Rat Model Of Neuropathic Pain Research Articles

Pharmacological activation of mediodorsal thalamic GABA-A receptors modulates morphine/cetirizine-induced changes in the prefrontal cortical GFAP expression in a rat model of neuropathic pain

The present study investigated the involvement of mediodorsal thalamic (MD) GABA-A receptors in cetirizine/morphine-induced anti-allodynia using a rat model of neuropathic pain. To assess the importance of the prefrontal cortex (PFC) for chronic pain processing, its expression level changes of glial fibrillary acidic protein (GFAP) were measured following drug treatments. Each animal was subjected to chronic constriction of the sciatic nerve surgery simultaneously with the MD cannulation under stereotaxic surgery. The results showed that the administration of morphine (3–5 mg/kg) or cetirizine (1–3 mg/kg) produced significant analgesia in neuropathic rats. Systemic administration of cetirizine (2.5 and 3 mg/kg) potentiated the analgesic response to a low and intolerance dose of morphine (3 mg/kg). Intra-MD microinjection of muscimol, a selective GABA-A receptor agonist (0.005–0.01 μg/rat), increased the cetirizine/morphine-induced anti-allodynia, while muscimol by itself did not affect neuropathic pain. The neuropathic pain was associated with the increased PFC expression level of GFAP, suggesting the impact of chronic pain on PFC glial management. Interestingly, the anti-allodynia was associated with a decrease in the PFC expression level of GFAP under the drugs' co-administration. Thus, cetirizine has a significant potentiating effect on morphine response in neuropathic pain via interacting with the MD GABA-A receptors. It seems that neuropathic pain affects the prefrontal cortex GFAP signaling pathway. In clinical studies, these findings can be considered to create a combination therapy with low doses of GABA-A receptor agonist plus cetirizine and morphine to manage neuropathic pain.

Gelsemine relieves the neuropathic pain by down-regulating DPP4 level in rats

BackgroundBased on the previous findings on the relieving role of gelsemine in neuropathic pain, this research aims to further investigate the relevant regulatory mechanism. MethodsTargets of gelsemine were predicted using SwissTargetPrediction. The peripheral neuropathic pain rat model was established by ligating spinal nerves, and then gelsemine (10 μg for one day) or dipeptidyl peptidase 4 (DPP4) oligonucleotides (5 μg/day, for 7 days) was injected into intrathecal bolus of rats. The mechanical threshold (0, 1, 2, 4 h after the last injection) was examined to evaluate the mechanical allodynia of rats. After the mechanical threshold measurement, the rats were anesthetized with isoflurane and then sacrificed by cervical dislocation. IBA1- and DPP4-positive cells in the spinal dorsal horn of rats were determined using immunohistochemistry and immunofluorescence assays. The expressions of DPP4, IL-1β and TNF-α in the spinal dorsal horn of rats were measured by Western blot and quantitative real-time PCR. ResultsDPP4 was one of the targets of gelsemine. Gelsemine could elevate the down-regulated mechanical threshold, and lessen the up-regulated IBA1- and DPP4-positive cells and expressions of DPP4, IL-1β and TNF-α in the spinal dorsal horn of rats with neuropathic pain. DPP4 overexpression reversed the role of gelsemine in neuropathic pain. ConclusionGelsemine relieves neuropathic pain by down-regulating DPP4 level in rats, providing a novel drug candidate and biomarker for neuropathic pain treatment.

Major Differences in Transcriptional Alterations in Dorsal Root Ganglia Between Spinal Cord Injury and Peripheral Neuropathic Pain Models.

