Chemokine CCL2 and its receptor CCR2 in the dorsal root ganglion contribute to oxaliplatin-induced mechanical hypersensitivity

Activation of innate immune mechanisms within the dorsal root ganglion and spinal dorsal horn has been shown to play a key role in the development of neuropathic pain including paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). Here, we tested whether similar mechanisms are generalizable to oxaliplatin-induced CIPN. After a single intraperitoneal injection of 3 mg/kg oxaliplatin, mechanical withdrawal threshold and the expression of C-C chemokine ligand 2 (CCL2) and its receptor, CCR2, in the dorsal root ganglion were measured by behavioral testing and immunohistochemical staining, respectively. Mechanical responsiveness increased from the first day after oxaliplatin injection and persisted until day 15, the last day of this experiment. Immunohistochemical showed that the expression of CCL2/CCR2 started to increase by 4 hours after oxaliplatin treatment, was significantly increased at day 4, and then both signals became normalized by day 15. Cotreatment with intrathecal anti-CCL2 antibodies prevented the development of oxaliplatin-induced mechanical hyperresponsiveness, and transiently reversed established hyperalgesia when given 1 week after chemotherapy. This is the first study to demonstrate CCL2/CCR2 signaling in a model of oxaliplatin-related CIPN; and it further shows that blocking of this signal can attenuate the development of oxaliplatin-induced mechanical hyperalgesia. Activation of innate immune mechanisms may therefore be a generalized basis for...
Source: Pain - Category: Anesthesiology Tags: Research Paper Source Type: research

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Inhibition of voltage-gated calcium (CaV) channels is a potential therapy for many neurological diseases including chronic pain. Neuronal CaV1/CaV2 channels are composed of α, β, γ and α2δ subunits. The β subunits of CaV channels are cytoplasmic proteins that increase the surface expression of the pore-forming α subunit of CaV. We targeted the high-affinity protein–protein interface of CaVβ's pocket within the CaVα subunit. Structure-based virtual screening of 50,000 small molecule library docked to the β subunit led to the identification of 2-(3,5-dimethylisoxa...
Source: Pain - Category: Anesthesiology Tags: Research Paper Source Type: research
to JB Abstract Painful peripheral neuropathy is the most dose-limiting side effect of paclitaxel (PTX), a widely used anti-cancer drug to treat solid tumours. The understanding of the mechanisms involved in this side effect is crucial to the development of new therapeutic approaches. CXCL1 chemokine and its receptor CXCR2 have been pointed as promising targets to treat chronic pain. Herein, we sought to evaluate the possible involvement of CXCL1 and CXCR2 in the pathogenesis of PTX-induced neuropathic pain in mice. PTX treatment led to increased levels of CXCL1 in both dorsal root ganglion and spinal cord samples....
Source: Neuropharmacology - Category: Drugs & Pharmacology Authors: Tags: Neuropharmacology Source Type: research
This study not only provides biological evidence to support the use of duloxetine as the first standard CIPN drug but will also lead to potential new targets for CIPN drug development. Introduction A major dose-limiting complication of chemotherapy is chemotherapy-induced peripheral neuropathy (CIPN). The greatest contributors to CIPN are taxanes (e.g., paclitaxel) and platinum-based (e.g., oxaliplatin) treatments (Krukowski et al., 2015). Paclitaxel (PTX) can effectively treat several of the most common cancers including breast cancer, lung cancer, and ovarian cancer (Ewertz et al., 2015; Cetinkaya-Fisgin et al., ...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
ConclusionThis small multicenter retrospective case series provides preliminary evidence that the painful symptoms of general peripheral neuropathy in the lower extremities, as well as associated pain medication usage, can be effectively managed by DRG stimulation at the L4 ‐S1 spinal level. Importantly, this treatment appears efficacious for peripheral neuropathy.
Source: Neuromodulation: Technology at the Neural Interface - Category: Biotechnology Authors: Tags: Case Series Source Type: research
The Federal Pain Research Strategy recommended development of nonopioid analgesics as a top priority in its strategic plan to address the significant public health crisis and individual burden of chronic pain faced by>100 million Americans. Motivated by this challenge, a natural product extracts library was screened and identified a plant extract that targets activity of voltage-gated calcium channels. This profile is of interest as a potential treatment for neuropathic pain. The active extract derived from the desert lavender plant native to southwestern United States, when subjected to bioassay-guided fractionation, a...
Source: Pain - Category: Anesthesiology Tags: Research Paper Source Type: research
AbstractPurpose of ReviewThe purpose of this article is to illustrate the recent advances made in the field of neuromodulation for chronic pain management and it provides a brief review of the literature supporting their safe and efficacious use.Recent FindingsSpinal cord stimulation (SCS) has been an effective therapy for the management of intractable pain conditions including complex regional pain syndrome (CRPS), peripheral neuropathy, and failed back surgery syndrome (FBSS). With the introduction of high-frequency and burst SCS waveforms, there has been a noted improvement in the treatment outcomes of these pain syndro...
Source: Current Anesthesiology Reports - Category: Anesthesiology Source Type: research
Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of cancer treatment that significantly compromises quality of life of cancer patients and survivors. Identification of targets for pharmacological intervention to prevent or reverse CIPN is needed. We investigated exchange protein regulated by cAMP (Epac) as a potential target. Epacs are cAMP-binding proteins known to play a pivotal role in mechanical allodynia induced by nerve injury and inflammation. We demonstrate that global Epac1-knockout (Epac1−/−) male and female mice are protected against paclitaxel-induced mechanical allodynia. In...
Source: Pain - Category: Anesthesiology Tags: Research Paper Source Type: research
Chemotherapeutic drugs such as paclitaxel cause painful peripheral neuropathy in many cancer patients and survivors. Although NMDA receptors (NMDARs) at primary afferent terminals are known to be critically involved in chemotherapy-induced chronic pain, the upstream signaling mechanism that leads to presynaptic NMDAR activation is unclear. Group I metabotropic glutamate receptors (mGluRs) play a role in synaptic plasticity and NMDAR regulation. Here we report that the Group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) significantly increased the frequency of miniature excitatory postsynaptic currents (EPSCs) and t...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Molecular Bases of Disease Source Type: research
Objective: To evaluate functional and morphometric magnetic resonance neurography of the dorsal root ganglion and peripheral nerve segments in patients with Fabry painful neuropathy. Methods: In this prospective study, the lumbosacral dorsal root ganglia and proximal peripheral nerve segments of the lower extremity were examined in 11 male patients with Fabry disease by a standardized 3T magnetic resonance neurography protocol. Volumes of L3 to S2 dorsal root ganglia, perfusion parameters of L5-S1 dorsal root ganglia and the spinal nerve L5, and the cross-sectional area of the proximal sciatic nerve were compared to healt...
Source: Neurology - Category: Neurology Authors: Tags: MRI, Metabolic disease (inherited), Peripheral neuropathy, Neuropathic pain ARTICLE Source Type: research
Spinal Cord Stimulation (SCS) has been utilized as an accepted pain-treatment modality for chronic neuropathic pain. However, some drawbacks of SCS include inability to cover discrete painful regions, such as in the foot, without generating extraneous paresthesia elsewhere in the lower extremity. Also, SCS electrodes have been known to migrate, resulting in varied intensity and location of paresthesia. A novel form of neurostimulation has arrived in the form of dorsal root ganglion stimulation (DRGS).
Source: The Journal of Pain - Category: Materials Science Authors: Source Type: research
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