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Negative affect (NA) is a significant cause of disability for chronic pain patients. While little is known about the mechanism underlying pain-comorbid NA, previous studies have implicated neuroinflammation in the pathophysiology of both depression and chronic pain. Here, we tested the hypothesis that NA in pain patients is linked to elevations in the brain levels of the glial marker 18 kDa translocator protein (TSPO), and changes in functional connectivity. 25 cLBP patients (42.4 ± 13 years old; 13F, 12M) with chronic low back pain (cLBP) and 27 healthy control subjects (48.9 ± 13 years old; 14F, 13M) received an integrated (i.e., simultaneous) positron emission tomography (PET)/magnetic resonance imaging (MRI) brain scan with the second-generation TSPO ligand [C]PBR28. The relationship between [C]PBR28 signal and NA was assessed first with regression analyses against Beck Depression Inventory (BDI) scores in patients, and then by comparing cLBP patients with little-to-no, or mild-to-moderate depression against healthy controls. Further, the relationship between PET signal, BDI and frontolimbic functional connectivity was evaluated in patients with mediation models. PET signal was positively associated with BDI scores in patients, and significantly elevated in patients with mild-to-moderate (but not low) depression compared with controls, in anterior middle and pregenual anterior cingulate cortices (aMCC, pgACC). In the pgACC, PET signal was also associated with this region's functional connectivity to the dorsolateral PFC (pgACC-dlPFC), and mediated of the association between pgACC-dlPFC connectivity and BDI. These observations support a role for glial activation in pain-comorbid NA, identifying in neuroinflammation a potential therapeutic target for this condition.
Learn More >Mechanical sensitization is one of the most difficult clinical pain problems to treat. However, the molecular and genetic bases of mechanical nociception are unclear. Here we develop a model of mechanical nociception to investigate the ion channels and signaling pathways that regulate mechanical nociception. We fabricated Von Frey filaments that span the sub-threshold to high noxious range for larvae. Utilizing these, we discovered that pressure (force/area) rather than force per se is the main determinant of aversive rolling responses to noxious mechanical stimuli. We demonstrated that the RTK PDGF/VEGF receptor (Pvr) and its ligands (Pvfs 2 and 3) are required for mechanical nociception and normal dendritic branching. Pvr is expressed and functions in class IV sensory neurons, while Pvf2 and Pvf3 are produced by multiple tissues. Constitutive overexpression of Pvr and its ligands or inducible overexpression of Pvr led to mechanical hypersensitivity that could be partially separated from morphological effects. Genetic analyses revealed that the Piezo and Pain ion channels are required for mechanical hypersensitivity observed upon ectopic activation of Pvr signaling. Platelet-derived growth factor (PDGF), but not vascular endothelial growth factor (VEGF) peptides caused mechanical hypersensitivity in rats. Pharmacological inhibition of vascular endothelial growth factor receptor type 2 (VEGFR-2) signaling attenuated mechanical nociception in rats, suggesting a conserved role for PDGF and VEGFR-2 signaling in regulating mechanical nociception. VEGFR2 inhibition also attenuated morphine analgesic tolerance in rats. Our results reveal that a conserved RTK signaling pathway regulates baseline mechanical nociception in flies and rats.Hypersensitivity to touch is poorly understood and extremely difficult to treat. Using a refined model of mechanical nociception, we discovered a conserved VEGF-related receptor tyrosine kinase signaling pathway that regulates mechanical nociception in flies. Importantly, pharmacological inhibition of VEGFR-2 signaling in rats causes analgesia and blocks opioid tolerance. We have thus established a robust, genetically tractable system for the rapid identification and functional analysis of conserved genes underlying mechanical pain sensitivity.
Learn More >Dysregulated excitability within the spinal dorsal horn is a critical mediator of chronic pain. In the rodent nerve injury model of neuropathic pain, BDNF-mediated loss of inhibition (disinhibition) gates the potentiation of excitatory GluN2B N-methyl-d-aspartate receptor (NMDAR) responses at lamina I dorsal horn synapses. However, the centrality of this mechanism across pain states and species, as well as the molecular linker involved, remain unknown. Here, we show that KCC2-dependent disinhibition is coupled to increased GluN2B-mediated synaptic NMDAR responses in a rodent model of inflammatory pain, with an associated downregulation of the tyrosine phosphatase STEP61. The decreased activity of STEP61 is both necessary and sufficient to prime subsequent phosphorylation and potentiation of GluN2B NMDAR by BDNF at lamina I synapses. Blocking disinhibition reversed the downregulation of STEP61 as well as inflammation-mediated behavioural hypersensitivity. For the first time, we characterize GluN2B-mediated NMDAR responses at human lamina I synapses and show that a human ex vivo BDNF model of pathological pain processing downregulates KCC2 and STEP61 and upregulates phosphorylated GluN2B at dorsal horn synapses. Our results demonstrate that STEP61 is the molecular brake that is lost following KCC2-dependent disinhibition and that the decrease in STEP61 activity drives the potentiation of excitatory GluN2B NMDAR responses in rodent and human models of pathological pain. The ex vivo human BDNF model may thus form a translational bridge between rodents and humans for identification and validation of novel molecular pain targets.
Learn More >Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Patients (n = 3005) were assigned and treated (n = 2583, safety population): 1938 lasmiditan (200 mg n = 528, 100 mg n = 532, and 50 mg n = 556 included in primary analysis) and 645 placebo (540 included in primary analysis). Most patients (79.2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38.8%, odds ratio 2.3, 95% confidence interval 1.8-3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3-2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1-1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4-2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2-2.0, P < 0.001; 50 mg: 40.8%, odds ratio 1.4, 1.1-1.8, P = 0.009 versus placebo 33.5%). Treatment-emergent adverse events were reported in 253 of 649 (39.0%), 229 of 635 (36.1%), and 166 of 654 (25.4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11.6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence and paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.