Chronic, often intractable, pain is caused by neuropathic conditions such as traumatic peripheral nerve injury (PNI) and spinal cord injury (SCI). These conditions are associated with alterations in gene and protein expression correlated with functional changes in somatosensory neurons having cell bodies in dorsal root ganglia (DRGs). Most studies of DRG transcriptional alterations have utilized PNI models where axotomy-induced changes important for neural regeneration may overshadow changes that drive neuropathic pain. Both PNI and SCI produce DRG neuron hyperexcitability linked to pain, but contusive SCI produces little peripheral axotomy or peripheral nerve inflammation. Thus, comparison of transcriptional signatures of DRGs across PNI and SCI models may highlight pain-associated transcriptional alterations in sensory ganglia that do not depend on peripheral axotomy or associated effects such as peripheral Wallerian degeneration. Data from our rat thoracic SCI experiments were combined with meta-analysis of published whole-DRG RNA-seq datasets from prominent rat PNI models. Striking differences were found between transcriptional responses to PNI and SCI, especially in regeneration-associated genes (RAGs) and long noncoding RNAs (lncRNAs). Many transcriptomic changes after SCI also were found after corresponding sham surgery, indicating they were caused by injury to surrounding tissue, including bone and muscle, rather than to the spinal cord itself. Another unexpected finding was of few transcriptomic similarities between rat neuropathic pain models and the only reported transcriptional analysis of human DRGs linked to neuropathic pain. These findings show that DRGs exhibit complex transcriptional responses to central and peripheral neural injury and associated tissue damage. Although only a few genes in DRG cells exhibited similar changes in expression across all the painful conditions examined here, these genes may represent a core set whose transcription in various DRG cell types is sensitive to significant bodily injury, and which may play a fundamental role in promoting neuropathic pain.

Using Network Pharmacology and Animal Experiment to Investigate the Therapeutic Mechanisms of Polydatin against Vincristine-Induced Neuropathic Pain.

Background Polydatin (PD) is the primary active compound in Polygonum cuspidatum Sieb and has been demonstrated to exert anti-inflammatory and neuroprotective activities. In the present study, we aimed to explore the therapeutic mechanisms of PD against chemotherapy-induced neuropathic pain. Methods The putative targets of PD were obtained from the CTD and SwissTargetPrediction databases. Neuropathic pain- and VIN-related targets were collected from the CTD and GeneCards databases. Subsequently, the intersection targets were obtained using the Venn tool, and the protein-protein interaction (PPI) was constructed by the STRING database. GO and KEGG enrichment analyses were performed to investigate the biological functions of the intersection targets. Further, a rat model of VIN-induced neuropathic pain was established to confirm the reliability of the network pharmacology findings. Results A total of 46 intersection targets were identified as potential therapeutic targets, mainly related to neuroinflammation. KEGG pathway analysis indicated that the IL-17 signaling pathway was involved in the mechanism of the antinociceptive effect of PD. PPI network analysis indicated that RELA, IL-6, TP53, MAPK3, and MAPK1 were located at crucial nodes in the network. Additionally, PD exerted an antinociceptive effect by increasing the nociceptive threshold. The results of qRT-PCR, western blot, and immunohisochemistry indicated that PD inhibited the IL-6, TP53, and MAPK1 levels in VIN-induced neuropathic pain rats. Conclusions Overall, this research provided evidence that suppressing inflammatory signaling pathways might be a potential mechanism action of PD's antinociceptive effect against VIN-induced neuropathic pain.

O095 / #831 SPINAL CORD STIMULATION USING TIME-DYNAMIC PULSES ACHIEVES FASTER AND LONGER REVERSAL OF ALLODYNIA IN A RAT MODEL OF NEUROPATHIC PAIN: TRACK 1: NEUROMODULATION FOR PAINFUL NEUROPATHIES / PERIPHERAL NERVE STIMULATION

Spinal cord stimulation (SCS) using time-dynamic pulses (TDPs) is an emerging field of neuromodulation and a promising advancement in SCS that, unlike conventional tonic SCS, modulates stimulation pulse parameters with signals that change continuously and automatically. Previously [1], we demonstrated the analgesic efficacy of TDPs delivered at sub-paresthesia amplitudes in a rat model of neuropathic pain (n=8 rats), and reported that TDPs with rate or amplitude modulation significantly reversed allodynia.

PO160 / #661 MULTIPLE FAST-ACTING SUB-PERCEPTION THRESHOLD WAVEFORMS PROVE TO PRODUCE EFFICIENT PAIN RELIEF IN AN EXPERIMENTAL ANIMAL MODEL OF CHRONIC NEUROPATHIC PAIN: E-POSTER VIEWING

Spinal cord stimulation (SCS) is an established treatment for chronic neuropathic pain1. Besides paresthesia-inducing conventional (con-SCS), paresthesia-free (i.e., sub-perception) SCS paradigms have also been developed, but they exhibit a longer duration until analgesia, which may complicate clinical device programming2. In contrast, Fast-Acting-Sub-Perception-Threshold-SCS (FAST-SCS) is a novel sub-perception paradigm that induces a rapid onset of analgesia3. We assessed 4 variations of FAST-SCS in a rat model of chronic neuropathic pain to evaluate the effect of stimulation amplitude (at 40 or 60% motor threshold (MT)) and the effect of active (FAST-A-SCS) or pseudo-passive (FAST-P-SCS) charge balance.

