Mechanisms Involved in Superiority of Angiotensin Receptor Blockade over ACE Inhibition in Attenuating Neuropathic Pain Induced in Rats.
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ABSTRACT:
SUBMITTER: Hegazy N
PROVIDER: S-EPMC7609714 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Peripheral nerve damage initiates a complex series of structural and cellular processes that culminate in chronic neuropathic pain. The recent success of a type 2 angiotensin II (Ang II) receptor (AT2R) antagonist in a phase II clinical trial for the treatment of postherpetic neuralgia suggests angiotensin signaling is involved in neuropathic pain. However, transcriptome analysis indicates a lack of AT2R gene (Agtr2) expression in human and rodent sensory ganglia, raising questions regarding the tissue/cell target underlying the analgesic effect of AT2R antagonism. We show that selective antagonism of AT2R attenuates neuropathic but not inflammatory mechanical and cold pain hypersensitivity behaviors in mice. Agtr2-expressing macrophages (M?s) constitute the predominant immune cells that infiltrate the site of nerve injury. Interestingly, neuropathic mechanical and cold pain hypersensitivity can be attenuated by chemogenetic depletion of peripheral M?s and AT2R-null hematopoietic cell transplantation. Our study identifies AT2R on peripheral M?s as a critical trigger for pain sensitization at the site of nerve injury, and therefore proposes a translatable peripheral mechanism underlying chronic neuropathic pain.
| S-EPMC6112686 | biostudies-literature
Project description:Neuropathic pain is a major clinic probelm as it is very difficult to treat and mechanism remain unknown. Here, we investigated the differential expression of proteins in the central nuecleus of amygdala (CeA) in neuropathic pain moldel spinal nerve transection (SNT)in rats. CeA was excised from naive, sham, SNTmodels at days 3, 7, 14 and 21 rats. The aim was to quatify the differential proteins in CeA including memebrane proteins. We used gel- and mass spectrometry- based proteomics. For gel-proteomics, total tissue lysate proteins were separated by 2D-PAGE. The 2D gels from different SNT time points against Sham and control rats were compared using Progenesis SameSpot software. The spots with fold change greater then 2 excised for the proteins IDs by LC-MS/MS. Protein spots were digested using trypsin. Extracted peptides were injected on the nano C18 column and measured by a LTQ Orbitrap XL or a LTQ Orbitrap Velos mass spectrometers. For the identification of membrane proteins in CeA, we used 1-SDS-PAGE and cut the gel region of MW 80 kDa and higher for nano-LC-MS/MS analysis. We also quantified membrane proteins by utilising triplex stabel isotope dimethyl labelling at the peptide level. Sham, control and day 3, 7 and 21 after SNT surgery rats CeA membrane proteins were purified and digested by trypsin and labelled with "light", "medium" and "heavy" dimethyl labelling reagents. The resulting peptides were analysed by a nano LC connected to the Q Exactive mass spectrometer. Quantification of peptide was processed using Proteome Discoverer 1.3.
2020-02-21 | PXD017473 | Pride
Project description:Aberrant neuronal activity in injured peripheral nerves is believed to be an important factor in the development of neuropathic pain. Pharmacological blockade of that activity has been shown to mitigate the onset of associated molecular events in the nervous system. However, results in preventing onset of pain behaviors by providing prolonged nerve blockade have been mixed. Furthermore, the experimental techniques used to date to provide that blockade were limited in clinical potential in that they would require surgical implantation. To address these issues, we have used liposomes (SDLs) containing saxitoxin (STX), a site 1 sodium channel blocker, and the glucocorticoid agonist dexamethasone to provide nerve blocks lasting ~1 wk from a single injection. This formulation is easily injected percutaneously. Animals undergoing spared nerve injury (SNI) developed mechanical allodynia in 1 wk; nerve blockade with a single dose of SDLs (duration of block 6.9 ± 1.2 d) delayed the onset of allodynia by 2 d. Treatment with three sequential SDL injections resulting in a nerve block duration of 18.1 ± 3.4 d delayed the onset of allodynia by 1 mo. This very prolonged blockade decreased activation of astrocytes in the lumbar dorsal horn of the spinal cord due to SNI. Changes in expression of injury-related genes due to SNI in the dorsal root ganglia were not affected by SDLs. These findings suggest that formulations of this kind, which could be easy to apply clinically, can mitigate the development of neuropathic pain.