Learn More >Cortical spreading depression (CSD) is a wave of neuronal depolarization thought to underly migraine aura. Calcitonin gene-related peptide (CGRP) is a potent vasodilator involved in migraine pathophysiology. Evidence for functional connectivity between CSD and CGRP has triggered scientific interest in the possibility that CGRP antagonism may disrupt vascular responses to CSD, and the ensuing plasma protein extravasation (PPE). Using imaging tools that allow us to generate continuous, live, high-resolution views of spatial and temporal changes that affect arteries and veins in the dura and pia, we determined the extent to which CGRP contributes to the induction of arterial dilatation or PPE by CSD in female rats, and how these events are affected by the anti-CGRP monoclonal antibody (anti-CGRP-mAb) fremanezumab. We found that the CSD-induced brief dilatation and prolonged constriction of pial arteries, prolonged dilatation of dural arteries and PPE are all unaffected by fremanezumab, whereas the brief constriction and prolonged dilatation of pial veins are. In comparison, whereas CGRP infusion gave rise to the expected dilatation of dural arteries, which was effectively blocked by fremanezumab, it did not induce dilatation in pial arteries, pial veins, or dural veins. It also failed to induce PPE. Regardless of whether the nociceptors become active before or after the induction of arterial dilatation or PPE by CSD, fremanezumab's inability to prevent them suggests that these events are not mediated by CGRP; a conclusion with important implications for our understanding of anti-CGRP-mAbs' mechanism of action in migraine prevention.The current study identifies fundamental differences between two commonly used models of migraine, CSD induction and systemic CGRP infusion. It raises the possibility that conclusions drawn from one model may not be true or relevant to the other. It sharpens the need to accept the view that to migraine pathophysiology and that it is unlikely that one theory will explain all types of migraine headache or the mechanisms of action of drugs that prevent it. Regarding the latter, it is concluded that not all vascular responses in the meninges are born alike and consequently, that drugs that prevent vascular dilatation through different molecular pathways may have different therapeutic outcomes in different types of migraine.
Learn More >Central sensitization is a driving mechanism in many chronic pain patients, and manifests as hyperalgesia and allodynia beyond any apparent injury. Recent studies have demonstrated analgesic effects of motor cortex (M1) stimulation in several chronic pain disorders, yet its neural mechanisms remain uncertain. We evaluated whether anodal M1 transcranial direct current stimulation (tDCS) would mitigate central sensitization as measured by indices of secondary hyperalgesia. We used a capsaicin-heat pain model to elicit secondary mechanical hyperalgesia in 27 healthy subjects. In an assessor and subject-blind randomized, sham-controlled, crossover trial, anodal M1 tDCS decreased the intensity of pinprick hyperalgesia more than cathodal or sham tDCS. To elucidate the mechanism driving analgesia, subjects underwent fMRI of painful mechanical stimuli prior to and following induction of the pain model, after receiving M1 tDCS. We hypothesized that anodal M1 tDCS would enhance engagement of a descending pain modulatory (DPM) network in response to mechanical stimuli. Anodal tDCS normalized the effects of central sensitization on neurophysiological responses to mechanical pain in the medial prefrontal cortex, pregenual anterior cingulate cortex, and periaqueductal gray, important regions in the DPM network. Taken together, these results provide support for the hypothesis that anodal M1-tDCS reduces central sensitization-induced hyperalgesia through the DPM network in humans.
Learn More >Opioid-galanin receptor heteromers differentiate the dopaminergic effects of morphine and methadone.
As the opioid addiction crisis reaches epidemic levels, the identification of opioid analgesics that lack abuse potential may provide a path to safer treatment of chronic pain. Preclinical studies have demonstrated that galanin affects physical dependence and rewarding actions associated with morphine. In the brain and periphery, galanin and opioids signal through their respective GPCRs, GalR1-3 and the μ-opioid receptor (MOR). In this issue of the JCI, Cai and collaborators reveal that heteromers between GalR1 and MOR in the rat ventral tegmental area attenuate the potency of methadone, but not other opioids, in stimulating the dopamine release that produces euphoria. These studies help us understand why some synthetic opioids, such as methadone, do not trigger the release of dopamine in the mesolimbic system but still possess strong analgesic properties.
Learn More >Transient receptor potential ankyrin 1 (TRPA1) channels may have a role in migraine as some substances known to cause headache activate the channel. In the craniovascular system such activation causes a calcitonin gene-related peptide (CGRP)-dependent increase in meningeal blood flow. TRPA1 channels in the endothelium of cerebral arteries cause vasodilation when activated. The headache preventive substance feverfew inhibits activation of TRPA1 channels. In this study we aim to compare and characterize the effect of the TRPA1 agonist allyl isothiocyanate (AITC) on the diameter of rat dural and pial arteries in vivo.
Learn More >The cold and menthol sensitive Transient Receptor Potential Melastatin 8 (TRPM8) channel is important for both physiological temperature detection and cold allodynia. Activation of G-protein coupled receptors (GPCRs) by pro-inflammatory mediators inhibits these channels. It was proposed that this inhibition proceeds via direct binding of G to the channel. TRPM8 requires the plasma membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P or PIP] for activity. It was claimed however that a decrease in cellular levels of this lipid upon receptor activation does not contribute to channel inhibition. Here we show that supplementing the whole cell patch pipette with PI(4,5)P reduced inhibition of TRPM8 by activation of G-coupled receptors in mouse dorsal root ganglion (DRG) neurons isolated from both sexes. Stimulating the same receptors activated Phospholipase C (PLC) and decreased plasma membrane PI(4,5)P levels in these neurons. PI(4,5)P also reduced inhibition of TRPM8 by activation of heterologously expressed G-coupled muscarinic M1 receptors. Co-expression of a constitutively active G protein that does not couple to PLC inhibited TRPM8 activity, and in cells expressing this protein decreasing PI(4,5)P levels using a voltage sensitive 5'-phosphatase induced a stronger inhibition of TRPM8 activity than in control cells. Our data indicate that upon GPCR activation, G binding reduces the apparent affinity of TRPM8 for PI(4,5)P and thus sensitizes the channel to inhibition induced by decreasing PI(4,5)P levels.Increased sensitivity to heat in inflammation is partially mediated by inhibition of the cold- and menthol sensitive TRPM8 ion channels. Most inflammatory mediators act via GPCR-s that activate the Phospholipase C pathway leading to the hydrolysis of PI(4,5)P How receptor activation by inflammatory mediators leads to TRPM8 inhibition is not well understood. Here we propose that direct binding of G both reduces TRPM8 activity, and sensitizes the channel to inhibition by decreased levels of its cofactor PI(4,5)P Our data demonstrate the convergence of two downstream effectors of receptor activation G and PI(4,5)P hydrolysis in regulation of TRPM8.
