Mechanisms Underlying Gastrodin Alleviating Vincristine-Induced Peripheral Neuropathic Pain.
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ABSTRACT:
SUBMITTER: Wang X
PROVIDER: S-EPMC8716817 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Oxycodone is a μ-opioid receptor agonist, used for the treatment of a large variety of painful disorders. Several studies have reported that oxycodone is a more potent pain reliever than morphine, and that it improves the quality of life of patients. However, the neurobiological mechanisms underlying the therapeutic action of these two opioids are only partially understood. The aim of this study was to define the molecular changes underlying the long-lasting analgesic effects of oxycodone and morphine in an animal model of peripheral neuropathy induced by a chemotherapic agent, vincristine. Using a behavioural approach, we show that oxycodone maintains an optimal analgesic effect after chronic treatment, whereas the effect of morphine dies down. In addition, using DNA microarray technology on dorsal root ganglia, we provide evidence that the long-term analgesic effect of oxycodone is due to an up-regulation in GABAB receptor expression in sensory neurons. These receptors are transported to their central terminals within the dorsal horn, and subsequently reinforce a presynaptic inhibition, since only the long-lasting (and not acute) anti-hyperalgesic effect of oxycodone was abolished by intrathecal administration of a GABAB receptor antagonist; in contrast, the morphine effect was unaffected. Our study demonstrates that the GABAB receptor is functionally required for the alleviating effect of oxycodone in neuropathic pain condition, thus providing new insight into the molecular mechanisms underlying the sustained analgesic action of oxycodone.
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Project description:Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose- and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P450-epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxel-treated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity. In a drug repurposing screen targeting CYP2J2, the human ortholog of murine CYP2J6, we identified telmisartan, a widely used angiotensin II receptor antagonist, as a potent inhibitor. In a translational approach, administration of telmisartan reduces EpOME concentrations in DRGs and in plasma and reverses mechanical hypersensitivity in paclitaxel-treated mice. We therefore suggest inhibition of CYP2J isoforms with telmisartan as a treatment option for paclitaxel-induced neuropathic pain.
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Project description:BackgroundTo evaluate the efficacy of gabapentin at 20 mg/kg per day in the treatment of vincristine-related neuropathic pain.ProcedureChildren aged 1-18 years who developed vincristine-induced neuropathy on a St Jude frontline acute lymphoblastic leukemia trial were prospectively enrolled on a randomized, double-blind, placebo-controlled, phase II trial with two treatment arms: gabapentin plus opioid versus placebo plus opioid. Daily evaluations of morphine dose (mg/kg per day) and pain scores were conducted for up to 21 days; the values of the two arms were compared to assess analgesic efficacy.ResultsOf 51 study participants, 49 were eligible for analyses. Twenty-five participants were treated with gabapentin, with a mean (SD) dose of 17.97 (2.76) mg/kg per day (median 18.26, range 6.82-21.37). The mean (SD) opioid doses taken, expressed as morphine equivalent daily (mg/kg per day), were 0.26 (0.43) in the gabapentin group (25 patients, 432 days) and 0.15 (0.22) in the placebo group (24 patients, 411 days; P = .15). Only the risk classification of acute lymphoblastic leukemia was significantly associated with the daily morphine dosage (P = .0178): patients in the lower risk arm received higher daily morphine dosages. Multivariate analyses revealed a significant difference between the groups' average daily scores for the previous 24 h and "right now."ConclusionIn this population of children with vincristine-related neuropathic pain, opioid consumption and pain scores were higher in the gabapentin group than in the placebo group. Future randomized, double-blind, placebo-controlled studies should test gabapentin given longer or at a higher dose.
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Project description:Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a progressive and disturbing peripheral neuropathy with currently no effective treatment. Aberrant production of reactive oxygen species (ROS) in macrophages near peripheral nerves plays a dominant role in CIPNP; however, traditional ROS scavengers have difficulty maintaining viability to target macrophages in vivo. Mannose-coated superparamagnetic iron oxide nanoparticles (mSPIONs) were synthesized to treat CIPNP. The anti-ROS and anti-inflammatory effects of mSPIONs were assessed in J774A.1 cells and sciatic nerves in a nociception mouse model induced with vincristine (VCR). We found that the mSPIONs significantly reduced ROS levels in vitro and in vivo. Furthermore, mSPIONs administration specifically reduced IL-6 and TNF-α levels in macrophages near the sciatic nerve and relieved VCR-induced peripheral neuropathic pain. Inhibition of the VCR-upregulated HIF1α/NF-κB signaling pathway may be involved in the alleviation of inflammation. These results provide a new approach for relieving CIPNP using a nanozyme.