| S-EPMC3491532 | biostudies-literature
Project description:The loss of descending inhibitory control is thought critical to the development of chronic pain but what causes this loss in function is not well understood. We have investigated the dynamic contribution of prelimbic cortical neuronal projections to the periaqueductal grey (PrL-P) to the development of neuropathic pain in rats using combined opto- and chemogenetic approaches. We found PrL-P neurons to exert a tonic inhibitory control on thermal withdrawal thresholds in uninjured animals. Following nerve injury, ongoing activity in PrL-P neurons masked latent hypersensitivity and improved affective state. However, this function is lost as the development of sensory hypersensitivity emerges. Despite this loss of tonic control, opto-activation of PrL-P neurons at late post-injury timepoints could restore the anti-allodynic effects by inhibition of spinal nociceptive processing. We suggest that the loss of cortical drive to the descending pain modulatory system underpins the expression of neuropathic sensitisation after nerve injury.
| S-EPMC7895525 | biostudies-literature
Project description:Peripheral nerve injury alters the expression of hundreds of proteins in dorsal root ganglia (DRG). Targeting some of these proteins has led to successful treatments for acute pain, but not for sustained postoperative neuropathic pain. The latter may require targeting multiple proteins. Since a single microRNA (miR) can affect the expression of multiple proteins, here, we describe an approach to identify chronic neuropathic pain-relevant miRs. We used two variants of the spared nerve injury (SNI): Sural-SNI and Tibial-SNI and found distinct pain phenotypes between the two. Both models induced strong mechanical allodynia, but only Sural-SNI rats maintained strong mechanical and cold allodynia, as previously reported. In contrast, we found that Tibial-SNI rats recovered from mechanical allodynia and never developed cold allodynia. Since both models involve nerve injury, we increased the probability of identifying differentially regulated miRs that correlated with the quality and magnitude of neuropathic pain and decreased the probability of detecting miRs that are solely involved in neuronal regeneration. We found seven such miRs in L3-L5 DRG. The expression of these miRs increased in Tibial-SNI. These miRs displayed a lower level of expression in Sural-SNI, with four having levels lower than those in sham animals. Bioinformatics analysis of how these miRs could affect the expression of some ion channels supports the view that, following a peripheral nerve injury, the increase of the 7 miRs may contribute to the recovery from neuropathic pain while the decrease of four of them may contribute to the development of chronic neuropathic pain. The approach used resulted in the identification of a small number of potentially neuropathic pain relevant miRs. Additional studies are required to investigate whether manipulating the expression of the identified miRs in primary sensory neurons can prevent or ameliorate chronic neuropathic pain following peripheral nerve injuries. To identify the miRs that were differentially dysregulated between Tibial-SNI and Sural-SNI, we first performed 12 microarrays in a limited number of samples (in four individual DRGs per group: Sham, Tibial-SNI and Sural-SNI; two L3-DRG and two L4-DRG). Then, miRs identified as having differential expression were corroborated with real time qRT-PCR in RNA isolated from individual DRGs (L3, L4 and L5) derived from 4 rats per group (not presented here, but in the manuscript).
