Silent cold-sensing neurons contribute to cold allodynia in neuropathic pain.
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ABSTRACT:
SUBMITTER: MacDonald DI
PROVIDER: S-EPMC8320254 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundWhile the PKCγ neurons in spinal dorsal horn play an indispensable part in neuropathic allodynia, the exact effect of PKCγ neurons of brain regions in neuropathic pain remains elusive. Mounting research studies have depicted that the anterior cingulate cortex (ACC) is closely linked with pain perception and behavior, the present study was designed to investigate the contribution of PKCγ neurons in ACC to neuropathic allodynia and pain-related emotion in newly developed Prkcg-P2A-Tdtomato mice.MethodsThe c-fos expression in response to innocuous stimulation was used to monitor the activity of PKCγ in CCI (chronic constriction injury of the sciatic nerve) induced neuropathic pain condition. Activating or silencing ACC PKCγ neurons by chemogenetics was applied to observe the changes of pain behavior. The excitability of ACC PKCγ neurons in normal and CCI mice was compared by patch-clamp whole-cell recordings.ResultsThe PKCγ-Tdtomato neurons were mainly distributed in layer III-Vof ACC. The Tdtomato was mainly expressed in ACC pyramidal neurons demonstrated by intracellular staining. The c-fos expression in ACC PKCγ neurons in response to innocuous stimulation was obviously elevated in CCI mice. The patch clamp recordings showed that ACC PKCγ-Tdtomato neurons were largely activated in CCI mice. Chemogenetic activation of ACC PKCγ neurons in Prkcg-icre mice induced mechanical allodynia and pain-related aversive behavior, conversely, silencing them in CCI condition significantly reversed the mechanical allodynia and pain-related place aversive behavior.ConclusionWe conclude that the PKCγ neurons in ACC are closely linked with neuropathic allodynia and pain-related emotional behaviors.
| S-EPMC8679404 | biostudies-literature
Project description:Cholinergic modulation of the brain cortex is critical for cognitive processes, and altered cholinergic modulation of the prefrontal cortex is emerging as an important mechanism of neuropathic pain. Sex differences in pain prevalence and perception are well known, yet the precise nature of the mechanisms responsible for sexual dimorphism in chronic neuropathic pain are poorly understood. Here we investigated potential sex differences in cholinergic modulation of layer five commissural pyramidal neurons of the rat prelimbic cortex in control conditions and in the SNI model of neuropathic pain. We discovered that cholinergic modulation is stronger in cells from male compared with female rats, and that in neuropathic pain rats, cholinergic excitation of pyramidal neurons was more severely impaired in males than in females. Finally, we found that selective pharmacological blockade of the muscarinic M1 subunit in the prefrontal cortex induces cold sensitivity (but not mechanical allodynia) in naïve animals of both sexes.
| S-EPMC9947152 | biostudies-literature
Project description:Paclitaxel-induced neuropathic pain (PINP) is refractory to currently used analgesics. Previous studies show a pivotal role of oxidative stress in PINP. Because the nuclear factor erythroid-2-related factor 2 (Nrf2) has been considered as the critical regulator of endogenous antioxidant defense, we here explored whether activation of Nrf2 could attenuate PINP. A rat model of PINP was established by intraperitoneal injection of paclitaxel (2 mg/kg) every other day with a final cumulative dose of 8 mg/kg. Hind paw withdrawal thresholds (PWTs) in response to von Frey filament stimuli were used to assess mechanical allodynia. We showed that a single dose of Nrf2 activator, oltipraz (10, 50, and 100 mg/kg), dose-dependently attenuated established mechanical allodynia, whereas repeated injection of oltipraz (100 mg· kg-1· d-1, i.p. from d 14 to d 18) almost abolished the mechanical allodynia in PINP rats. The antinociceptive effect of oltipraz was blocked by pre-injection of Nrf2 inhibitor trigonelline (20 mg/kg, i.p.). Early treatment with oltipraz (100 mg· kg-1· d-1, i.p. from d 0 to d 6) failed to prevent the development of the PINP, but delayed its onset. Western blot and immunofluorescence analysis revealed that the expression levels of Nrf2 and HO-1 were significantly upregulated in the spinal cord of PINP rats. Repeated injection of oltipraz caused further elevation of the expression levels of Nrf2 and HO-1 in the spinal cord of PINP rats, which was reversed by pre-injection of trigonelline. These results demonstrate that oltipraz ameliorates PINP via activating Nrf2/HO-1-signaling pathway in the spinal cord.