Differences and Similarities in Spontaneous Activity Between Animal Models of Cancer-Induced Pain and Neuropathic Pain.

BackgroundClinical data on cancer-induced pain (CIP) demonstrate widespread changes in sensory function. It is characterized in humans not only by stimulus-invoked pain, but also by spontaneous pain. In our previous studies in an animal model of CIP, we observed changes in intrinsic membrane properties and excitability of dorsal root ganglion (DRG) sensory neurons corresponding to mechanical allodynia and hyperalgesia, of which abnormal activities of Aβ-fiber sensory neurons are consistent in a rat model of peripheral neuropathic pain (NEP).ObjectiveTo investigate whether there are related peripheral neural mechanisms between the CIP and NEP models of spontaneous pain, we compared the electrophysiological properties of DRG sensory neurons at 2–3 weeks after CIP and NEP model induction.MethodsCIP models were induced with metastasis tumour-1 rat breast cancer cells implanted into the distal epiphysis of the femur. NEP models were induced with a polyethylene cuff implanted around the sciatic nerve. Spontaneous pain in animals is measured by spontaneous foot lifting (SFL). After measurement of SFL, the animals were prepared for electrophysiological recordings of spontaneous activity (SA) in DRG neurons in vivo.ResultsOur data showed that SFL and SA occurred in both models. The proportion of SFL and SA of C-fiber sensory neurons in CIP was more significantly increased than in NEP models. There was no difference in duration of SFL and the rate of SA between the two models. The duration of SFL is related to the rate of SA in C-fiber in both models.ConclusionThus, SFL may result from SA activity in C-fiber neurons in CIP and NEP rats. The differences and similarities in spontaneous pain between CIP and NEP rats is related to the proportion and rate of SA in C-fibers, respectively.

Structure-Activity Relationship Development Efforts towards Peripherally Selective Analogs of the Cannabinoid Receptor Partial Agonist BAY 59-3074.

Selective modulation of peripheral cannabinoid receptors (CBRs) has potential therapeutic applications in medical conditions, including obesity, diabetes, liver diseases, GI disorders and pain. While there have been considerable efforts to produce selective antagonists or full agonists of CBRs, there has been limited reports on the development of partial agonists. Partial agonists targeting peripheral CBRs may have desirable pharmacological profiles while not producing centrally mediated dissociative effects. Bayer reported that BAY 59-3074 is a CNS penetrant partial agonist of both CB1 and CB2 receptors with efficacy in rat models of neuropathic and inflammatory pain. In this report, we demonstrate our efforts to synthesize analogs that would favor peripheral selectivity, while maintaining partial agonism of CB1. Our efforts led to the identification of a novel compound, which is a partial agonist of the human CB1 (hCB1) receptor with vastly diminished brain exposure compared to BAY 59-3074.

Effects of glucocorticoid receptor agonists on hyperalgesia of rats with neuropathic pain and its mechanisms