2014-09-29 | E-GEOD-60033 | biostudies-arrayexpress
Project description:Peripheral nerve injury alters the expression of hundreds of proteins in dorsal root ganglia (DRG). Targeting some of these proteins has led to successful treatments for acute pain, but not for sustained postoperative neuropathic pain. The latter may require targeting multiple proteins. Since a single microRNA (miR) can affect the expression of multiple proteins, here, we describe an approach to identify chronic neuropathic pain-relevant miRs. We used two variants of the spared nerve injury (SNI): Sural-SNI and Tibial-SNI and found distinct pain phenotypes between the two. Both models induced strong mechanical allodynia, but only Sural-SNI rats maintained strong mechanical and cold allodynia, as previously reported. In contrast, we found that Tibial-SNI rats recovered from mechanical allodynia and never developed cold allodynia. Since both models involve nerve injury, we increased the probability of identifying differentially regulated miRs that correlated with the quality and magnitude of neuropathic pain and decreased the probability of detecting miRs that are solely involved in neuronal regeneration. We found seven such miRs in L3-L5 DRG. The expression of these miRs increased in Tibial-SNI. These miRs displayed a lower level of expression in Sural-SNI, with four having levels lower than those in sham animals. Bioinformatics analysis of how these miRs could affect the expression of some ion channels supports the view that, following a peripheral nerve injury, the increase of the 7 miRs may contribute to the recovery from neuropathic pain while the decrease of four of them may contribute to the development of chronic neuropathic pain. The approach used resulted in the identification of a small number of potentially neuropathic pain relevant miRs. Additional studies are required to investigate whether manipulating the expression of the identified miRs in primary sensory neurons can prevent or ameliorate chronic neuropathic pain following peripheral nerve injuries.
2014-09-29 | GSE60033 | GEO
Project description:BackgroundIt has been reported that the P2Y12 receptor (P2Y12R) is involved in satellite glial cells (SGCs) activation, indicating that P2Y12R expressed in SGCs may play functional roles in orofacial neuropathic pain mechanisms. However, the involvement of P2Y12R in orofacial neuropathic pain mechanisms is still unknown. We therefore studied the reflex to noxious mechanical or heat stimulation of the tongue, P2Y12R and glial fibrillary acidic protein (GFAP) immunohistochemistries in the trigeminal ganglion (TG) in a rat model of unilateral lingual nerve crush (LNC) to evaluate role of P2Y12R in SGC in lingual neuropathic pain.ResultsThe head-withdrawal reflex thresholds to mechanical and heat stimulation of the lateral tongue were significantly decreased in LNC-rats compared to sham-rats. These nocifensive effects were apparent on day 1 after LNC and lasted for 17 days. On days 3, 9, 15 and 21 after LNC, the mean relative number of TG neurons encircled with GFAP-immunoreactive (IR) cells significantly increased in the ophthalmic, maxillary and mandibular branch regions of TG. On day 3 after LNC, P2Y12R expression occurred in GFAP-IR cells but not neuronal nuclei (NeuN)-IR cells (i.e. neurons) in TG. After 3 days of successive administration of the P2Y12R antagonist MRS2395 into TG in LNC-rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly decreased coincident with a significant reversal of the lowered head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue compared to vehicle-injected rats. Furthermore, after 3 days of successive administration of the P2YR agonist 2-MeSADP into the TG in naïve rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly increased and head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue were significantly decreased in a dose-dependent manner compared to vehicle-injected rats.ConclusionsThe present findings provide the first evidence that the activation of P2Y12R in SGCs of TG following lingual nerve injury is involved in the enhancement of TG neuron activity and nocifensive reflex behavior, resulting in neuropathic pain in the tongue.
