliably or permanently eliminates neuropathic pain. This is because most techniques are predominantly aimed at reducing pain, not inflammation. In addition, while single factors reduce pain, increasing evidence indicates significant and longer-lasting pain relief requires multiple factors acting simultaneously. Therefore, it is not surprising that extensive data indicate that the application of platelet-rich plasma provides more significant and longer-lasting pain suppression than other techniques, although its analgesia is neither complete nor permanent. However, several case reports indicate that platelet-rich plasma can induce permanent neuropathic pain elimination when the platelet concentration is significantly increased and is applied to longer nerve lengths. This review examines the primary triggers of the development and maintenance of neuropathic pain and techniques that reduce chronic neuropathic pain. The application of plateletrich plasma holds great promise for providing complete and permanent chronic neuropathic pain elimination.
基金supported by the Key Program of the National Natural Science Foundation of China(82130122)the National Natural Science Foundation of China(81973949).
文摘Pain is a subjective and unpleasant sensation that significantly impacts the daily lives of individuals.Chronic pain represents one of the most challenging public health issues,and ensuring effective pain management is a fundamental right of individuals and a sacred duty of healthcare providers.Cannabis,one of the earliest recognized medicinal plants,contains cannabinoids,which are non-opioid substances that modulate nociceptive responses.Electroacupuncture(EA),characterized by its low-risk and well-tolerated nature,is pivotal in pain management.The endocannabinoid system consists of endocannabinoids,cannabinoid receptors,and enzymes involved in endocannabinoid synthesis,degradation,and transport.Recently,the role of the endocannabinoid system in pain development and EA analgesia has attracted considerable research attention.Studies have highlighted the role of the endocannabinoid system in various types of pain,including inflammatory pain,neuropathic pain,and cancer-related pain,as well as in EA analgesia.This study aims to review the mechanisms of endocannabinoid system involvement in pain modulation and EA analgesia to provide insights to inform clinical approaches to pain management.
基金Supported by National Natural Science Foundation of China,No.81273843 and No.81674073National Key Basic Research Program of China(973 Program)+1 种基金No.2015CB554501Project of Shanghai Municipal Commission of Health and Family Planning,No.20144Y0153 and No.2017BR047
文摘AIM To investigate the effects of herb-partitioned moxibustion(HPM) on phosphorylation of mitogen-activated extracellular signal-regulated kinase(MEK)1, extracellular signal-regulated kinase(ERK)1/2 and c AMP response element binding protein(CREB) in spinal cord of rats with chronic inflammatory visceral pain(CIVP), and to explore the central mechanism of HPM in treating CIVP.METHODS Male Sprague-Dawley rats were randomized into normal, model, HPM, sham-HPM, MEK-inhibitor and dimethyl sulfoxide(DMSO) groups. The CIVP model was established using an enema mixture of trinitrobenzene sulfonic acid and ethanol. HPM was applied at bilateral Tianshu(ST25) and Qihai(CV6) acupoints in the HPM group, while in the sham-HPM group, moxa cones and herb cakes were only placed on the same points but not ignited. The MEK-inhibitor and DMSO groups received L5-L6 intrathecal injection of U0126 and 30% DMSO, respectively. Abdominal withdrawal reflex(AWR), mechanical withdrawal threshold(MWT) and thermal withdrawal latency(TWL) were applied for the assessment of pain behavior. The colonic tissue was observed under an optical microscope after hematoxylin-eosin staining. Expression of phosphor(p)MEK1, p ERK1/2 and p CREB in rat spinal cord was detected using Western blotting. The levels of MEK, ERK and CREB m RNA in rat spinal cord were detected using real-time polymerase chain reaction. RESULTS Compared with the normal group, the AWR scores were increased significantly(P < 0.01) and the MWT and TWL scores were decreased significantly(P < 0.05) in the model, sham-HPM and DMSO groups. Compared with the model group, the AWR scores were decreased significantly(P < 0.01) and the MWT and TWL scores were increased significantly in the HPM and MEK-inhibitor groups(P < 0.05). Compared with the sham-HPM and DMSO groups, the AWR scores were decreased significantly(P < 0.01) and the MWT and TWL scores were increased significantly(P < 0.05) in the HPM and MEK-inhibitor groups. Compared with the normal group, the expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were increased significantly in the model, sham-HPM and DMSO groups(P < 0.01 or < 0.05). Compared with the model group, the expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were reduced significantly in the HPM and MEK-inhibitor groups(P < 0.01 or < 0.05). Compared with the sham-HPM and DMSO groups, expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were reduced significantly in the HPM and MEK-inhibitor groups(P < 0.01 or < 0.05). CONCLUSION HPM down-regulates protein phosphorylation of MEK1, ERK1/2 and CREB, and m RNA expression of MEK, ERK and CREB, inhibiting activation of the MEK/ERK/CREB signaling pathway in the spinal cord of CIVP rats, which is possibly a critical central mechanism of the analgesic effect of HPM.