To investigate the effects of glucocorticoid receptor agonists on hyperalgesia in rats with neuropathic pain (NPP) by regulating nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)/interleukin-1β (IL-1β) pathway and its mechanisms. Forty SD rats were divided into control group, NPP model group, NPP treated with NLRP3 inhibitor group and dexamethasone treatment group with 10 rats in each group. The NPP rat model was induced by vincristine. The model group was established according to the above method, the NLRP3 inhibitor group was treated with NLRP3 inhibitor (MCC950) after the NPP model was established, and the treatment group was treated with glucocorticoid receptor agonist (dexamethasone) after the model was established according to the design. The rats of the control group were given the same amount of normal saline. After 7 days of intervention, the mechanical pain threshold, thermal pain threshold, morphological changes of spinal dorsal horn, pain factors (prostaglandin E2 (PGE2), substance P (SP), 5-hydroxytryptamine (5-HT)), inflammatory factors (interleukin-8 (IL-8), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6)), and NLRP3/IL-1β protein expressions were determined and compared among the four groups. Compared with the model group, the pathological changes of spinal dorsal horn neurons in NLRP3 inhibitor group and treatment group were alleviated significantly, the arrangement of neurons was tended to be close, the number of neurons was gradually returned to normal, and the pyknosis of neurons was decreased. Compared with the control group, the mechanical pain threshold and thermal pain threshold of the model group were decreased significantly (P＜0.05), and the expressions of inflammatory factors, pain factors and NLRP3, IL-1β protein were increased significantly (P＜0.05); compared with the model group, the mechanical pain threshold and thermal pain threshold of the NLRP3 inhibitor group and the dexamethasone treatment group were increased significantly (P＜0.05), and the expressions of inflammatory factors, pain factors and NLRP3, IL-1β protein were decreased significantly (P＜ 0.05). The difference between NLRP3 inhibitor group and treatment group was not statistically significant (P＞0.05). Glucocorticoid receptor agonists may reduce the hyperalgesia of neuropathic pain rat model by down regulating NLRP3/IL-1β pathway, which may be the mechanism of dexamethasone on antiinflammatory of analgesia in early stage of NPP.

Effect of rPMS on N-type calcium channel in rats with neuropathic pain

Purpose: To investigate the effect of repetitive peripheral magnetic stimulation (rPMS) on N-type calcium channel of rats with neuropathic pain (NP).
 Methods: Thirty-two Sprague-Dawley (SD) rats were randomized into control, mock surgical, model, and rPMS groups. For the model and rPMS groups, rat NP models were made based on chronic constriction injury (CCI) model from January 2018 to June 2019; the mock surgical group was treated to expose the sciatic nerve, while the control group received no treatment.
 Results: Compared to the control group, the model group demonstrated a prominent increase in spontaneous pain-like behaviors, threshold of claw withdrawal in reaction to mechanical stimulation, substance P, glutamic acid, calcitonin gene-related peptide (CGRP), and calcium current, with a decrease in paw withdrawal thermal latency (PwTL) (p < 0.05). In comparison to the model group, alleviated spontaneous pain-like behaviors, reduced threshold of claw withdrawal in reaction to mechanical stimulation, substance P, glutamic acid, CGRP, and calcium current rPMS, with increased PwTL were observed in the rPMS group (p < 0.05).
 Conclusion: rPMS alleviates NP syndromes and inhibits the activity of N-type calcium channel in rats. This finding provides a theoretical basis and reference for the clinical application of rPMS in the treatment of NP.
 Keywords: Repetitive peripheral magnetic stimulation (rPMS); Neuropathic pain; N-type calcium channel; Paw withdrawal thermal latency

Development of a PET radioligand for α2δ-1 subunit of calcium channels for imaging neuropathic pain

Neuropathic pain affects 7–10% of the adult population. Being able to accurately monitor biological changes underlying neuropathic pain will improve our understanding of neuropathic pain mechanisms and facilitate the development of novel therapeutics. Positron emission tomography (PET) is a noninvasive molecular imaging technique that can provide quantitative information of biochemical changes at the whole-body level by using radiolabeled ligands. One important biological change underlying the development of neuropathic pain is the overexpression of α2δ-1 subunit of voltage-dependent calcium channels (the target of gabapentin). Thus, we hypothesized that a radiolabeled form of gabapentin may allow imaging changes in α2δ-1 for monitoring the underlying pathophysiology of neuropathic pain. Here, we report the development of two 18F-labeled derivatives of gabapentin (trans-4-[18F]fluorogabapentin and cis-4-[18F]fluorogabapentin) and their evaluation in healthy rats and a rat model of neuropathic pain (spinal nerve ligation model). Both isomers were found to selectively bind to the α2δ-1 receptor with trans-4-[18F]fluorogabapentin having higher affinity. Both tracers displayed around 1.5- to 2-fold increased uptake in injured nerves over the contralateral uninjured nerves when measured by gamma counting ex vivo. Although the small size of the nerves and the signal from surrounding muscle prevented visualizing these changes using PET, this work demonstrates that fluorinated derivatives of gabapentin retain binding to α2δ-1 and that their radiolabeled forms can be used to detect pathological changes in vitro and ex vivo. Furthermore, this work confirms that α2δ-1 is a promising target for imaging specific features of neuropathic pain.

