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Simvastatin single treatment reduced mechanical hyperalgesia during CPIP. CPIP was induced via a 3-h hindpaw I/R injury, and animals treated with different doses of simvastatin (5, 10, 50, and 100 mg/kg, 1x/day, p.o.) evaluated at 7 (A), 14 (B), and 21 (C) days after nerve injury. Imipramine (20 mg/kg, i.p.) was used as positive control drug. Response of frequency of the ipsilateral withdrawal thresholds assessed at several time-points by von Frey hair test. (B) Baseline withdrawal threshold before I/R injury. Data are expressed as mean ± SEM (n = 6/group), and are representative of two independent experiments. ##P < 0.001 vs. naïve group, ∗P < 0.05 and ∗∗P < 0.001 vs. I/R group (two-way ANOVA followed by Bonferroni’s test).
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Simvastatin is a lipid-lowering agent that blocks the production of cholesterol through inhibition of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase. In addition, recent evidence has suggested its anti-inflammatory and antinociceptive actions during inflammatory and pain disorders. Herein, we investigated the effects of simvastatin in an...
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Background
Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine involved in pain processing and hypersensitivity. It regulates not only the expression of a variety of inflammatory mediators but also the functional activity of some ion channels. Acid-sensing ion channels (ASICs), as key sensors for extracellular protons, are expressed in n...
Citations
... Current treatments have depicted poor overall efficacy and adverse effects, motivating the development of new animal models that underlie distinct mechanisms associated with CRPS-induced pain. Chronic post-ischemia pain (CPIP) is a model of CRPS-I that induces neuropathic-like pain syndrome following prolonged hind paw ischemia and reperfusion [4][5][6]. The lesion caused in the CPIP induces allodynia and increases inflammation and oxidative stress responses [4]. ...
... Chronic post-ischemia pain (CPIP) was induced by ischemia and reperfusion (IR) injury of the left hind paw, according to previously described [4][5][6]40]. Briefly, Swiss mice were anesthetized over 3 h with a bolus (7%, 0.6 ml/kg, i.p.) of chloral hydrate (VETEC, São Paulo, Brazil) and 20% of the initial volume at the end of the first and second hour [41]. ...
CTK 01512–2 toxin is a recombinant peptide of the Phα1β version derived from the venom of the Phoneutria nigriventer spider. It acts as an N-type voltage-gated calcium channel (VGCC) blocker and shows a prolonged effect on preventing and reducing nociception. Herein, CTK 01512–2 was tested on two models of persistent pain, the chronic post-ischemia pain (CPIP) and the paclitaxel-induced peripheral neuropathy, to evaluate its systemic, intrathecal, and intracerebroventricular effects on mechanical hypersensitivity and thermal allodynia. Glial cell viability was also investigated using the MTT test. The results showed that CTK 01512–2 intrathecal and systemic treatments reduced the mechanical hypersensitivity induced by CPIP, mainly between 1–4 h after its administration. Additionally, intrathecal treatment reduced the CPIP-induced thermal allodynia. In its turn, the intracerebroventricular treatment showed mechanical antihyperalgesic and thermal antiallodynic effects in the paclitaxel-induced peripheral neuropathy. These data reinforce the therapeutic potential of CTK 01512–2 to treat persistent pain conditions and offer a perspective to use the systemic route. Moreover, CTK 01512–2 increased the glial cell viability in the MTT reduction assay, and it may indicate a new approach to managing chronic pain. The results found in this study help to pave new perspectives of pain relief treatments to patients affected by chronic pain.
... Notably, HC-030031 inhibited allodynia in both the acute and chronic phases of CPIP. Furthermore, no differences in the sexual distribution of CPIP-induced allodynia were reported in mice, and the pain-related behavior was almost completely inhibited in TRPA1-deficient mice (91,92). The level of oxidative stress markers was reported to increase in the tibial nerve of CPIP mice. ...