Learn More >The G-protein-coupled μ-opioid receptor (μ-OR) mediates the majority of analgesia effects for morphine and other pain relievers. Despite extensive studies of its structure and activation mechanisms, the inherently low maturation efficiency of μ-OR represents a major hurdle to understanding its function. Here we computationally designed μ-OR mutants with altered stability to probe the relationship between cell-surface targeting, signal transduction, and agonist efficacy. The stabilizing mutation T315Y enhanced μ-OR trafficking to the plasma membrane and significantly promoted the morphine-mediated inhibition of downstream signaling. In contrast, the destabilizing mutation R165Y led to intracellular retention of μ-OR and reduced the response to morphine stimulation. These findings suggest that μ-OR stability is an important factor in regulating receptor signaling and provide a viable avenue to improve the efficacy of analgesics. This article is protected by copyright. All rights reserved.
Learn More >Tramadol is often prescribed to treat pain and is associated physical disability in osteoarthritis (OA). Due to the pharmacologic mechanism of tramadol, it may lead to fewer associated adverse effects (i.e. gastrointestinal bleeding or renal problems) compared to non-steroidal anti-inflammatory drugs (NSAIDs). This is an update of a Cochrane Review originally published in 2006.
Learn More >Cannabis is commonly used to manage chronic pain, but cannabis use patterns among individuals with chronic pain has not been well-characterized. We report cannabinoid, administration route, and product selection preferences among medical cannabis users with chronic pain from an ongoing, online survey. We also examined whether these preferences are affected by differences in sex, intentions behind use (medical only [MED] vs. medical + recreational [MEDREC]), and experience with cannabis (novice: <1 year vs. experienced: ≥1 year). 1,321 participants (59% female) completed the survey. 76.5% of participants used cannabis every day. 93.4% used 2 or more administration routes, with 72.5% using 3 or more. Female, MED, and novice users were less likely to smoke or vaporize (all p < 0.0001), but more likely to rank edibles, tinctures, and topicals as a first-choice administration route than their counterparts. Female and MED users also preferred low THC: high CBD ratios significantly more than their counterparts. Overall, only 2.6% of participants selected cannabis products with input from a medical professional, although 54.9% relied on advice from dispensary employees. More male, MEDREC, and experienced users selected products based on factors that reflected greater comfort with cannabis (e.g., smell, visual properties, cannabis variety). The wide variability in cannabis use among these different groups indicates the need for further research to investigate how specific use routines relate to clinical outcomes. Perspective: Medical cannabis users with chronic pain show distinct differences in cannabinoid preferences and administration associated with user sex, intentions behind use, and experience with cannabis. This article highlights the wide variability in cannabis preferences among medical cannabis users with chronic pain, which may be relevant for clinical outcomes.
Learn More >Itch is a common sensation that drives an intense urge to scratch. Itch and scratching have persisted in humans and many other species, suggesting that they play an important role in survival. This commentary discusses the function of itch as a danger signal, why itch feels unpleasant, and why we feel relief and pleasure when we scratch an itch. In addition, we explore the ways that this system becomes dysfunctional in conditions of chronic itch and important implications for treatment. This article is protected by copyright. All rights reserved.
Learn More >10Hz repetitive transcranial magnetic stimulation (10Hz-rTMS) to the left dorsolateral prefrontal cortex (L-DLPFC) produces analgesia, probably by activating the pain modulation system. A newer rTMS paradigm, called theta burst stimulation (TBS), has been developed. Unlike 10Hz-rTMS, prolonged continuous TBS (pcTBS) mimics endogenous theta rhythms, which can improve induction of synaptic long-term potentiation. Therefore, this study investigated whether pcTBS to the L-DLPFC reduced pain sensitivity more efficiently compared with 10Hz-rTMS, the analgesic effects lasted beyond the stimulation period, and the reduced pain sensitivity was associated with increased efficacy of conditioned pain modulation (CPM) and/or intra-cortical excitability. Sixteen subjects participated in a randomized cross-over study with pcTBS and 10Hz-rTMS. Pain thresholds to heat (HPT), cold (CPT), pressure (PPT), intra-cortical excitability assessment, and CPM with mechanical and heat supra-pain threshold test stimuli and the cold pressor test as conditioning were collected before (Baseline), 3 (Day3) and 4 days (Day4) after 3-day session of rTMS. HPTs and PPTs increased with 10Hz-rTMS and pcTBS at Day3 and Day4 compared with Baseline (P=0.007). Based on pooled data from pcTBS and 10Hz-rTMS, the increased PPTs correlated with increased efficacy of CPM at Day3 (P=0.008), while no correlations were found at Day4 or with the intra-cortical excitability. PERSPECTIVE: Preliminary results of this comparative study did not show stronger pain sensitivity reduction by pcTBS compared with 10Hz-rTMS to the L-DPFC. Both protocols maintained increased pain thresholds up to 24-hours after the last session, which were partially associated with modulation of CPM efficacy but not with the intra-cortical excitability changes.
Learn More >The benefits of opioid-based treatments to mitigate chronic pain can be hindered by the side effects of opioid-induced hyperalgesia (OIH) that can lead to higher consumption and risk of addiction. The present study advances the understanding of the molecular mechanisms associated with OIH by comparing mice presenting OIH symptoms in response to chronic morphine exposure (OIH treatment) relative to control mice (CON treatment). Using RNA-Seq profiles, gene networks were inferred in the trigeminal ganglia (TG), a central nervous system region associated with pain signaling, and in the nucleus accumbens (NAc), a region associated with reward dependency. The biological process of nucleic acid processing was over-represented among the 122 genes that exhibited a region-dependent treatment effect. Within the 187 genes that exhibited a region-independent treatment effect, circadian rhythm processes were enriched among the genes over-expressed in OIH relative to CON mice. This enrichment was supported by the differential expression of the period circadian clock 2 and 3 genes (Per2 and Per3). Transcriptional regulators in the PAR bZip family that are influenced by the circadian clock and that modulate neurotransmission associated with pain and drug addiction were also over-expressed in OIH relative to CON mice. Also notable was the under-expression in OIH relative to CON mice of the Toll-like receptor, nuclear factor-kappa beta, and interferon gamma genes and enrichment of the adaptive immune processes. The results from the present study offer insights to advance the effective use of opioids for pain management while minimizing hyperalgesia.