| S-EPMC3386019 | biostudies-literature
Project description:Chemotherapeutic drugs are widely utilized in the treatment of human cancers. Painful chemotherapy-induced neuropathy is a common, debilitating, and dose-limiting side effect for which there is currently no effective treatment. Previous studies have demonstrated the potential utility of peptides from the marine snail from the genus Conus for the treatment of neuropathic pain. α-Conotoxin RgIA and a potent analog, RgIA4, have previously been shown to prevent the development of neuropathy resulting from the administration of oxaliplatin, a platinum-based antineoplastic drug. Here, we have examined its efficacy against paclitaxel, a chemotherapeutic drug that works by a mechanism of action distinct from that of oxaliplatin. Paclitaxel was administered at 2 mg/kg (intraperitoneally (IP)) every other day for a total of 8 mg/kg. Sprague Dawley rats that were co-administered RgIA4 at 80 µg/kg (subcutaneously (SC)) once daily, five times per week, for three weeks showed significant recovery from mechanical allodynia by day 31. Notably, the therapeutic effects reached significance 12 days after the last administration of RgIA4, which is suggestive of a rescue mechanism. These findings support the effects of RgIA4 in multiple chemotherapeutic models and the investigation of α9α10 nicotinic acetylcholine receptors (nAChRs) as a non-opioid target in the treatment of chronic pain.
| S-EPMC7024385 | biostudies-literature
Project description:Neuropathic pain caused by nervous system damage or system dysfunction. The pathogenesis and the mechanism underlying neuropathic pain remains unclear. The only known neurobiological component involved in the neuropathic pain is nitric oxide (NO). NO is synthesized by nitric oxide synthase (nNOS) from L-arginine and oxygen. nNOS is involved in the inflammatory pain and neuropathic pain. In this study, we aimed to identify whether KN93 reduced the pain in the rats. Sixty adult male SD rat were randomly divided into 4 groups. Sham group and model group were not received treatment. Experimental group received intrathecal injection of KN93, and negative control group received DMSO injection 30 min before pain test. After last test of pain threshold, the rats were sacrificed and lumbar spinal tissues were sampled for analysis of the expression of pnNOS and pCaMK II by quantitative PCR and Western blotting. Pain threshold was increased in the rats received KN93 treatment (P<0.01), and the expression levels of pnNOS was increased (P<0.05) in experimental group and accompanied with decrease of CaMK II expression (P<0.05). By administration of KN93, the interaction of nNOS and the adaptor protein CAPON was reduced through inhibition of CaMK II by KN93. In conclusion, this study reveals that KN93 can reduce neuropathic pain via inhibiting the activity of CaMK II, and then increase the level of phosphorylated nNOS, to reduce the interaction with CAPON.
| S-EPMC4680409 | biostudies-literature
Project description:SIP30 (SNAP25 interacting protein of 30) is a SNAP25 interaction protein of 30 kDa that functions in neurotransmitter release. Using a chronic constriction injury (CCI) model of neuropathic pain, we profiled gene expression in the rat spinal cord and brain and identified sip30, which was upregulated after CCI. Here, we show that CCI induced a bilateral increase of SIP30 in the rostral anterior cingulate cortex (rACC), a key brain region that has been implicated in pain affect. We put rats in a chamber with one half painted white (light area) and the other half painted black (dark area), and measured neuropathic pain-evoked place escape/avoidance paradigm (PEAP) to quantify the level of negative emotion evoked by painful stimuli using a Von Frey hair. Inhibition of CCI-mediated induction of SIP30 by intra-rACC injection of shRNA targeting the rat sip30 gene reduced PEAP. Interestingly, knockdown of SIP30 did not affect CCI-induced evoked pain such as heat hyperalgesia and mechanical allodynia. Neither did it affect general learning and memory. CCI-induced upregulation of SIP30 was correlated with activation of ERK, PKA, and CREB in the rACC. Intra-rACC administration of PKA or ERK inhibitors suppressed CCI-induced SIP30 upregulation and blocked the induction of PEAP. Additionally, knockdown of SIP30 suppressed the frequency of mEPSCs and increased paired-pulse ratios in rACC slices and decreased extracellular glutamate concentrations. Together, our results highlight SIP30 as a target of PKA and ERK in the rACC to mediate neuropathic pain-evoked negative emotion via modulation of glutamate release and excitatory synaptic transmission.
| S-EPMC6608160 | biostudies-literature