Complex regional pain syndrome (CRPS) is a chronic pain syndrome that occurs in tissue injuries as the result of surgery, trauma, or ischemia. The clinical features of this severely painful condition include redness and swelling of the affected skin. Intriguingly, it was recently suggested that transient receptor potential ankyrin 1 (TRPA1) is involved in chronic post-ischemia pain, a CRPS model. TRPA1 is a non-selective cation channel expressed in calcitonin gene-related peptide (CGRP)-positive primary nociceptors that becomes highly activated in ischemic conditions, leading to the generation of pain. In this review, we summarize the history of TRPA1 and its involvement in pain sensation, inflammation, and CRPS. Furthermore, bone atrophy is also thought to be a characteristic clinical sign of CRPS. The altered bone microstructure of CRPS patients is thought to be caused by aggravated bone resorption via enhanced osteoclast differentiation and activation. Although TRPA1 could be a target for pain treatment in CRPS patients, we also discuss the paradoxical situation in this review. Nociceptor activation decreases the risk of bone destruction via CGRP secretion from free nerve endings. Thus, TRPA1 inhibition could cause severe bone atrophy. However, the suitable therapeutic strategy is controversial because the pathologic mechanisms of bone atrophy in CRPS are unclear. Therefore, we propose focusing on the remission of abnormal bone turnover observed in CRPS using a recently developed concept: senso-immunology.
... Furthermore, some studies used pharmacological agents in peripheral nerve regeneration, including statins or inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase from the mevalonate pathway [17]. Statins are drugs that act on the limiting phase of cholesterol biosynthesis by inhibiting HMG-CoA reductase; this action lowers blood cholesterol levels [17]. ...
... Furthermore, some studies used pharmacological agents in peripheral nerve regeneration, including statins or inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase from the mevalonate pathway [17]. Statins are drugs that act on the limiting phase of cholesterol biosynthesis by inhibiting HMG-CoA reductase; this action lowers blood cholesterol levels [17]. However, beyond their hypolipidemic action, these compounds have pleiotropic or cholesterolindependent effects, including anti-inflammatory, immunomodulatory, neuroprotective, antioxidant, and antinociceptive effects [17][18][19][20][21]. ...
... Statins are drugs that act on the limiting phase of cholesterol biosynthesis by inhibiting HMG-CoA reductase; this action lowers blood cholesterol levels [17]. However, beyond their hypolipidemic action, these compounds have pleiotropic or cholesterolindependent effects, including anti-inflammatory, immunomodulatory, neuroprotective, antioxidant, and antinociceptive effects [17][18][19][20][21]. ...
To determine whether the effects of photobiomodulation (PBM) were associated with the use of Simvastatin in the functional recovery from sciatic nerve in mice submitted to crush injury. Fifty Swiss mice (approximately 3 months old; average weight 40 g) were randomly divided into six groups: naive, sham, control, PBM (660 nm, 10 J/cm²; 30 mW; 0.6 J per day for 28 days; 0.06 cm²; 16.8 J total and 20 s), Simvastatin (20 mg/kg), and PBM/Simv (association of the two protocols). The sciatic functional index (SFI), thermal heat hyperalgesia, mechanical hyperalgesia, and thermographic evaluation were used as analyses. The evaluations were performed preoperatively and 7, 14, 21, and 28 days after the initial injury analyzed by two-way analysis of variance (ANOVA) for mixed models followed by the Bonferroni post-test. All groups except sham and naive presented an SFI compatible with severe peripheral nerve injury on the 7th day of evaluation. The PBM group presented better results in the SFI analysis (p < 0.001) on the 21st postoperative day compared to the control group. This benefit was maintained when compared to the Simvastatin (p < 0.001) and PBM/Simv groups (p < 0.01). The results of the thermal and mechanical hyperalgesia and thermography analyses were not significant (p > 0.05). The obtained results showed that PBM alone was more effective compared to Simvastatin alone or PBM combined with Simvastatin for sciatic nerve injury in mice.