Learn More >Effective management of patients with pain requires accurate information about the prevalence, outcomes, and co-occurrence of common pain conditions. However, the transition from ICD-9-CM to ICD-10-CM diagnostic coding in 2015 left researchers without methods for comparing the prevalence of pain conditions before and after the transition. In this study, we developed and assessed a diagnostic framework to serve as a crosswalk between ICD-9-CM and ICD-10-CM diagnosis codes for common pain-related health conditions. We refined existing ICD-9-CM definitions for diagnostic clusters of common pain conditions consistent with the US National Pain Strategy and developed corresponding ICD-10-CM definitions. We then assessed the stability of prevalence estimates and associated patient socio-demographic features of each diagnostic cluster during one-year periods before and after the transition to ICD-10-CM in three US health care systems using electronic health records data for in-person encounters. Prevalence estimates and socio-demographic characteristics were similar before and after the transition. The Pain Condition ICD-9-CM to ICD-10-CM Crosswalk includes a full spectrum of common pain conditions to enable prevalence estimates of multiple and chronic overlapping pain conditions. This allows the tool to serve as a foundation for a broad array of pain-related health services research utilizing electronic databases. Perspective: This article details the development and assessment of the Pain Condition ICD-9-CM to ICD-10-CM Crosswalk, a diagnostic framework for assessing pain condition prevalence across the ICD-9-CM to ICD-10-CM transition. This framework can serve as a standardized tool for research on pain conditions, including health services and epidemiologic research.
Learn More >The role of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) in atopic dermatitis (AD) is unknown. This study is envisioned to lead to the previously unreported SNARE function in AD-related cytokine secretion and epidermis-nerve communication. Herein, we report that various cytokines were simultaneously upregulated and co-released in the innate immunity-activated primary human keratinocytes (phKCs). AD-related cytokines thymic stromal lymphopoietin (TSLP), endothelin-1 (ET-1) or inflammatory TNF-α activated distinct but overlapping sensory neurons. Interestingly, TNF-α potentiated TSLP-induced Ca-influx, whereas ET-1 caused itch-selective B-type natriuretic peptide (BNP) release. In phKCs, BNP upregulated genes promoting dermatological and neuroinflammatory diseases and conditions. VAMP3, SNAP-29 and syntaxin4 proved important in driving cytokine release from phKCs. Depletion of VAMP3 inhibited nearly all the cytokine release including TSLP and ET-1. Accordingly, VAMP3 co-occurred with ET-1 in AD patient skin. Our study pinpoints the pivotal role of SNAREs in mediating cytokine secretion related to AD. VAMP3 is identified as a suitable target for developing broad-spectrum anti-cytokine therapeutics for controlling itch and atopic skin inflammation.
Learn More >Chronic postsurgical pain (CPSP) is a significant detriment to post-surgical recovery and a risk factor for prolonged opioid use. Emerging evidence suggests the estimated heritability for chronic pain is 45% and that genetic factors partially explain individual susceptibility to CPSP. The aim of this study was to systematically review, assess quality and summarize the studies in humans that have investigated genetic factors associated with CPSP. We also conducted a meta-analysis to derive a single effect size for evaluable genetic associations with CPSP. Our comprehensive literature search included review of 21 full-text articles evaluating variants of 69 genes for association with CPSP. We found significant gene variant associations reported for variants/haplotypes of 26 genes involved in neurotransmission, pain signaling, immune responses and neuroactive ligand-receptor interaction, with CPSP. Six variants of five genes (COMT: rs4680 and rs6269, OPRM1: rs1799971, GCH1: rs3783641, KCNS1: rs734784 and TNFA: rs1800629), were evaluated by more than one study and were included in the meta-analysis. At rs734784 (A>G) of KCNS1, presence of G allele marginally increased risk of CPSP (Additive genetic model; Odds ratio: 1.511; 95% CI 1 to 2.284; p-value 0.050), while the other variants did not withstand meta-analyses criteria. Our findings demonstrate the role of genetic factors with different functions in CPSP, and also emphasize that single genetic factors have small effect sizes in explaining complex conditions like CPSP. Heterogeneity in surgical cohorts, population structure and outcome definitions, as well as small number of available studies evaluating same variants, limit the meta-analysis. There is a need for large-scale, homogenous, replication studies to validate candidate genes, and understand the underlying biological networks underpinning CPSP. Perspective: Our systematic review comprehensively describes 21 studies evaluating genetic association with CPSP, and limitations thereof. A meta-analysis of 6 variants (5 genes) found marginally increased risk for CPSP associated with rs734784 A>G of the potassium voltage-gated channel gene (KCNS1). Understanding genetic predisposition for CPSP will enable prediction and personalized management.
Learn More >Kappa opioid receptor (KOR) agonists show promise in ameliorating disorders, such as addiction and chronic pain, but are limited by dysphoric and aversive side effects. Clinically beneficial effects of KOR agonists (e.g., analgesia) are predominantly mediated by heterotrimeric G protein signaling, whereas β-arrestin signaling is considered central to their detrimental side effects (e.g., dysphoria/aversion). Here we show that Regulator of G protein Signaling-12 (RGS12), via independent signaling mechanisms, simultaneously attenuates G protein signaling and augments β-arrestin signaling downstream of KOR, exhibiting considerable selectivity in its actions for KOR over other opioid receptors. We previously reported that RGS12-null mice exhibit increased dopamine transporter-mediated dopamine (DA) uptake in the ventral (vSTR), but not dorsal striatum (dSTR), as well as reduced psychostimulant-induced hyperlocomotion; in the current study, we found that these phenotypes are reversed following KOR antagonism. Fast-scan cyclic voltammetry studies of dopamine (DA) release and reuptake suggest that striatal disruptions to KOR-dependent DAergic neurotransmission in RGS12-null mice are restricted to the nucleus accumbens. In both ventral striatal tissue and transfected cells, RGS12 and KOR are seen to interact within a protein complex. Ventral striatal-specific increases in KOR levels and KOR-induced G protein activation are seen in RGS12-null mice, as well as enhanced sensitivity to KOR agonist-induced hypolocomotion and analgesia-G protein signaling-dependent behaviors; a ventral striatal-specific increase in KOR levels was also observed in β-arrestin-2-deficient mice, highlighting the importance of β-arrestin signaling to establishing steady-state KOR levels in this particular brain region. Conversely, RGS12-null mice exhibited attenuated KOR-induced conditioned place aversion (considered a β-arrestin signaling-dependent behavior), consistent with the augmented KOR-mediated β-arrestin signaling seen upon RGS12 over-expression. Collectively, our findings highlight a role for RGS12 as a novel, differential regulator of both G protein-dependent and -independent signaling downstream of KOR activation.