Nonopioid analgesics discovery and the Valley of Death: EMA401 from concept to clinical trial.

Translation of promising preclinical efficacy data for investigational analgesics to positive clinical trial outcomes is limited, despite the large collective effort to date. However, one target with positive proof-of-concept clinical trial data is the angiotensin II type 2 (AT2) receptor. This review addresses the obstacles impeding successful preclinical to clinical research translation in the novel analgesics field, and it also provides an overview of the discovery and development of EMA401, a peripherally restricted, highly selective, orally active, small-molecule AT2 receptor antagonist for relief of neuropathic pain. Multiple AT2 receptor antagonists evoked dose-dependent antiallodynia in the chronic constriction injury of the sciatic nerve rat model of neuropathic pain. In AT2 receptor knockout chronic constriction injury mice, antiallodynia was abolished, affirming the AT2 receptor as the target. Subsequently, AT2 receptor antagonists were shown to evoke pain relief in multiple rodent chronic pain models. EMA401 (sodium salt) was selected as the drug candidate based on its >10,000-fold binding selectivity c.f. the angiotensin II type 1 receptor, good potency, and favourable pharmacokinetics. Animal toxicology and safety testing along with phase 1 clinical trials in healthy volunteers showed that oral EMA401 was safe and well-tolerated. Based on these data, a proof-of-concept clinical trial of oral EMA401 was undertaken in patients with postherpetic neuralgia. This 4-week trial showed that EMA401 evoked superior relief of postherpetic neuralgia relative to placebo and there were no serious adverse events in the EMA401 group.

Anti-neuropathic pain activity of Ajugarin-I via activation of Nrf2 signaling and inhibition of TRPV1/TRPM8 nociceptors in STZ-induced diabetic neuropathy

This study aimed to investigate the anti-neuropathic pain activity and its underlying molecular mechanism of Ajugarin-I (Aju-I) in a rat model of diabetic neuropathic pain. The rats were given a single injection of 60 mg/kg of streptozotocin (STZ) intraperitoneally (i.p.) to induce diabetic neuropathic pain. After two weeks, rats were given Aju-I (1 and 5 mg/kg/day) i.p. for four consecutive weeks. The results demonstrated that in diabetic rats, treatment with Aju-I decreased STZ-induced hyperglycemia. It reduced the pain hypersensitivity (mechanical, thermal, and cold nociception) caused by STZ. It effectively restored STZ-associated pathological changes in the pancreas. In the sciatic nerve and spinal cord, it attenuated STZ-associated histopathological alterations and DNA damage. It suppressed oxidative stress by increasing the expression of nuclear factor-erythroid factor 2-related factor 2 (Nrf2), thioredoxin (Trx), and heme oxygenase (HO-1), but decreasing the immunoreactivity of Kelch-like ECH-associated protein 1 (Keap1). Additionally, TRPV1 (transient receptor potential vanilloid 1) and TRPM8 (transient receptor potential melastatin 8) expression levels were considerably reduced by Aju-I treatment. It enhanced antioxidant levels and suppressed inflammatory cytokines production. Taken together, this research suggests that Aju-I treatment reduces pain behaviors in the STZ model of diabetic neuropathy via modulating Nrf2/Keap-1/HO-1 signaling and TRPV1/TRPM8 nociceptors.

Habenula activation patterns in a preclinical model of neuropathic pain accompanied by depressive-like behaviour.

Pain and depression are complex disorders that frequently co-occur, resulting in diminished quality of life. The habenula is an epithalamic structure considered to play a pivotal role in the neurocircuitry of both pain and depression. The habenula can be divided into two major areas, the lateral and medial habenula, that can be further subdivided, resulting in 6 main subregions. Here, we investigated habenula activation patterns in a rat model of neuropathic pain with accompanying depressive-like behaviour. Wistar rats received active surgery for the development of neuropathic pain (chronic constriction injury of the sciatic nerve; CCI), sham surgery (surgical control), or no surgery (behavioural control). All animals were evaluated for mechanical nociceptive threshold using the paw pressure test and depressive-like behaviour using the forced swimming test, followed by evaluation of the immunoreactivity to cFos—a marker of neuronal activity—in the habenula and subregions. The Open Field Test was used to evaluate locomotor activity. Animals with peripheral neuropathy (CCI) showed decreased mechanical nociceptive threshold and increased depressive-like behaviour compared to control groups. The CCI group presented decreased cFos immunoreactivity in the total habenula, total lateral habenula and lateral habenula subregions, compared to controls. No difference was found in cFos immunoreactivity in the total medial habenula, however when evaluating the subregions of the medial habenula, we observed distinct activation patterns, with increase cFos immunoreactivity in the superior subregion and decrease in the central subregion. Taken together, our data suggest an involvement of the habenula in neuropathic pain and accompanying depressive-like behaviour.