... 9,10 Epidemiological studies have demonstrated that dyslipidemia may be a risk factor for the occurrence and development of CNP. [11][12][13] Additionally, CNP might be highly comorbid with dyslipidemia. 14 The lipid-pain relationship may be bidirectional [15][16][17] : dyslipidemia may lead to gain (sensitization) or loss (desensitization) of function relative to the incoming CNP signals, whereas CNP may conversely have a feedback effect on serum lipid levels. ...
Objective
The association of chronic non-malignant pain (CNP) with dyslipidemia is unclear. This retrospective study was performed to evaluate the association between CNP and dyslipidemia in elderly patients with femoral neck fractures (FNFs) treated by primary unilateral total hip arthroplasty (THA).
Methods
We retrospectively identified 521 consecutive patients with FNFs (AO/OTA type 31B) who underwent primary unilateral THA from 2009 to 2021. The study population was divided into patients with and without CNP. Serum lipids were measured for each patient. The association between CNP and dyslipidemia was assessed using a multivariate binary logistic regression model.
Results
In total, 436 patients (220 with CNP, 216 without CNP) were eligible for analysis. In the quantile regression, the adverse effect of CNP was significantly attenuated by resilience in patients with a high high-density lipoprotein (HDL) concentration and low low-density lipoprotein (LDL) concentration. The multivariate binary logistic regression model showed that the HDL and LDL concentrations were the only variables significantly associated with the development of CNP.
Conclusion
Both a low HDL and high LDL concentration may result in the occurrence of CNP in elderly patients with FNFs treated by primary unilateral THA.
... However, it is still unknown whether these plasma lipids are related to pain during the onset and development of pain over time. Simvastatin, a lipid-lowering agent that blocks the production of cholesterol, inhibited mechanical hyperalgesia in a model of neuropathic pain, as well as attenuating the development of morphine tolerance (Vieira et al. 2017). In our study, plasma levels of the three CEs, PC(18:0/18:2), and SM(d34:1) which were significantly elevated in the DMM model, were correlated with the extent of articular cartilage damage in the knee joint at 16 weeks post-surgery. ...
IntroductionOsteoarthritis (OA) is the most common form of joint disease, causing pain and disability. Previous studies have demonstrated the role of lipid mediators in OA pathogenesis.Objectives
To explore potential alterations in the plasma lipidomic profile in an established mouse model of OA, with a view to identification of potential biomarkers of pain and/or pathology.Methods
Pain behaviour was assessed following destabilisation of the medial meniscus (DMM) model of OA (n = 8 mice) and compared to sham controls (n = 7). Plasma and knee joints were collected at 16 weeks post-surgery. Plasma samples were analysed using ultra-high performance liquid chromatography accurate mass high resolution mass spectrometry (UHPLC-HR-MS) to identify potential differences in the lipidome, using multivariate and univariate statistical analyses. Correlations between pain behaviour, joint pathology and levels of lipids were investigated.Results24 lipids, predominantly from the lipid classes of cholesterol esters (CE), fatty acids (FA), phosphatidylcholines (PC), N-acylethanolamines (NAE) and sphingomyelins (SM), were differentially expressed in DMM plasma compared to sham plasma. Six of these lipids which were increased in the DMM model were identified as CE(18:2), CE(20:4), CE(22:6), PC(18:0/18:2), PC(38:7) and SM(d34:1). CEs were positively correlated with pain behaviour and all six lipid species were positively correlated with cartilage damage. Pathways shown to be involved in altered lipid homeostasis in OA were steroid biosynthesis and sphingolipid metabolism.Conclusion
We identify plasma lipid species associated with pain and/or pathology in a DMM model of OA.
... CRPS can be further divided into two subtypes: type-I without identifiable nerve injury and type-II with identifiable nerve injury (Urits et al., 2018). CRPS-I is usually initiated after an initial noxious event and is accompanied with edema, changes in skin blood flow as well as thermal and mechanical hyperalgesia/allodynia in the affected area (Shah and Kirchner, 2011;Vieira et al., 2017). Physiotherapy, sympathetic blockade, corticosteroids, and non-steroidal anti-inflammatory drugs are available treatment options for CRPS-I (Hord and Oaklander, 2003). ...