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Project description:The present study was designed to investigate the effects of histamine on spontaneous neuropathic pain (NP) induced by peripheral axotomy. Rats and mice were subjected to complete transection of the left sciatic and saphenous nerves to induce spontaneous NP (the neuroma model). Rats were then treated with drugs once daily for 30 days (histidine and loratadine, i.p.) or 21 days (histamine, i.c.v.). Autotomy behavior was scored daily until day 50 post-operation (PO). On days 14 to 21 PO, some rats in the control group were subjected to single-fiber recording. Autotomy behavior was also monitored daily in histidine decarboxylase (the key enzyme for histamine synthesis) knockout (HDC(-/-)) and wild-type mice for 42 days. We found that both histidine (500 mg/kg) (a precursor of histamine that increases histamine levels in the tissues) and histamine (50 μg/5 μL) significantly suppressed autotomy behavior in rats. HDC(-/-) mice lacking endogenous histamine showed higher levels of autotomy than the wild-type. In addition, the analgesic effect of histidine was not antagonized by loratadine (a peripherally-acting H1 receptor antagonist), while loratadine alone significantly suppressed autotomy. Electrophysiological recording showed that ectopic spontaneous discharges from the neuroma were blocked by systemic diphenhydramine (an H1 receptor antagonist). Our results suggest that histamine plays an important role in spontaneous NP. It is likely that histamine in the central nervous system is analgesic, while in the periphery, via H1 receptors, it is algesic. This study justifies the avoidance of a histamine-rich diet and the use of peripherally-acting H1 receptor antagonists as well as agents that improve histamine action in the central nervous system in patients with spontaneous NP.
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Project description:ERK plays an important role in chronic neuropathic pain. However, the underlying mechanism is largely unknown. Here we show that in chronic constriction injury-treated rat spinal cords, up-regulation of SIP30 (SNAP25-interacting protein 30), which is involved in the development and maintenance of chronic constriction injury-induced neuropathic pain, correlates with ERK activation and that the up-regulation of SIP30 is suppressed by intrathecal delivery of the MEK inhibitor U0126. In PC12 cells, up-regulation of SIP30 by nerve growth factor is also dependent on ERK activation. We found that there is an ERK-responsive region in the rat sip30 promoter. Activation of ERK promotes the recruitment of the transcription factor cyclic AMP-response element-binding protein to the sip30 gene promoter. Taken together, our results provide a potential downstream target of ERK activation-mediated neuropathic pain.
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Project description:Bortezomib is a mainstay of therapy for multiple myeloma, frequently complicated by painful neuropathy. The objective of this study was to describe clinical, electrophysiological, and pathological changes of bortezomib-induced peripheral neuropathy (BiPN) in detail and to correlate pathological changes with pain descriptors. Clinical data, nerve conduction studies, and lower leg skin biopsies were collected from 22 BiPN patients. Skin sections were immunostained using anti-protein gene product 9.5 (PGP9.5) and calcitonin gene-related peptide (CGRP) antibodies. Cumulative bortezomib dose and clinical assessment scales indicated light-moderate sensory neuropathy. Pain intensity >4 (numerical rating scale) was present in 77% of the patients. Median pain intensity and overall McGill Pain Questionnaire (MPQ) sum scores indicated moderate to severe neuropathic pain. Sural nerve sensory nerve action potentials were abnormal in 86%, while intraepidermal nerve fiber densities of PGP9.5 and CGRP were not significantly different from healthy controls. However, subepidermal nerve fiber density (SENFD) of PGP9.5 was significantly decreased and the axonal swelling ratio, a predictor of neuropathy, and upper dermis nerve fiber density (UDNFD) of PGP9.5, presumably representing sprouting of parasympathetic fibers, were significantly increased in BiPN patients. Finally, significant correlations between UDNFD of PGP9.5 versus the evaluative Pain Rating Index (PRI) and number of words count (NWC) of the MPQ, and significant inverse correlations between SENFD/UDNFD of CGRP versus the sensory-discriminative MPQ PRI/NWC were found. BiPN is a sensory neuropathy, in which neuropathic pain is the most striking clinical finding. Bortezomib-induced neuropathic pain may be driven by sprouting of parasympathetic fibers in the upper dermis and impaired regeneration of CGRP fibers in the subepidermal layer.
