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Spinal cord injury (SCI) and its accompanying changes of brain structure and function have been widely studied and reviewed. Debilitating chronic neuropathic pain (NP) is reported in 53% of SCI patients, and brain changes have been shown to be involved with the presence of this secondary complication. However, there is yet a synthesis of current studies that investigated brain structure, resting connectivity, and metabolite changes that accompanies this condition. In this review, a systematic search was performed using Medical Subject Headings heading search terms in PubMed and SCOPUS to gather the appropriate published studies. Neuroimaging studies that investigated supraspinal structural, resting-state connectivity, and metabolite changes in SCI subjects with NP were included. To this end, voxel-based morphometry, diffusion tensor imaging, resting-state functional MRI, magnetic resonance spectroscopy, and PET studies were summarized and reviewed. Further inclusion and exclusion criteria allowed delineation of appropriate studies that included SCI subgroups with and without NP. A total of 12 studies were eligible for qualitative synthesis. Overall, current studies that investigated NP-associated changes within the SCI cohort show primarily metabolite concentration alterations in sensory-pain processing regions, alongside bidirectional changes of brain structure. Moreover, in comparison to healthy controls, there remains limited evidence of structural and connectivity changes but a range of alterations in metabolite concentrations in SCI subjects with NP. There is some evidence suggesting that the magnitude and presence of NP following SCI results in both adaptive and maladaptive structural plasticity of sensorimotor regions, alongside altered metabolism of brain areas involved with descending pain modulation, pain perception (i.e., anterior cingulate cortex) and sensory integration (i.e., thalamus). However, based on the fact that only a few studies investigated structural and glucose metabolic changes in chronic SCI subjects with NP, the underlying mechanisms that accompany this condition remains to be further elucidated. Future cross-sectional or longitudinal studies that aim to disentangle NP related to SCI may benefit from stricter constraints in subject cohorts, controlled subgroups, improved pain phenotyping, and implementation of multimodal approaches to discover sensitive biomarkers that profile pain and optimize treatment in SCI subjects with NP.
Learn More >Oliceridine is a novel G protein-biased µ-opioid receptor agonist designed to provide intravenous (IV) analgesia with a lower risk of opioid-related adverse events (ORAEs) than conventional opioids.
Learn More >Sigma-1 receptor antagonism increases the effects of morphine on nociceptive pain, even in morphine-tolerant animals. However, it is unknown whether these receptors are able to modulate morphine antinociception and tolerance during inflammatory pain. Here we used a mouse model to test the modulation of morphine effects by the selective sigma-1 antagonist S1RA (MR309), by determining its effect on inflammatory tactile allodynia (von Frey filaments) and on grip strength deficits induced by joint inflammation (a measure of pain-induced functional disability), and compared the results with those for nociceptive heat pain recorded with the unilateral hot plate (55°C) test. The subcutaneous (s.c.) administration of morphine induced antinociceptive effects to heat stimuli, and restored mechanical threshold and grip strength in mice with periarticular inflammation induced by Complete Freund's Adjuvant. S1RA (80 mg/kg, s.c.) administered alone did not induce any effect on nociceptive heat pain or inflammatory allodynia, but was able to partially reverse grip strength deficits. The association of S1RA with morphine, at doses inducing little or no analgesic-like effects when administered alone, resulted in a marked antinociceptive effect to heat stimuli and complete reversion of inflammatory tactile allodynia. However, S1RA administration did not increase the effect of morphine on grip strength deficits induced by joint inflammation. When S1RA (80 mg/kg, s.c.) was administered to morphine-tolerant animals, it rescued the analgesic-like effects of this opioid in all three pain measures. However, when S1RA was repeatedly given during the induction of morphine tolerance (and not on the day of behavioral evaluation) it failed to affect tolerance to the effects of morphine on nociceptive heat pain or inflammatory allodynia, but completely preserved the effects of this opioid on grip strength deficits. These effects of S1RA on morphine tolerance cannot be explained by pharmacokinetic interactions, given that the administration of S1RA did not modify concentrations of morphine or morphine-3-glucuronide (a major morphine metabolite) in morphine-tolerant animals in plasma or brain tissue. We conclude that sigma-1 receptors play a pivotal role in the control of morphine analgesia and tolerance in nociceptive and inflammatory pain, although in a manner dependent on the type of painful stimulus explored.
Learn More >The aim of this study was to measure brain alterations in patients with herpes zoster (HZ) and postherpetic neuralgia (PHN) and compare their differences using a voxel-based morphometry (VBM) technique.
Learn More >The brainstem plays a significant role in migraine pathogenesis, but a relationship between volume alterations of brainstem subregions and migraine aura characteristics has not been sufficiently investigated. The aim of this study is to compare the volume of the brainstem, and its subregions, between patients with a migraine with aura (MwA) and healthy controls (HC), and also to correlate characteristics of MwA and the volume of the brainstem subregions.