Learn More >Migraine is a neurological disorder characterized by paroxysms of head pain accompanied by trigeminovascular system activation and autonomic dysfunction. Diagnosis is currently based on clinical diagnostic criteria. Though physiological differences exist between migraineurs and non-headache controls, true physiological biomarkers have been elusive, especially for the full clinical spectrum of migraine, inclusive of chronic, episodic, and probable migraine. We used edge-light pupil cycle time (PCT) as a probe of the pupillary light circuit in migraine, paired with clinical assessment of migraine characteristics, and compared these to non-headache controls. We found significantly increased PCT in probable, episodic, and chronic migraine, compared to controls. Additionally, increased PCT correlated with the presence of craniofacial autonomic symptoms, linking pupillary circuit dysfunction to peripheral trigeminal sensitization. The sensitivity of PCT, especially for all severities of disease, distinguishes it from other physiological phenotypes, which may make it useful as a potential biomarker.
Learn More >The prime task of nociceptors is the transformation of noxious stimuli into action potentials that are propagated along the neurites of nociceptive neurons from the periphery to the spinal cord. This function of nociceptors relies on the coordinated operation of a variety of ion channels. In this review, we summarize how members of nine different families of ion channels expressed in sensory neurons contribute to nociception. Furthermore, data on 35 different types of G protein coupled receptors are presented, activation of which controls the gating of the aforementioned ion channels. These receptors are not only targeted by more than 20 separate endogenous modulators, but can also be affected by pharmacotherapeutic agents. Thereby, this review provides information on how ion channel modulation via G protein coupled receptors in nociceptors can be exploited to provide improved analgesic therapy.
Learn More >Widespread pain is a common comorbidity in several chronic diseases and is suspected to be caused by the underlying disease that has provoked a state of central sensitization. However, this argument is currently limited by evidence that has not sufficiently captured the temporal nature of the relationship between diagnosis of the underlying disease and onset of widespread pain. The aim of this study was to investigate whether patients with rheumatoid arthritis (RA), endometriosis or inflammatory bowel disease (IBD) have a higher risk of developing widespread pain (fibromyalgia or chronic widespread pain [CWP]).
Learn More >Chronic pain is an important problem after critical care admission. Estimates of the prevalence of chronic pain in the year after discharge range from 14% to 77% depending on the type of cohort, the tool used to measure pain, and the time point when pain was assessed. The majority of data available come from studies using health-related quality of life tools, although some have included pain-specific tools. Nociceptive, neuropathic, and nociplastic pain can occur in critical care survivors, but limited information about the aetiology, body site, and temporal trajectory of pain is currently available. Older age, pre-existing pain, and medical co-morbidity have been associated with pain after critical care admission. No trials were identified of interventions to target chronic pain in survivors specifically. Larger studies, using pain-specific tools, over an extended follow-up period are required to confirm the prevalence, identify risk factors, explore any association between acute and chronic pain in this setting, determine the underlying pathological mechanisms, and inform the development of future analgesic interventions.
Learn More >Peripheral mechanisms of primary headaches such as a migraine remain unclear. Meningeal afferents surrounded by multiple mast cells have been suggested as a major source of migraine pain. Extracellular ATP released during migraine attacks is a likely candidate for activating meningeal afferents via neuronal P2X receptors. Recently, we showed that ATP also increased degranulation of resident meningeal mast cells (Nurkhametova et al., 2019). However, the contribution of ATP-induced mast cell degranulation in aggravating the migraine pain remains unknown. Here we explored the role of meningeal mast cells in the pro-nociceptive effects of extracellular ATP. The impact of mast cells on ATP mediated activation of peripheral branches of trigeminal nerves was measured electrophysiologically in the dura mater of adult wild type (WT) or mast cell deficient mice. We found that a spontaneous spiking activity in the meningeal afferents, at baseline level, did not differ in two groups. However, in WT mice, meningeal application of ATP dramatically (24.6-fold) increased nociceptive firing, peaking at frequencies around 10 Hz. In contrast, in mast cell deficient animals, ATP-induced excitation was significantly weaker (3.5-fold). Application of serotonin to meninges in WT induced strong spiking. Moreover, in WT mice, the 5-HT3 antagonist MDL-7222 inhibited not only serotonin but also the ATP induced nociceptive firing. Our data suggest that extracellular ATP activates nociceptive firing in meningeal trigeminal afferents via amplified degranulation of resident mast cells in addition to direct excitatory action on the nerve terminals. This highlights the importance of mast cell degranulation via extracellular ATP, in aggravating the migraine pain.
Learn More >Low back pain (LBP) is one of the most prevalent and potentially disabling conditions for which people seek health care. Patients, providers, and payers agree that greater effort is needed to prevent acute LBP from transitioning to chronic LBP.
Learn More >Pain is a major complication of sickle cell disease (SCD), spanning vaso-occlusive crises and persistent pain. Although it is known that persistent pain is associated with considerable impairment in youth without SCD, little is known about the functional effects of persistent pain in SCD. The current study aimed to (a) characterize persistent pain in youth with SCD and (b) determine the extent to which youth with SCD and persistent pain differ in disease morbidity, functional impairment, and neurocognitive and psychological functioning.
Learn More >As a complex multidimensional construct, fatigue may play an important role in the physical and psychosocial functioning of youth with chronic pain. Based on a model previously tested in adults, the current study similarly utilized Patient-Reported Outcomes Measurement System (PROMIS) to examine how fatigue contributes to functional outcomes for youth with chronic pain. The model tested self-reported ratings of pain intensity, depressive symptoms, and sleep disturbance as predictors of outcomes (mobility, pain-related interference, and school functioning) as mediated by ratings of fatigue.
Learn More >Osteoarthritis is the most common musculoskeletal disease worldwide, often characterized by degradation of the articular cartilage, chronic joint pain and disability. Cognitive dysfunction, anxiety and depression are common comorbidities that impact the quality of life of these patients. In this study, we evaluated the involvement of sigma-1 receptor (σ1R) on the nociceptive, cognitive and emotional alterations associated with chronic osteoarthritis pain. Monosodium iodoacetate (MIA) was injected into the knee of Swiss-albino CD1 mice to induce osteoarthritis pain, which then received a repeated treatment with the σ1R antagonist E-52862 or its vehicle. Nociceptive responses and motor performance were assessed with the von Frey and the Catwalk gait tests. Cognitive alterations were evaluated using the novel object recognition task, anxiety-like behavior with the elevated plus maze and the zero-maze tests, whereas depressive-like responses were determined using the forced swimming test. We also studied the local effect of the σ1R antagonist on cartilage degradation, and its central effects on microglial reactivity in the medial prefrontal cortex. MIA induced mechanical allodynia and gait abnormalities that were prevented by the chronic treatment with the σ1R antagonist. E-52862 also reduced the memory impairment and the depressive-like behavior associated to osteoarthritis pain. Interestingly, the effect of E-52862 on depressive-like behavior was not accompanied by a modification of anxiety-like behavior. The pain-relieving effects of the σ1R antagonist were not due to a local effect on the articular cartilage, since E-52862 treatment did not modify the histological alterations of the knee joints. However, E-52862 induced central effects revealed by a reduction of the cortical microgliosis observed in mice with osteoarthritis pain. These findings show that σ1R antagonism inhibits mechanical hypersensitivity, cognitive deficits and depressive-like states associated with osteoarthritis pain in mice. These effects are associated with central modulation of glial activity but are unrelated to changes in cartilage degradation. Therefore, targeting the σ1R with E-52862 represents a promising pharmacological approach with effects on multiple aspects of chronic osteoarthritis pain that may go beyond the strict inhibition of nociception.