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Project description:Background Paclitaxel is commonly used as a cancer chemotherapy drug that frequently causes peripheral neuropathic pain. Inflammasome is a multiprotein complex consisting of Nod-like receptor proteins (NLRPs), apoptosis-associated speck-like protein, and caspase-1, which functions to switch on the inflammatory process and the release of interleukin-1?. Growing evidences have supported that peripheral interleukin-1? is critical in enhancing paclitaxel-induced neuropathic pain. However, whether activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain is still unclear. Results Paclitaxel induced mechanical allodynia of rats from day 3 and worsened gradually till 3 weeks after injection. Paclitaxel resulted in expression of NLRP3 and activated fragments of caspase-1 and interleukin-1? in L4-6 dorsal root ganglia and sciatic nerve three weeks after injection, indicating activation of NLRP3 inflammasome. The expression of NLRP3 was located in CD68-labeled macrophages infiltrating in L4-6 dorsal root ganglia and sciatic nerve, and paclitaxel increased the expression of NLRP3 in macrophage. Moreover, the paclitaxel elicited mitochondria damage, which became swollen and enlarged in macrophages and axons of sciatic nerve three weeks after injection. In vitro, paclitaxel increased the number of damaged mitochondria and mitochondrial reactive oxygen species production in the rat alveolar macrophage cell line NR8383. The administration of a non-specific reactive oxygen species scavenger, phenyl-N-tert-butylnitrone, markedly alleviated mechanical allodynia and inhibited the activation of NLRP3 inflammasome in L4-6 dorsal root ganglia and sciatic nerve of the paclitaxel-induced neuropathic pain model. Conclusions Paclitaxel induced mechanical allodynia and activation of NLRP3 inflammasome in infiltrated macrophages of L4-6 dorsal root ganglia and sciatic nerve. Paclitaxel elicited mitochondria damage and reactive oxygen species production may result in activation of NLRP3 inflammasome in peripheral nerve, which contributes to paclitaxel-induced neuropathic pain.
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Project description:Vincristine-induced peripheral neurotoxicity (VIPN) is a very common side effect of vincristine chemotherapy among pediatric patients with cancer. Neuropathy may be sensory, motor and/or autonomic, with consequent reduction, delay or discontinuation of vincristine-chemotherapy, but also pain, disability, reduced quality of life of patients and an increase in medical costs. Vincristine acts out its antineoplastic function by altering the normal assembly and disassembly of microtubules, with their consequent mitosis block and death. Vincristine leads to VIPN through a complex mechanism of damage, which occurs not only on the microtubules, but also on the endothelium and the mitochondria of nerve cells. Furthermore, both patient-related risk factors (age, race, ethnicity and genetic polymorphisms) and treatment-related risk factors (dose, time of infusion and drug-drug interactions) are involved in the pathogenesis of VIPN. There is a lack of consensus about the prophylaxis and treatment of VIPN among pediatric oncologic patients, despite several molecules (such as gabapentin, pyridoxine and pyridostigmine, glutamic acid and glutamine) having been already investigated in clinical trials. This review describes the molecular mechanisms of VIPN and analyzes the risk factors and the principal drugs adopted for the prophylaxis and treatment of VIPN in pediatric patients with cancer.
| S-EPMC8073828 | biostudies-literature
Project description:Vincristine is a chemotherapeutic agent that is a component of many combination regimens for a variety of malignancies, including several common pediatric tumors. Vincristine treatment is limited by a progressive sensorimotor peripheral neuropathy. Vincristine-induced peripheral neuropathy (VIPN) is particularly challenging to detect and monitor in pediatric patients, in whom the side effect can diminish long term quality of life. This review summarizes the current state of knowledge regarding VIPN, focusing on its description, assessment, prediction, prevention, and treatment. Significant progress has been made in our knowledge about VIPN incidence and progression, and tools have been developed that enable clinicians to reliably measure VIPN in pediatric patients. Despite these successes, little progress has been made in identifying clinically useful predictors of VIPN or in developing effective approaches for VIPN prevention or treatment in either pediatric or adult patients. Further research is needed to predict, prevent, and treat VIPN to maximize therapeutic benefit and avoid unnecessary toxicity from vincristine treatment.
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