基金We thank Bo Yuan and Tao Wang from the Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences,Beijing,China,for technical assistance.This work was supported by the National Natural Science Foundation of China(81771205,91632113)the Natural Science Foundation and Major Basic Research Program of Shanghai Municipality,China(16JC1420500 and 16JC1420502)+1 种基金the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2017-I2M-3-008)the National Natural Science Foundation for Young Scientists of China(81600956).
文摘Topical irritants such as capsaicin(CAP),peppermint oil(PO),and mustard oil(MO)are effective in relieving inflammatory muscle pain.We investigated the effects of topical irritants in a rat model of inflammatory muscle pain produced by injecting complete Freund's adjuvant(CFA)into the tibialis anterior muscle.CFAinduced mechanical hypersensitivity and the spontaneous activity of muscular nociceptive afferents,and decreased weight-bearing of the hindlimb were relieved by topical application of CAP,PO,or MO on the skin overlying the inflamed muscle.The effects of topical irritants were abolished when applied to the skin on the ipsilateral plantar region or on the contralateral leg,or when the relevant cutaneous nerve or dorsal root was transected.Our results demonstrated that topical irritants may alleviate inflammatory muscle pain via activating cutaneous nociceptors and subsequently inhibiting the abnormal activity of muscular nociceptive neurons.
基金supported by the National Key R&D Program of China(2019YFA0709504)the National Natural Science Foundation of China(31930042,31771164,31900719,and 91630314)+6 种基金the Innovative Research Team of High-level Local Universities in ShanghaiDevelopment Project of Shanghai Peak Disciplines Integrated Chinese and Western MedicineShanghai Science and Technology Committee Rising-Star Program(19QA1401400)111 Project(B18015)Key Project of Shanghai Science&Technology(16JC1420402)Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJLab。
文摘As the most common symptomatic reason to seek medical consultation,pain is a complex experience that has been classified into different categories and stages.In pain processing,noxious stimuli may activate the anterior cingulate cortex(ACC).But the function of ACC in the different pain conditions is not well discussed.In this review,we elaborate the commonalities and differences from accumulated evidence by a variety of pain assays for physiological pain and pathological pain including inflammatory pain,neuropathic pain,and cancer pain in the ACC,and discuss the cellular receptors and signaling molecules from animal studies.We further summarize the ACC as a new central neuromodulation target for invasive and non-invasive stimulation techniques in clinical pain management.The comprehensive understanding of pain processing in the ACC may lead to bridging the gap in translational research between basic and clinical studies and to develop new therapies.
基金supported by the National Natural Science Foundation of China,Nos. 82071556 (to WM), 81873793 (to WM), 82001198 (to YQZ), 82101310 (to DQL)the National Key Research and Development Program of China,No. 2020YFC2005300 (to WM)。
文摘Nitric oxide(NO)/cyclic guanosine 3′,5′-monophosphate(cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the NO/cGMP signaling pathway involved in chronic pain, including neuropathic pain, bone cancer pain, inflammatory pain, and morphine tolerance. The main process in the NO/cGMP signaling pathway in cells involves NO activating soluble guanylate cyclase, which leads to subsequent production of cGMP. cGMP then activates cGMP-dependent protein kinase(PKG), resulting in the activation of multiple targets such as the opening of ATP-sensitive K+ channels. The activation of NO/cGMP signaling in the spinal cord evidently induces upregulation of downstream molecules, as well as reactive astrogliosis and microglial polarization which participate in the process of chronic pain. In dorsal root ganglion neurons, natriuretic peptide binds to particulate guanylyl cyclase, generating and further activating the cGMP/PKG pathway, and it also contributes to the development of chronic pain. Upregulation of multiple receptors is involved in activation of the NO/cGMP signaling pathway in various pain models. Notably the NO/cGMP signaling pathway induces expression of downstream effectors, exerting both algesic and analgesic effects in neuropathic pain and inflammatory pain. These findings suggest that activation of NO/cGMP signaling plays a constituent role in the development of chronic pain, and this signaling pathway with dual effects is an interesting and promising target for chronic pain therapy.