Learn More >Voltage-gated sodium channels (VGSCs), formed by 24 transmembrane segments arranged into four domains, have a key role in the initiation and propagation of electrical signaling in excitable cells. VGSCs are involved in a variety of diseases, including epilepsy, cardiac arrhythmias, and neuropathic pain, and, therefore, have been regarded as appealing therapeutic targets for the development of anticonvulsant, antiarrhythmic, and local anesthetic drugs. In this review, we discuss recent advances in understanding the structures and biological functions of VGSCs. In addition, we systematically summarize eight pharmacologically distinct ligand-binding sites in VGSCs and representative isoform-selective VGSC modulators in clinical trials. Finally, we review studies on molecular modeling and computer-aided drug design (CADD) for VGSCs to help understanding of biological processes involving VGSCs.
Learn More >Painful diabetic neuropathy (PDN) is a serious symptom that compromises quality of life and remains without effective pharmacological treatment. The transient receptor vanilloid 4 (TRPV4) is a cation-permeable channel implicated in sensory transduction and pain signalling. Therefore, drugs that act on TRPV4 may have therapeutic applications to treat PDN. In the present work, we assessed the effect of the selective TRPV4 channel antagonist HC-067047 on painful neuropathy associated with streptozotocin (STZ)-induced diabetes in mice. STZ-treated animals presented both mechanical and cold allodynia at 6 weeks after diabetes induction. Notably, HC-067047 (1 mg/kg, s.c.) given daily between 2 and 6 weeks after diabetes induction significantly prevented the development of mechanical allodynia. Additionally, both single and repeated treatments with HC-067047 (10 mg/kg, s.c.) significantly reverted established mechanical allodynia induced by STZ. However, HC-067047 was not capable of affecting either thermal cold allodynia or hyperglycemia. Similarly, HC-067047 treatments showed no effect on body weight, temperature, locomotor activity or motor coordination of control mice. Immunohistochemistry assay showed that TRPV4 expression was not different in sciatic nerve, dorsal root ganglia (DRG) or hind paw plantar skin from diabetic and non-diabetic mice, suggesting that HC-067047 acts on constitutive receptors to inhibit mechanical allodynia. Taken together, the data generated in the present study show the potential relevance of using TRPV4 antagonists to treat painful neuropathy associated with diabetes.
Learn More >To estimate the prevalence of having at least one or two or more chronic health conditions among US adults with self-reported migraine or severe headaches.
Learn More >Cannabinoids: Current and Future Options to Treat Chronic and Chemotherapy-Induced Neuropathic Pain.
Increases in cancer diagnosis have tremendous negative impacts on patients and their families, and major societal and economic costs. The beneficial effect of chemotherapeutic agents on tumor suppression comes with major unwanted side effects such as weight and hair loss, nausea and vomiting, and neuropathic pain. Chemotherapy-induced peripheral neuropathy (CIPN), which can include both painful and non-painful symptoms, can persist 6 months or longer after the patient's last chemotherapeutic treatment. These peripheral sensory and motor deficits are poorly treated by our current analgesics with limited effectiveness. Therefore, the development of novel treatment strategies is an important preclinical research focus and an urgent need for patients. Approaches to prevent CIPN have yielded disappointing results since these compounds may interfere with the anti-tumor properties of chemotherapeutic agents. Nevertheless, the first (serotonin noradrenaline reuptake inhibitors [SNRIs], anticonvulsants, tricyclic antidepressants) and second (5% lidocaine patches, 8% capsaicin patches and weak opioids such as tramadol) lines of treatment for CIPN have shown some efficacy. The clinical challenge of CIPN management in cancer patients and the need to target novel therapies with long-term efficacy in alleviating CIPN are an ongoing focus of research. The endogenous cannabinoid system has shown great promise and efficacy in alleviating CIPN in preclinical and clinical studies. In this review, we will discuss the mechanisms through which the platinum, taxane, and vinca alkaloid classes of chemotherapeutics may produce CIPN and the potential therapeutic effect of drugs targeting the endocannabinoid system in preclinical and clinical studies, in addition to cannabinoid compounds diffuse mechanisms of action in alleviation of CIPN.
Learn More >To investigate the association between the presence of self-reported neck pain in patients with migraine and clinical features, upper cervical mobility, and neck muscle performance.
Learn More >It remains unknown whether migraine headache has a progressive component in its pathophysiology. Quantitative MRI may provide valuable insight into abnormal changes in the migraine interictum and assist in identifying disrupted brain networks. We carried out a data-driven study of structural integrity and functional connectivity of the resting brain in migraine without aura. MRI scanning was performed in 36 patients suffering from episodic migraine without aura and 33 age-matched healthy subjects. Voxel-wise analysis of regional brain volume was performed by registration of the T1-weighted MRI scans into a common study brain template using the tensor-based morphometry (TBM) method. Changes in functional synchronicity of the brain networks were assessed using probabilistic independent component analysis (ICA). TBM revealed that migraine is associated with reduced volume of the medial prefrontal cortex (mPFC). Among 375 functional brain networks, resting-state connectivity was decreased between two components spanning the visual cortex, posterior insula, and parietal somatosensory cortex. Our study reveals structural and functional alterations of the brain in the migraine interictum that may stem from underlying disease risk factors and the "silent" aura phenomenon. Longitudinal studies will be needed to investigate whether interictal brain changes are progressive and associated with clinical disease trajectories.