| S-EPMC7470811 | biostudies-literature
Project description:Clinical data have shown that chronic exposure to stress may be accompanied by an enhancement of inflammation-related pain sensitivity. In this context, little is however known on the impact of stress on neuropathic pain. In the present study we addressed this issue by combining the chronic constriction injury (CCI) model with an ongoing social stress (OSS) paradigm. Cold plate and von Frey tests were performed in 48 rats divided into four groups: OSS exposed to OSS, CCI subjected to chronic nerve constriction, OSS+CCI with a combination of neuropathy and stress and CON, a control group lacking any manipulation. While we did not observe any stress-related differences in mechanical sensitivity throughout the observation period, CCI rats were more sensitive to cold stimulation than OSS+CCI in the initial phase of neuropathy. A switch was observed at a later stage, leading to a hypersensitivity of the OSS+CCI compared to the CCI rats. At this time point we investigated the spinal mRNA expression of neuron and glia related molecules potentially involved in neuropathic pain and stress. The combination of psychosocial stress and neuropathic pain seemed to enhance glial cell activation, pro-inflammatory cytokine and neurotrophic factor mRNA levels, rather than glutamatergic transmission. Our data show that long lasting social stress may lead to time-dependent alteration of neuropathy-related cold pain sensitivity while mechanically-induced pain remains unchanged.
| S-EPMC5422477 | biostudies-literature
Project description:Chemotherapy-induced neuropathic pain (CINP) is a severe adverse effect of platinum- and taxane-derived anticancer drugs. The pathophysiology of CINP includes damage to neuronal networks and dysregulation of signal transduction due to abnormal Ca2+ levels. Therefore, methods that aid the recovery of neuronal networks could represent a potential treatment for CINP. We developed a mouse model of paclitaxel-induced peripheral neuropathy, representing CINP, to examine whether intrathecal injection of decursin could be effective in treating CINP. We found that decursin reduced capsaicin-induced intracellular Ca2+ levels in F11 cells and stimulated neurite outgrowth in a concentration-dependent manner. Decursin directly reduced mechanical allodynia, and this improvement was even greater with a higher frequency of injections. Subsequently, we investigated whether decursin interacts with the transient receptor potential vanilloid 1 (TRPV1). The web server SwissTargetPrediction predicted that TRPV1 is one of the target proteins that may enable the effective treatment of CINP. Furthermore, we discovered that decursin acts as a TRPV1 antagonist. Therefore, we demonstrated that decursin may be an important compound for the treatment of paclitaxel-induced neuropathic pain that functions via TRPV1 inhibition and recovery of damaged neuronal networks.
| S-EPMC8001788 | biostudies-literature
Project description:Mechanical allodynia, induced by normally innocuous low-threshold mechanical stimulation, represents a cardinal feature of neuropathic pain. Blockade or ablation of high-threshold, small-diameter unmyelinated group C nerve fibers (C-fibers) has limited effects on mechanical allodynia. Although large, myelinated group A fibers, in particular A?-fibers, have previously been implicated in mechanical allodynia, an A-fiber-selective pharmacological blocker is still lacking. Here we report a new method for targeted silencing of A-fibers in neuropathic pain. We found that Toll-like receptor 5 (TLR5) is co-expressed with neurofilament-200 in large-diameter A-fiber neurons in the dorsal root ganglion (DRG). Activation of TLR5 with its ligand flagellin results in neuronal entry of the membrane-impermeable lidocaine derivative QX-314, leading to TLR5-dependent blockade of sodium currents, predominantly in A-fiber neurons of mouse DRGs. Intraplantar co-application of flagellin and QX-314 (flagellin/QX-314) dose-dependently suppresses mechanical allodynia after chemotherapy, nerve injury, and diabetic neuropathy, but this blockade is abrogated in Tlr5-deficient mice. In vivo electrophysiology demonstrated that co-application of flagellin/QX-314 selectively suppressed A?-fiber conduction in naive and chemotherapy-treated mice. TLR5-mediated A?-fiber blockade, but not capsaicin-mediated C-fiber blockade, also reduced chemotherapy-induced ongoing pain without impairing motor function. Finally, flagellin/QX-314 co-application suppressed sodium currents in large-diameter human DRG neurons. Thus, our findings provide a new tool for targeted silencing of A?-fibers and neuropathic pain treatment.
| S-EPMC4752254 | biostudies-literature
Project description:BackgroundPlastic changes in the anterior cingulate cortex (ACC) are critical in the pathogenesis of pain hypersensitivity caused by injury to peripheral nerves. Cdh1, a co-activator subunit of anaphase-promoting complex/cyclosome (APC/C) regulates synaptic differentiation and transmission. Based on this, we hypothesised that the APC/C-Cdh1 played an important role in long-term plastic changes induced by neuropathic pain in ACC.ResultsWe employed spared nerve injury (SNI) model in rat and found Cdh1 protein level in the ACC was down-regulated 3, 7 and 14 days after SNI surgery. We detected increase in c-Fos expression, numerical increase of organelles, swollen myelinated fibre and axon collapse of neuronal cells in the ACC of SNI rat. Additionally, AMPA receptor GluR1 subunit protein level was up-regulated on the membrane through a pathway that involves EphA4 mediated by APC/C-Cdh1, 3 and 7 days after SNI surgery. To confirm the effect of Cdh1 in neuropathic pain, Cdh1-expressing lentivirus was injected into the ACC of SNI rat. Intra-ACC treatment with Cdh1-expressing lentivirus vectors elevated Cdh1 levels, erased synaptic strengthening, as well as alleviating established mechanical allodynia in SNI rats. We also found Cdh1-expressing lentivirus normalised SNI-induced redistribution of AMPA receptor GluR1 subunit in ACC by regulating AMPA receptor trafficking.ConclusionsThese results provide evidence that Cdh1 in ACC synapses may offer a novel therapeutic strategy for treating chronic neuropathic pain.