Learn More >The calcitonin gene-related peptide (CGRP) receptor is composed of the calcitonin receptor-like receptor (CLR, a class B GPCR) and a single-pass membrane protein known as receptor activity modifying protein type 1 (RAMP1). The levels of the CGRP peptide increase during a migraine attack and infusion of CGRP can provoke a migraine attack. Consequently, there is much interest in inhibiting the actions of CGRP as a way to control migraine. Here we describe the development of small molecule antagonists designed to bind to the CGRP receptor to block its action by preventing binding of the CGRP peptide. We also describe the development of antibody drugs, designed to bind either to the CGRP receptor to block its action, or to bind directly to the CGRP peptide. The field has been very active, with one antibody drug approved and three antibody drugs in phase III clinical trial. Initial programs on the development CGRP antagonists were frustrated by liver toxicity but the current outlook is very promising with five small molecule antagonists in various stages of clinical trial.
Learn More >Ketamine has been shown to reduce chronic pain; however, the adverse events associated with ketamine makes it challenging for use outside of the perioperative setting. The ketamine metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) has a therapeutic effect in mice models of depression, with minimal side effects. The objective of this study is to determine if (2R,6R)-HNK has efficacy in both acute and chronic mouse pain models.
Learn More >Sigma-1 receptors (S1R) and sigma-2 receptors (S2R) may modulate nociception without the liabilities of opioids, offering a promising therapeutic target to treat pain. The purpose of this study was to investigate the analgesic and anti-allodynic activity of two novel sigma receptor antagonists, the S1R-selective CM-304 and its analog the non-selective S1R/S2R antagonist AZ-66. Inhibition of thermal, induced chemical or inflammatory pain, as well as the allodynia resulting from chronic nerve constriction injury (CCI) and cisplatin exposure as models of neuropathic pain were assessed in male mice. Both sigma receptor antagonists dose-dependently (10-45 mg/kg, i.p.) reduced allodynia in the CCI and cisplatin neuropathic pain models, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg, i.p.), although AZ-66 demonstrated a much longer duration of action. Both CM-304 and AZ-66 produced antinociception in the writhing test [0.48 (0.09-1.82) and 2.31 (1.02-4.81) mg/kg, i.p., respectively] equivalent to morphine [1.75 (0.31-7.55) mg/kg, i.p.]. Likewise, pretreatment (i.p.) with either sigma-receptor antagonist dose-dependently produced antinociception in the formalin paw assay of inflammatory pain. However, CM-304 [17.5 (12.7-25.2) mg/kg, i.p.) and AZ-66 [11.6 (8.29-15.6) mg/kg, i.p.) were less efficacious than morphine [3.87 (2.85-5.18) mg/kg, i.p.] in the 55°C warm-water tail-withdrawal assay. While AZ-66 exhibited modest sedative effects in a rotarod assay and conditioned place aversion, CM-304 did not produce significant effects in the place conditioning assay. Overall, these results demonstrate the S1R selective antagonist CM-304 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, supporting the use of S1R antagonists as potential treatments for chronic pain.
Learn More >Signaling through bioactive lipids regulates nervous system development and functions. Lysophosphatidic acid (LPA), a membrane-derived lipid mediator particularly enriched in brain, is able to induce many responses in neurons and glial cells by affecting key processes like synaptic plasticity, neurogenesis, differentiation and proliferation. Early studies noted sustained elevations of neuronal intracellular calcium, a primary response to LPA exposure, suggesting functional modifications of NMDA and AMPA glutamate receptors. However, the crosstalk between LPA signaling and glutamatergic transmission has only recently been shown. For example, stimulation of presynaptic LPA receptors in hippocampal neurons regulates glutamate release from the presynaptic terminal, and excess of LPA induce seizures. Further evidence indicating a role of LPA in the modulation of neuronal transmission has been inferred from animal models with deficits on LPA receptors, mainly LPA which is the most prevalent receptor in human and mouse brain tissue. LPA null-mice exhibit cognitive and attention deficits characteristic of schizophrenia which are related with altered glutamatergic transmission and reduced neuropathic pain. Furthermore, silencing of LPA receptor in mice induced a severe down-regulation of the main glutaminase isoform (GLS) in cerebral cortex and hippocampus, along with a parallel sharp decrease on active matrix-metalloproteinase 9. The downregulation of both enzymes correlated with an altered morphology of glutamatergic pyramidal cells dendritic spines towards a less mature phenotype, indicating important implications of LPA in synaptic excitatory plasticity which may contribute to the cognitive and memory deficits shown by LPA-deficient mice. In this review, we present an updated account of current evidence pointing to important implications of LPA in the modulation of synaptic excitatory transmission.
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