基金grants from the National Natural Science Foundation of China(31720103908 and31530028)the National Key Technology Support Program of the Ministry of Science and Technology of China(2017YFA0701300)
文摘Investigation of pain requires measurements of nociceptive sensitivity and other pain-related behaviors.Recent studies have indicated the superiority of gait analysis over traditional evaluations(e.g., skin sensitivity and sciatic function index [SFI]) in detecting subtle improvements and deteriorations in animal models. Here,pain-related gait parameters, whose criteria include(1)alteration in pain models,(2) correlation with nociceptive threshold, and(3) normalization by analgesics, were identified in representative models of neuropathic pain(spared nerve injury: coordination data) and inflammatory pain(intraplantar complete Freund’s adjuvant: both coordination and intensity data) in the DigiGait^TM and CatWalk^TM systems. DigiGait^TM had advantages in fixed speed(controlled by treadmill) and dynamic SFI, while CatWalk^TM excelled in intrinsic velocity, intensity data,and high-quality 3 D images. Insights into the applicability of each system may provide guidance for selecting the appropriate gait imaging system for different animal models and optimization for future pain research.
文摘AIM: To provoke persistent/chronic multiorgan inflammatory response and to contribute to stones formation followed by fibrosis in hepatobiliary and pancreatic tissues.METHODS: Tumor necrosis factor receptors 1 and 2 (TNFR1/R2) deficient mice reared in-house were given dibutyltin dichloride (DBTC) twice within 10 d by oral gavage delivery. Sham control animals received vehicle treatment and naïve animals remained untreated throughout the study. Animals were monitored daily for symptoms of pain and discomfort. The abdominal and hindpaw hypersensitivity were assessed with von Frey microfilaments. Exploratory behaviors were recorded at the baseline, after initiation of treatment, and before study termination. Histopathological changes were examined postmortem in tissues. Collagen accumulation and fibrosis were confirmed with Sirius Red staining.RESULTS: Animals lost weight after oral administration of DBTC and developed persistent inflammatory abdominal and hindpaw hypersensitivity compared to sham-treated controls (P < 0.0001). These pain related secondary mechanical hypersensitivity responses increased more than 2-fold in DBTC-treated animals. The drastically diminished rearing and grooming rates persisted after DBTC administration throughout the study. Gross as well as micropathology at one month confirmed that animals treated with DBTC developed chronic hepatobiliary injuries evidenced with activation of stellate cells, multifocal necrosis, fatty degeneration of hepatocytes, periportal infiltration of inflammatory cells, and prominent biliary ductal dilation. The severity of hepatitis was scored 3.7 ± 0.2 (severe) in DBTC-treated animals vs score 0 (normal) in sham-treated animals. Fibrotic thickening was extensive around portal ducts, in hepatic parenchyma as well as in lobular pancreatic structures and confirmed with Sirius Red histopathology. In addition, pancreatic microarchitecture was presented with distortion of islets, and parenchyma, infiltration of inflammatory cells, degeneration, vacuolization, and necrosis of acinar cells and distention of pancreatic ducts. Extent of pancreatic damage and pancreatitis were scored 3.6 ± 0.4 (severe) for DBTC-treated in contrast to score 0 (normal) in sham-treated animals. The gall bladder became expanded with ductal distention, and occasional bile stones were detected along with microscopic hepatic lesions. DBTC-treated animals developed splenic hypertrophy with increased weight and length (P < 0.01) along with thymic atrophy (P < 0.001). Finally, colitic lesions and colitis were prominent in DBTC-treated animals and scored 3.4 ± 0.3 (moderately severe) vs 0 (normal) for the sham-treated animals.CONCLUSION: This is the first report of chronic inflammatory multiorgan hepatobiliary pancreatitis, along with fibrosis and calculi formation induced reliably utilizing oral DBTC administration in TNFR1/R2 deficient mice.
文摘The normal gastrointestinal interdigestive migrating motor complex cycle was interrupted, and paroxysmal contraction appeared after formaldehyde-induced stomach ache. Activities of nitric oxide synthase, acetylcholinesterase and vasoactive intestinal peptide neurons were significantly reduced, whereas activities of calcitonin gene-related peptide neurons were significantly increased in the pyloric sphincter muscular layer, myenteric nerve plexus and submucous nerve plexus. Electroacupuncture at Zusanfi （ST36） suppressed paroxysmal contraction in rats with formaldehyde-induced stomach ache, and neurons in the enteric nervous system were normal. These results indicated that nitrergic neurons, cholinergic neurons, vasoactive intestinal peptide neurons and calcitonin gene-related peptide neurons in the enteric nervous system may be involved in changes to the gastrointestinal interdigestive migrating motor complex following stomach ache, and that electroacupuncture can regulate this process.