... Chronic post-ischemia pain (CPIP) rat model is a well-recognized animal model of CRPS-I, which reproduces peripheral pathology of CRPS-I via ischemia/reperfusion of the hind paws of rats (Coderre et al., 2004). The CPIP model induces early hyperemia and edema, which are followed by chronic neuropathic-like pain symptoms, including spontaneous pain, long-term mechanical and thermal hypersensitivities (Coderre et al., 2004;Luo et al., 2016;Vieira et al., 2017;Garrido-Suarez et al., 2018;Tang et al., 2018). These symptoms recapitulate the typical features of CRPS-I in human patients. ...
Complex regional pain syndrome type 1 (CRPS-I) is a debilitating pain condition that significantly affects life quality of patients. It remains a clinically challenging condition and the mechanisms of CRPS-I have not been fully elucidated. Here, we investigated the involvement of TRPV1, a non-selective cation channel important for integrating various painful stimuli, in an animal model of CRPS-I. A rat model of chronic post-ischemia pain (CPIP) was established to mimic CRPS-I. TRPV1 expression was significantly increased in hind paw tissue and small to medium-sized dorsal root ganglion (DRG) neurons of CPIP rats. CPIP rats showed increased TRPV1 current density and capsaicin responding rate in small-sized nociceptive DRG neurons. Local pharmacological blockage of TRPV1 with the specific antagonist AMG9810, at a dosage that does not produce hyperthermia or affect thermal perception or locomotor activity, effectively attenuated thermal and mechanical hypersensitivity in bilateral hind paws of CPIP rats and reduced the hyperexcitability of DRG neurons induced by CPIP. CPIP rats showed bilateral spinal astrocyte and microglia activations, which were significantly attenuated by AMG9810 treatment. These findings identified an important role of TRPV1 in mediating thermal and mechanical hypersensitivity in a CRPS-I animal model and further suggest local pharmacological blocking TRPV1 may represent an effective approach to ameliorate CRPS-I.
... Moreover, the treatment with simvastatin inhibited the hypersensitivity induced both by the intraplantar injection of an acidified saline, an acid-sensing ion channels (ASIC) activator, and by injection of the bradykinin, demonstrating even the involvement of ASIC and bradykinin signaling pathways. 21 Marcondes Sari MH and collaborators demonstrated the antinociceptive action of the organoselenium compound p,p′-methoxyl-diphenyl diselenide ((OMePhSe)2) in an animal model of chronic pain induced by the partial sciatic nerve ligation (PSNL). They also reported the involvement of the supraspinal GABAergic system in the antinociceptive efficacy of (MeOPhSe)2. ...
... Metformin and simvastatin were effective in decreasing pain by reducing neuroinflammation. 20,21 Certainly, the neuroinflammation offers potential therapeutic targets in neuropathic pain, and among them, the receptors expressed in microglia (e.g. P2X7R and CX3CR1) might be the targets for treating the chronic pain state. ...
Neuropathic pain is characterized by abnormal hypersensitivity to stimuli (hyperalgesia) and nociceptive responses to non-noxious stimuli (allodynia). The conditions and the pathophysiological states that determine the onset of neuropathic pain are heterogeneous, such as metabolic disorders, neuropathy caused by viral infections, and autoimmune diseases affecting the central nervous system (CNS). Neuropathic pain in the general population is estimated to have a prevalence ranging between 3% and 17%. Most of the available treatments for neuropathic pain have moderate efficacy and present side effects that limit their use; therefore, other therapeutic approaches are needed for patients. In this article, the current standard of care treatment, the emerging pharmacological approaches from the completed phase III clinical trials, and the preclinical studies on novel promising therapeutic options will be reviewed.