Learn More >Over 100 million people are challenged by the effects of chronic pain in the United States alone. This burden also impacts the U.S. economy; 600 billion dollars annually is spent on medical care, medications, and lost productivity in the workplace.1 Current opioid treatments cause adverse effects including nausea, constipation, tolerance, and addiction liability.2 Nociceptive sensitization is thought to perpetuate chronic pain, but too little is known about its mechanisms. Components of the pathways that sensitize the nociceptors after injury are likely to be valuable targets for novel medications for the relief or prevention of chronic pain. Utilizing the Drosophila melanogaster cell targeting and RNA interference toolkit, we are investigating the Bone Morphogenetic Protein (BMP) pathway and its role in ultraviolet light (UV) injury-induced nociceptive sensitization. BMPs are well known as secreted developmental morphogens that control development, but other functions are known.3 We have previously identified BMP signaling components used in nociceptors to modulate injury-induced allodynia, including Decapentaplegic (Dpp, orthologous to mammalian BMP 2/4), and its downstream signaling components.4 The morphogen Hedgehog has also been shown to be necessary for allodynia following injury.5 Here, we show that two membrane-embedded regulators of the Dpp and Hedgehog pathways, Dally and Dally-like, are necessary for injury-induced thermal allodynia, as the formation of sensitization was reduced when either component was suppressed. These BMP components are highly conserved and, because dysregulation of nociceptor sensitization underlies chronic pain, the homologs of Dally and Dally-like may represent novel therapeutic targets in humans challenged by chronic pain. Furthermore, because of their extracellular location, Dally and Dally-like represent attractive therapeutic drug targets because such drugs would not need to cross the plasma membrane.
Learn More >The primary objective of this article is to assist oncologists and advanced practice prescribers to safely and effectively minimize risk when providing opioids for cancer pain relief. The majority of people with cancer are unlikely to misuse or divert opioid medications, yet the prescriber is often unaware of those who are at risk for these behaviors. To provide skillful pain management to each patient in the oncology setting, while limiting harm to the community, all prescribers must consider the potential for risk of misuse, addiction, or diversion. To minimize this risk to the greatest degree possible, it is imperative to include a thorough risk assessment when conducting a comprehensive pain evaluation. This information is then used to triage pain relief interventions based upon the degree of risk, including whether or not to incorporate opioids into the plan of care. Risk mitigation strategies, incorporating universal precautions, are implemented to assess, monitor, and reduce the potential for opioid misuse. Universal precautions include strategies such as the use of urine toxicology, state prescription drug monitoring programs, and agreements. Ongoing monitoring is conducted with the goal being to identify aberrant behaviors early so that they can be addressed and managed appropriately. Referral to addiction specialists may be warranted when substance use disorder precludes safe use of opioids. IMPLICATIONS FOR PRACTICE: Throughout the trajectory of cancer care, opioid use is often indicated, and, in fact, it may be unethical to limit or prohibit the use of opioids when pain is severe. Oncologists face the significant challenge of providing cancer pain control that is safe and effective, while limiting individual risk for abuse or overdose and keeping the community free of diverted substances. Most oncology providers report inadequate training in chronic pain principles and in managing addiction. Risk assessment and mitigation measures can be incorporated within oncology care to enhance effective pain management while reducing the potential for harm.
Learn More >There exists limited data on the association between unhealthy body weight and chronic pain, and whether this association is explained by frailty status of older adults.
Learn More >Background and aims There is high level evidence for physical activity (PA) improving outcomes in persistent pain disorders and one of the mechanisms proposed is the effect of exercise on central nociceptive modulation. Although laboratory studies and small field intervention studies suggest associations between physical activity and pain sensitivity, the association of objectively measured, habitual PA and sedentary behaviour (SB) with pain sensitivity requires further investigation. Current evidence suggests PA typically lowers pain sensitivity in people without pain or with single-site pain, whereas PA is frequently associated with an increase in pain sensitivity for those with multisite pain. The aim of this study was to explore the relationships of PA and SB with pain sensitivity measured by pressure pain thresholds and cold pain thresholds, considering the presence of single-site and multisite pain and controlling for potential confounders. Methods Participants from the Western Australian Pregnancy Cohort (Raine) Study (n = 714) provided data at age 22-years. PA and SB were measured via accelerometry over a 7-day period. Pain sensitivity was measured using pressure pain threshold (4 sites) and cold pain threshold (wrist). Participants were grouped by number of pain areas into "No pain areas" (n = 438), "Single-site pain" (n = 113) and "Multisite pain" (n = 163) groups. The association of PA and SB variables with pain sensitivity was tested separately within each pain group by multivariable regression, adjusting for potential confounders. Results For those with "Single-site pain", higher levels (>13 min/day) of moderate-vigorous PA in ≥10 min bouts was associated with more pressure pain sensitivity (p = 0.035). Those with "Multisite pain" displayed increased cold pain sensitivity with greater amounts of vigorous PA (p = 0.011). Those with "No pain areas" displayed increased cold pain sensitivity with decreasing breaks from sedentary time (p = 0.046). Conclusions This study was a comprehensive investigation of a community-based sample of young adults with "No pain areas", "Single-site pain" and "Multisite pain" and suggests some associations of measures of PA and SB with pain sensitivity. Implications The findings suggest that the pattern of accumulation of PA and SB may be important to inform improved clinical management of musculoskeletal pain disorders. This study provides a baseline for follow-up studies using the Raine Study cohort. Future research should consider temporal influences of PA and SB on pain sensitivity, pain experience and consider using a broader range of pain sensitivity measures.
Learn More >Background and aims Endometriosis is a gynecologic recurring persistent condition affecting from 8% to 15% of premenopausal women worldwide. About 80% of women with endometriosis have at least one form of chronic pain – a multidimensional experience influenced by a number of psychosocial factors, including pain-related beliefs. The Survey of Pain Attitudes is the most commonly used measure of pain-related beliefs. This study aims to evaluate the psychometric properties of a Portuguese version of a brief version of the SOPA (the SOPA-35) in a sample of Portuguese women with Endometriosis. Methods A sample of 199 Portuguese women with Endometriosis provided demographic and pain history information, and completed a Portuguese version of the SOPA-35 and measures of pain intensity, disability, and psychological function. Analyses were performed to evaluate the factor structure of the Portuguese SOPA-35 items as well as the internal consistency, composite reliability, convergent validity, and concurrent validity of the scale scores. Results Confirmatory factor analysis supported a six-factor solution for a 19-item version of the Portuguese version of the Survey of Pain Attitudes (SOPA-19-P). The six scales evidenced marginal to good reliability (Cronbach's alphas: between 0.60 and 0.84; composite reliability: between 0.61 and 0.84). Four scales evidenced acceptable to good convergent validity (AVE: between 0.51 and 0.63). The findings also supported the concurrent validity of the SOPA-19-P. Conclusions The results support the use of the Portuguese SOPA-19-P for research and clinical purposes with Portuguese women in chronic pain due to endometriosis. Future research is warranted to further develop a European Portuguese version of SOPA. Implications The findings provide psychometric information about the SOPA-19-P. The results are helpful to researchers wishing to study the role of pain-related beliefs and their association with adjustment and treatment outcomes in women with chronic pain due to endometriosis.