基金supported by grants from the National Council of Scientific and Technological Development(CNPq)grant#14/2013the Santa Catarina State Foundation in Support of Research and Innovation(FAPESC)grant#04/2012+1 种基金the Coordination of Higher Education Personnel Improvement(CAPES)the UNISUL Scientific Initiation Program(PUIC),Brazil
文摘Objective： The present study aimed to evaluate the analgesic and anti-inflammatory effects of far infrared-emitting ceramics （cFIRs） in a model of persistent inflammatory hyperalgesia and to elucidate the possible mechanisms of these effects. Methods： Mice were injected with complete Freund＇s adjuvant （CFA） and treated with cFIRs via place- ment on a pad impregnated with cFIRs on the bottom of the housing unit for different periods of time. Mice underwent mechanical hyperalgesia and edema assessments, and tumor necrosis factor-α （TNF-α）, interleukin-1β （IL-1β） and IL-10 levels were measured. Twenty-four hours after CFA injection and 30 min before cFIR treatment, mice were pretreated with a nonselective adenosinergic antagonist, caffeine, the selective adenosine receptor A antagonist, 1,3-dipropyl-8-cyclopentylxanthine （DPCPX）, the selective cannabinoid receptor type 1 antagonist, AM281, the selective cannabinoid receptor type 2 antagonist, AM630, or the nonselective opioid receptor antagonist, naloxone, and mechanical hyperalge- sia was assessed. Results： cFIRs statistically （P 〈 0.05） decreased CFA-induced mechanical hyperalgesia （82.86 ±5.21）% in control group vs （56.67±9.54）% in cFIR group） and edema （（1699.0 ± 77.8） gm in control group vs （988.7±107.6） gm in cFIR group）, cFIRs statistically （P 〈 0.05） reduced TNF-α （0.478± 0.072） pg/mg of protein in control group vs （0.273 ±0.055） pg/mg of protein in cFIR group） and IL-113 （（95.81 ± 3.95） pg/mg of protein in control group vs （80.61 ±4.71）pg/mg of protein in cFIR group） levels and statistically （P〈 0.05） increased IL-10 （（18.32 ±0.78） pg/mg of protein in control group vs （25.89 ±1.23） pg/mg of protein in cFIR group） levels in post-CFA-injected paws. Peripheral pre-administration of inhibitory neuroreceptor antagonists （caffeine, DPCPX, AM281, AM630 and naloxone） prevented the analgesic effects of cF1Rs （P 〈 0.05）.Conclusion： These data provide additional support for the use of cFIRs in the treatment of painful inflam- matory conditions and contribute to our understanding of the neurobiological mechanisms of the ther- apeutic effects of cFIRs.
基金the National Natural Science Foundation of China(31671088 and 31730041)the Natural Science Foundation of Shaanxi Province,China(2017ZDJC-01)。
文摘Tweety-homolog 1(Ttyh1)is expressed in neural tissue and has been implicated in the generation of several brain diseases.However,its functional significance in pain processing is not understood.By disrupting the gene encoding Ttyh1,we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice,along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey(PAG)in the basal state.More importantly,the peripheral inflammationevoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice.Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release.Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief.Thus,in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.
文摘<strong>Background: </strong>Pre-clinical and clinical studies have shown that inflammatory pain intensity is increased under diabetes condition. Open cholecystectomy (OC) is a surgical procedure with predictable postoperative pain. However, the comparison of postoperative pain due to open cholecystectomy in diabetic and non-diabetic patients remains unknown. The research question to answer was whether diabetic patients undergoing OC development greater intensity of postoperative pain than non-diabetic patients. <strong>Methods: </strong>The study was conducted between June 2016 and February 2018 at the Regional Hospital of High Specialty “Dr. Juan Graham Casasús” of Villahermosa, Tabasco, Mexico. Seventy patients in two groups of 35 patients each scheduled for OC under general anesthesia were studied. Pain was assessed using the 11-point numerical rating scale (NRS). The primary endpoint was to know NRS pain scores after awaking of general anesthesia. Secondary outcomes included the time of onset of pain and comparing NRS scores between diabetic and non-diabetic patients undergoing OC. <strong>Results:</strong> Diabetic patients reported significantly greater intensity pain than non-diabetic patients. The mean overall pain score in the diabetic and non-diabetic patients was 7.2 ± 0.3 and 5.3 ± 0.3 (P = 0.0002), respectively. Furthermore, 60% of diabetic patients had severe pain (NRS ≥ 8) compared to 20% of non-diabetics (P = 0.006). The time to onset postoperative pain was about 35 minutes in both groups (P = 0.876). <strong>Conclusions:</strong> Diabetic patients undergoing OC have greater intensity postoperative pain and also more frequency of patients with severe pain scores compared with non-diabetic patients. Therefore, analgesic treatment in those patients should consider this point in order to provide a satisfactory postoperative analgesia.