A3 receptor agonist modulates IL-1β hippocampus levels in a rat model of neuropathic pain

A3 receptor agonist modulates IL-1β hippocampus levels in a rat model of neuropathic pain

Metabotropic Glutamate Receptor 5 in the Dysgranular Zone of Primary Somatosensory Cortex Mediates Neuropathic Pain in Rats.

The primary somatosensory cortex (S1) plays a key role in the discrimination of somatic sensations. Among subdivisions in S1, the dysgranular zone of rodent S1 (S1DZ) is homologous to Brodmann’s area 3a of primate S1, which is involved in the processing of noxious signals from the body. However, molecular changes in this region and their role in the pathological pain state have never been studied. In this study, we identified molecular alteration of the S1DZ in a rat model of neuropathic pain induced by right L5 spinal nerve ligation (SNL) surgery and investigated its functional role in pain symptoms. Brain images acquired from SNL group and control group in our previous study were analyzed, and behaviors were measured using the von Frey test, acetone test, and conditioned place preference test. We found that metabotropic glutamate receptor 5 (mGluR5) levels were significantly upregulated in the S1DZ contralateral to the nerve injury in the SNL group compared to the sham group. Pharmacological deactivation of mGluR5 in S1DZ ameliorated symptoms of neuropathic allodynia, which was shown by a significant increase in the mechanical paw withdrawal threshold and a decrease in the behavioral response to cold stimuli. We further confirmed that this treatment induced relief from the tonic-aversive state of chronic neuropathic pain, as a place preference memory associated with the treatment-paired chamber was formed in rats with neuropathic pain. Our data provide evidence that mGluR5 in the S1DZ is involved in the manifestation of abnormal pain sensations in the neuropathic pain state.

Mechanisms of Neuropathic Pain and Pain-Relieving Effects of Exercise Therapy in a Rat Neuropathic Pain Model.

PurposePain disrupts the daily and social lives of patients with neuropathic pain. Effective treatment of neuropathic pain is difficult. Pharmacological treatments for neuropathic pain are limited, and 40–60% of patients do not achieve even partial relief of their pain. This study created a chronic constriction injury (CCI) model in rats to examine the effects of regular exercise on neuropathic pain relief, elucidate the mechanism, and determine the effects of neuropathic pain in the hippocampus.MethodsCCI model rats were randomly divided into exercise (Ex) and no exercise (No-Ex) groups. Normal rats (Normal group) were used as controls. The Ex group exercised on a treadmill at 20 m/min for 30 min, 5 days per week for 5 weeks post-CCI. The 50% pain response threshold was assessed by mechanical stimulation. Using immunohistochemistry, we examined activation of glial cells (microglia and astrocytes) by CCR2 and TRAF6 expression in the spinal cord dorsal horn and DCX and PROX1 expression in the hippocampal dentate gyrus.ResultsThe 50% pain response threshold was significantly lower in the Ex than in the No-Ex group at 5 weeks post-CCI, indicating pain relief. In the spinal cord dorsal horn, IBA1, CCR2, and TRAF6 expression was markedly lower in the Ex group than in the No-Ex group at 3 weeks post-CCI. IBA1, GFAP, CCR2, and TRAF6 expression was markedly lower in the Ex group than in the No-Ex group at 5 weeks post-CCI. In the hippocampus, DCX, but not PROX1, expression was significantly higher in the Ex group than in the No-Ex group at 3 weeks post-CCI. At 5 weeks post-CCI, both DCX and PROX1 expression was markedly increased in the Ex group compared to the No-Ex group.ConclusionOur findings suggest that regular exercise can improve the neuropathic pain-induced neurogenic dysfunction in the hippocampal dentate gyrus.

Analgesic Effects of Vilazodone, Indatraline, and Talsupram in a Rat Model of Neuropathic Pain.