Learn More >To examine independent associations of sleeplessness and high-sensitivity C-reactive protein (hsCRP) with risk of chronic musculoskeletal pain, and to explore the joint effect of sleeplessness and hsCRP on risk of chronic musculoskeletal pain.
Learn More >Triptans, the most efficient acute treatment for migraine attacks, are 5-HT1B/1D receptor agonists, but their precise mechanism of action is not completely understood. The extent to which triptans enter the central nervous system and bind to 5-HT1B receptors in the brain is unknown.
Learn More >The gasotransmitter hydrogen sulfide (HS) is known to regulate many pathophysiological processes. Preclinical assays have demonstrated that HS donors exhibit anti-inflammatory and antinociceptive activities, characterized by reduction of inflammatory mediators production, leukocytes recruitment, edema and mechanical allodynia. In the present study, the effects induced by 4-methylbenzenecarbothioamide (4-MBC) in models of pain and inflammation in mice, the mechanisms mediating such effects and the HS-releasing property of this compound were evaluated. 4-MBC spontaneously released HS in vitro in the absence of organic thiols. Intraperitoneal (i.p.) administration of 4-MBC (100 or 150 mg/kg) reduced the second phase of the nociceptive response induced by formaldehyde and induced a long lasting inhibitory effect on carrageenan mechanical allodynia. 4-MBC antiallodynic effect was not affected by previous administration of naltrexone or glibenclamide. 4-MBC (50, 100 or 150 mg/kg, i.p.) induced a long lasting inhibitory effect on paw edema induced by carrageenan. The highest dose (150 mg/kg, i.p.) of 4-MBC inhibited tumor necrosis factor-α and CXCL1 production and myeloperoxidase activity induced by carrageenan. Mechanical allodynia and paw edema induced by carrageenan were not inhibited by the 4-MBC oxo analogue (p-toluamide). In summary, 4-MBC, an HS releasing thiobenzamide, exhibits antinociceptive and anti-inflammatory activities. These activities may be due to reduced cytokine and chemokine production and neutrophil recruitment. The HS releasing property is likely essential for 4-MBC activity. Our results indicate that 4-MBC may represent a useful pharmacological tool to investigate the biological roles of HS.
Learn More >Successful preventive treatment in chronic migraine (CM) remains an unmet need in some cases, and new therapeutic strategies are emerging. We aimed to test the effect of noninvasive, transcutaneous supraorbital nerve stimulation (tSNS) in a group of patients with CM.
Learn More >Opioid prescriptions in the surgical setting have been implicated as contributors to the opioid epidemic. The authors hypothesized that a multidisciplinary approach to perioperative pain management for patients on chronic opioid therapy could decrease postoperative opioid requirements while reducing postoperative pain scores and improving functional outcomes. Therefore, a Perioperative Pain Program (PPP) for chronic opioid users was implemented. This study presents outcomes from the first 9 months of the PPP. Sixty-one patients met the inclusion criteria. Opioid consumption in morphine milligram equivalent (MME) was calculated and physical and health status of patients was assessed with the Brief Pain Inventory, Short-Form McGill Pain Questionnaire, and Short Form-12. Preliminary results showed significant reduction in MME, improved pain scores, and improved function for surgical patients on chronic opioids. PPP effectively reduced opioid usage without negatively influencing patient-reported outcomes, such as physical pain score assessment and health-related quality of life.
Learn More >Perturbation of neuronal excitability contributes to migraine. Neurosteroids modulate the activity of γ-aminobutyric acid A and N-methyl-d-aspartate receptors, and might be involved in the pathogenesis of migraine. Here, we measured plasma levels of four neurosteroids, i.e., allopregnanolone, epiallopregnanolone, dehydroepiandrosterone and deydroepiandrosterone sulfate, in patients affected by episodic migraine, chronic migraine, or cluster headache.
Learn More >Chronic pain, such as low-back pain, can be a highly disabling condition degrading people's quality of life (QoL). Not every patient responds to pharmacological therapies, thus alternative treatments have to be developed. The chronicity of pain can lead to a somatic dysperception, meaning a mismatch between patients' own body perception and its actual physical state. Since clinical evaluation of pain relies on patients' subjective reports, a body image disruption can be associated with an incorrect pain rating inducing incorrect treatment and a possible risk of drug abuse. Our aim was to reduce chronic low-back pain through a multimodal neurorehabilitative strategy using innovative technologies to help patients regain a correct body image.
Learn More >This study aimed to investigate the effect of oral treatment with ketotifen, a mast cell (MC) stabilizer, in a rat model of surgically induced endometriosis. At 14 days after Sprague-Dawley rats had surgery, they were treated with ketotifen (1 or 10 mg/kg/day). Pain behaviors were evaluated 3 days prior to surgery and then at 7, 14, 21, and 28 days after surgery. At day 28, rats were sacrificed and all samples were then processed for biochemical studies. We found that ketotifen-treated rats showed significantly shorter duration of hyperalgesia (<0.05); smaller cyst diameter (<0.05) and lower histopathologic score (<0.001); significantly lower MC number and degranulation (<0.001), blood vessel number (<0.001), lower expression levels of nerve growth factor (<0.001), cyclooxygenase-2 (<0.001), intercellular cell adhesion molecule-1 (<0.001), and vascular endothelial growth factor (<0.05) in cysts, and nerve growth factor (<0.001) and transient receptor potential cation channel, subfamily V, member 1 (<0.001) in dorsal root ganglia; and lower histamine (<0.05) and tumor necrosis factor-alpha (<0.05) concentrations in serum compared with placebo-treated animal subjects. Oral treatment with ketotifen significantly suppressed the development of hyperalgesia, probably by modulating MC activity in cysts, thereby reducing peripheral sensitization due to noxious signals from endometriotic lesions. Our results suggest that ketotifen may inhibit the development of endometriotic lesions and hyperalgesia in rats.
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