... 27 Furthermore, 14 days after CPIP model generation are considered to be a "chronic" phase. 43 Another study examined mechanical allodynia on day 1, day 2, day 7, and day 21 after the procedure. 6 Hence, based on these studies, day 21 was considered to be sufficient for confirming the generation of the CPIP model, and we classified the animals into CPIP-positive and CPIP-negative groups on day 21 after the application of the O-ring. ...
Purpose
Complex regional pain syndrome (CRPS) is a rare but refractory pain disorder. Recent advanced information retrieval studies using text-mining and network analysis have suggested nuclear factor kappa B (NFκB) as a possible central mediator of CRPS. The brain is also known to play important roles in CRPS. The aim of this study was to evaluate changes in cerebral NFκB in rats with CRPS.
Materials and methods
The chronic post-ischemia perfusion (CPIP) model was used as the CRPS animal model. O-rings were applied to the left hind paws of the rats. The rats were categorized into three groups according to the results of behavioral tests: the CPIP-positive (A) group, the CPIP-negative (B) group, and the control (C) group. Three weeks after the CPIP procedure, the right cerebrums of the animals were harvested to measure NFκB levels using an ELISA.
Results
Animals in group A had significantly decreased mechanical pain thresholds (P<0.01) and significantly increased cerebral NFκB when compared to those in groups B and C (P=0.024).
Conclusion
This finding indicates that peripheral injury increases cerebral NFκB levels and implies that minor peripheral injury can lead to the activation of pain-related cerebral processes in CRPS.
The International Association for the Study of Pain (IASP) defines neuropathic pain as pain caused by a lesion or disease of the somatosensory nervous system. It is characterized as a clinical condition in which diagnostic studies reveal an underlying cause of an abnormality in the peripheral or central nervous system. Many common causes of neuropathic pain in adults are rare in children. The purpose of this focused narrative review is, to 1) provide an overview of neuropathic pain in children, 2) highlight unique considerations related to the diagnosis and mechanisms of neuropathic pain in children, and 3) perform a comprehensive analysis of the pharmacological treatments available. We emphasize that data for routine use of pharmacological agents in children with neuropathic pain are largely inferred from adult literature with little research performed on pediatric populations, yet have clear evidence of harms to pediatric patients. Based on these findings, we propose risk mitigation strategies such as utilizing topical treatments whenever possible, assessing pain phenotyping to guide drug class choice, and considering pharmaceuticals in the broader context of the multidisciplinary treatment of pediatric pain. Furthermore, we highlight important directions for future research on pedi- atric neuropathic pain treatment.
The CTK 01512-2 toxin is a recombinant peptide of the Phα1β version derived from the venom of the Phoneutria nigriventer spider. It is an N-type voltage-gated calcium channel (VGCC) blocker showing a prolonged effect on the prevention and reduction of nociception. Herein, CTK 01512-2 toxin was tested in two models of persistent pain, the chronic post-ischemia pain (CPIP) and the peripheral neuropathy induced by paclitaxel, to evaluate its intrathecal, systemic, and intracerebroventricular effects on mechanical hypersensitivity and thermal allodynia. The astroglial cell viability using the MTT test was also investigated. The results showed that CTK 01512-2 intrathecal and systemic treatments reduced mechanical hypersensitivity induced by CPIP, mainly between 1 – 4 h after CTK 01512-2 administration. When the CTK 01512-2 intrathecal treatment was applied, it also reduced the thermal allodynia induced by CPIP. CTK 01512-2 intracerebroventricular treatment also showed mechanical antihyperalgesic and thermal antiallodynic effects in the peripheral neuropathy induced by paclitaxel, reinforcing CTK 01512-2 therapeutically potential to treat persistent pain conditions. CTK 01512-2 further altered the astroglial cell viability in the MTT reduction assay, which may indicate its effects on the mitochondrial activity of these cells, possibly as a compensatory mechanism on calcium signaling. The current study shows CTK 01512-2 antihyperalgesic effects in persistent pain models, helping to pave new perspectives of pain relief treatments to patients affected by peripheral neuropathy and chronic pain conditions.