Drugs that inhibit the reuptake of serotonin, norepinephrine, and/or dopamine are widely used for treating depressive disorders and have emerged as effective drugs for neuropathic pain. They have no substantial anti-nociceptive effects but are considered, with gabapentin/pregabalin, first-line drugs for neuropathic pain. In this study, three different antidepressant agents were used in different doses to investigate their anti-hyperalgesic effects in rat models of neuropathic pain using hot plate and tail flick methods. They have different mechanisms of action; vilazodone hydrochloride is a selective serotonin inhibitor and a 5-HT1A partial agonist; talsupram hydrochloride is a selective noradrenaline inhibitor, and it has a high affinity for noradrenaline transporter (NET), whereas indatraline hydrochloride is a triple reuptake inhibitor that inhibits transporters for 5-HT (SERT), dopamine (DAT), and NET. All the drugs used in the experiment were found to have an anti-hyperalgesic effect in both tests compared to the sham group. When anti-hyperalgesic effects of the three agents were compared to each other, it was found that talsupram hydrochloride was significantly more effective than the two other drugs in hot plate test. However, there was no statistically significant difference in the tail flick test. Indatraline hydrochloride was more effective than vilazodone hydrochloride at the same doses in the tail flick test. Our data suggest that three drugs are effective analgesics in rat models of neuropathic pain and inhibition of noradrenaline reuptake represents the cornerstone of analgesic mechanisms of effective antidepressants.

Corydecumine G inhibits microglia activation via MAPK pathway in a rat model of neuropathic pain

Background and purposeMicroglial activation plays an important role in the onset and progression of neuropathic pain by producing a variety of pro-inflammatory cytokines that interact with neurons to enhance neuronal hyperexcitability. Corydalis decumbens (Thunb.) pers., a traditional Chinese medicine has been used to treat mild cancer pain, dementia and to remit cerebral ischemia in clinics. Phenylphthalide isoquinolines are the major type of metabolites of C. decumbens and one of the derivatives, Corydecumine G (Cor G) has been shown to inhibit neuronal excitability. The present study aims to investigate the analgesic efficacy of Cor G in neuropathic pain rat model, the effects of Cor G on microglia activation and the possible mechanisms. Experimental approachNeuropathic pain was modeled using chronic constriction sciatic nerve injury (CCI) in rats. Western blot, immunofluorescence, and qRT-PCR were used to evaluate the levels of protein and mRNA. Key resultsIntraperitoneal administration of Cor G concentration-dependently ameliorates mechanical and thermo allodynia, suppresses CCI-induced p38/ERK phosphorylation and spinal cord microglia activation, and attenuates the expression levels of NO, inos, Tnf-α, Pge2 in dorsal horn of L4-L6 spinal cord on the ligation side in CCI rats. Pretreatment with 30 μM Cor G decreased LPS-induced BV2 microglia activation, which occurred via the inos, Tnf-α, Il-1β, Il-6 and phospho-p38/ERK pathways. Conclusions and implicationsTaken together, we suggest that Cor G, the specific phthalide isoquinoline from traditional Chinese medicine Corydalis Decumbentis Rhizoma, may be promising for treatment of neuropathic pain.

Targeting spinal microglia with fexofenadine-loaded nanoparticles prolongs pain relief in a rat model of neuropathic pain

Targeting microglial activation is emerging as a clinically promising drug target for neuropathic pain treatment. Fexofenadine, a histamine receptor 1 antagonist, is a clinical drug for the management of allergic reactions as well as pain and inflammation. However, the effect of fexofenadine on microglial activation and pain behaviors remains elucidated. Here, we investigated nanomedicinal approach that targets more preferentially microglia and long-term analgesics. Fexofenadine significantly abolished histamine-induced microglial activation. The fexofenadine-encapsulated poly(lactic-co-glycolic acid) nanoparticles (Fexo NPs) injection reduced the pain sensitivity of spinal nerve ligation rats in a dose-dependent manner. This alleviation was sustained for 4 days, whereas the effective period by direct fexofenadine injection was 3 h. Moreover, Fexo NPs inhibited microglial activation, inflammatory signaling, cytokine release, and a macrophage phenotype shift towards the alternative activated state in the spinal cord. These results show that Fexo NPs exhibit drug repositioning promise as a long-term treatment modality for neuropathic pain.