| S-EPMC4568074 | biostudies-literature
Project description:Neuropathic pain (NeuP), a challenging medical condition, has been suggested by neuroimaging studies to be associated with abnormalities of neural activities in some brain regions. However, aberrancies in brain functional alterations underlying the sensory-discriminative abnormalities and negative emotions in the setting of NeuP remain unexplored. Here, we aimed to investigate the functional alterations in neural activity relevant to pain as well as pain-related depressive-like and anxiety-like behaviors in NeuP by combining amplitude of low frequency fluctuation (ALFF) and degree centrality (DC) analyses methods based on resting-state functional magnetic resonance imaging (rs-fMRI). A rat model of NeuP was established via chronic constriction injury (CCI) of the sciatic nerve. Results revealed that the robust mechanical allodynia occurred early and persisted throughout the entire observational period. Depressive and anxiety-like behaviors did not appear until 4 weeks after injury. When the maximum allodynia was apparent early, CCI rats exhibited decreased ALFF and DC values in the left somatosensory and nucleus accumbens shell (ACbSh), respectively, as compared with sham rats. Both values were significantly positively correlated with mechanical withdrawal thresholds (MWT). At 4 weeks post-CCI, negative emotional states were apparent and CCI rats were noted to exhibit increased ALFF values in the left somatosensory and medial prefrontal cortex (mPFC) as well as increased DC values in the right motor cortex, as compared with sham rats. At 4 weeks post-CCI, ALFF values in the left somatosensory cortex and DC values in the right motor cortex were noted to negatively correlate with MWT and exhibition of anxiety-like behavior on an open-field test (OFT); values were found to positively correlate with the exhibition of depressive-like behavior on forced swimming test (FST). The mPFC ALFF values were found to negatively correlate with the exhibition of anxiety-like behavior on OFT and positively correlate with the exhibition of depressive-like behavior on FST. Our findings detail characteristic alterations of neural activity patterns induced by chronic NeuP and underscore the important role of the left somatosensory cortex, as well as its related networks, in the mediation of subsequent emotional dysregulation due to NeuP.
| S-EPMC9108233 | biostudies-literature
Project description:Oxaliplatin, a chemotherapy drug, induces acute peripheral neuropathy characterized by cold allodynia, spinal glial activation and increased levels of pro-inflammatory cytokines. Herein, we determined whether Cinnamomi Cortex (C. Cortex), a widely used medicinal herb in East Asia for cold-related diseases, could attenuate oxaliplatin-induced cold allodynia in rats and the mechanisms involved. A single oxaliplatin injection (6 mg/kg, i.p.) induced significant cold allodynia signs based on tail immersion tests using cold water (4 °C). Daily oral administration of water extract of C. Cortex (WECC) (100, 200, and 400 mg/kg) for five consecutive days following an oxaliplatin injection dose-dependently alleviated cold allodynia with only a slight difference in efficacies between the middle dose at 200 mg/kg and the highest dose at 400 mg/kg. WECC at 200 mg/kg significantly suppressed the activation of astrocytes and microglia and decreased the expression levels of IL-1? and TNF in the spinal cord after injection with oxaliplatin. Furthermore, oral administration of coumarin (10 mg/kg), a major phytocompound of C. Cortex, markedly reduced cold allodynia. These results indicate that C. Cortex has a potent anti-allodynic effect in oxaliplatin-injected rats through inhibiting spinal glial cells and pro-inflammatory cytokines. We also suggest that coumarin might play a role in the anti-allodynic effect of C. Cortex.
| S-EPMC6274362 | biostudies-literature
Project description:BACKGROUND AND PURPOSE: There is growing interest in using cannabinoid type 2 (CB(2)) receptor agonists for the treatment of neuropathic pain. In this report, we describe the pharmacological characteristics of MDA7 (1-[(3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl)carbonyl]piperidine), a novel CB(2) receptor agonist. EXPERIMENTAL APPROACH: We characterized the pharmacological profile of MDA7 by using radioligand-binding assays and in vitro functional assays at human cannabinoid type 1 (CB(1)) and CB(2) receptors. In vitro functional assays were performed at rat CB(1) and CB(2) receptors. The effects of MDA7 in reversing neuropathic pain were assessed in spinal nerve ligation and paclitaxel-induced neuropathy models in rats. KEY RESULTS: MDA7 exhibited selectivity and agonist affinity at human and rat CB(2) receptors. MDA7 treatment attenuated tactile allodynia produced by spinal nerve ligation or by paclitaxel in a dose-related manner. These effects were selectively antagonized by a CB(2) receptor antagonist but not by CB(1) or opioid receptor antagonists. MDA7 did not affect rat locomotor activity. CONCLUSION AND IMPLICATIONS: MDA7, a novel selective CB(2) agonist, was effective in suppressing neuropathic nociception in two rat models without affecting locomotor behaviour. These results confirm the potential for CB(2) agonists in the treatment of neuropathic pain.
| S-EPMC2597252 | biostudies-literature