基金Supported by Key Research Projects on the Modernization of TCM,the National Key Research and Development Program of the Ministry of Science and Technology(2018YFC1704600).
文摘In this review,we explored the dose-effect relationship of electroacupuncture(EA)analgesia and its stimulus parameters by searching articles on clinical and experimental research of EA analgesia in the past30 years.The impacts on the analgesic effects are discussed in terms of the pulse waveform,frequency,amplitude,wave width,and time effect,as well as parameter combinations,and the optimization of the EA parameters are summarized for the treatment of neuropathic,inflammatory,and cancer pains.It was initially discovered that the distant-dense(D-D)wave(2/15 Hz or 2/100 Hz)and stimulus for 30-45 min were appropriate in the treatment of chronic inflammatory pain,the strong stimulus was applicable to the acute stage of pain(twice a week),while the weak stimulus was for the stable stage(once weekly).The continuous(2 Hz)/D-D wave(2/100 Hz)and moderate/low intensity of stimulus for 30-45 min are preferred in the treatment of neuropathic pain with EA,once daily or every 2 days.Regarding the treatment of cancer pain,EA with continuous(2 Hz or 100 Hz)or D-D wave(2/100 Hz),moderate and low intensity of stimulus for 30-45 min is adopted,once every 2 days.There is a certain rule for the correlation of each parameter and the combination of parameters to ensure an analgesic effect of EA,which should be further explored in future studies.
基金the National Science Foundation of China,No.30800333
文摘BACKGROUND:Central sensitization,a state of increased excitability of nociceptive neurons in the spinal dorsal horn following peripheral tissue injury and/or inflammation,is an important mechanism underlying hyperalgesia and neuropathic pain.Participation of the glutamate-glutamine cycle in central sensitization of the spinal cord remains poorly understood.OBJECTIVE:To determine whether the astrocyte-neuronal glutamate-glutamine cycle is involved in formalin-induced central sensitization in the spinal cord.DESIGN,TIME AND SETTING:A randomized,controlled,animal experiment was performed at the Institute of Orthopedics,Second Hospital,Lanzhou University,China from September 2007 to August 2008.MATERIALS:Methionine sulfoximine(MSO,0.1 mmol/L),glutamine(0.25 mmol/L),and formalin were used for this study.METHODS:A total of 43 male,Sprague Dawley rats,aged 4 months,were randomly assigned to a sham operation group(n=6)and a model group(n=37).Rats in the model group received intrathecal infusion in the spinal cord.7 days later,37 model rats were randomly divided into PBS,MSO,glutamine,MSO+glutamine and formalin subcutaneous injection alone groups.The PBS,MSO,glutamine,MSO+glutamine groups were respectively intrathecally injected with PBS,MSO,glutamine,MSO+glutamine(50μL each),and then infused with 10μL of saline.Rats from the sham operation group were not subjected to intrathecal infusion in the spinal cord.At 15 minutes after intrathecal injection,a rat model of formalin-induced inflammatory pain was established by subcutaneous injection of 5%formalin(50μL)in the left hindpaw.MAIN OUTCOME MEASURES:Changes in spontaneous nociceptive behavior(licking/biting or flinching)were observed following formalin injection into the rat hindpaw.RESULTS:Compared with the PBS group,duration of licking/biting was significantly shortened,and flinching frequency was significantly diminished in the MSO group(P〈0.05).Compared with the MSO group,duration of licking/biting was significantly prolonged,and flinching frequency was significantly increased in the MSO+glutamine group(P〈0.05).There was no significant difference in inflammatory pain behaviors among the sham operation,PBS,glutamine,MSO+glutamine,and formalin subcutaneous injection alone groups(P〉0.05).CONCLUSION:The astrocyte-neuronal glutamate-glutamine cycle in the spinal cord was shown to be involved in central sensitization induced by formalin subcutaneous injection into the hindpaw.
