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The sacroiliac joint (SIJ) is often considered to be involved when people present for care with low back pain where the sacroiliac joint (SIJ) is located. However, determining why the pain has arisen can be challenging, especially in the absence of a specific cause such as pregnancy, disease, or trauma, where the SIJ may be identified as a source of symptoms with the help of manual clinical tests. Nonspecific SIJ-related pain is commonly suggested to be causally associated with movement problems in the sacroiliac joint(s); a diagnosis traditionally derived from manual assessment of movements of the SIJ complex. Management choices often consist of patient education, manual treatment, and exercise. Although some elements of management are consistent with guidelines, this perspective argues that the assumptions on which these diagnoses and treatments are based are problematic, particularly if they reinforce unhelpful, pathoanatomical beliefs. This article reviews the evidence regarding the clinical detection and diagnosis of SIJ movement dysfunction. In particular, it questions the continued use of assessing movement dysfunction despite mounting evidence undermining the biological plausibility and subsequent treatment paradigms based on such diagnoses. Clinicians are encouraged to align their assessment methods and explanatory models to contemporary science to reduce the risk of their diagnoses and choice of intervention negatively affecting clinical outcomes.
Learn More >Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist under investigation for acute treatment of migraine.
Learn More >The two-pore potassium channel, TRESK has been implicated in nociception and pain disorders. We have for the first time investigated TRESK function in human nociceptive neurons using induced pluripotent stem cell-based models. Nociceptors from migraine patients with the F139WfsX2 mutation show loss of functional TRESK at the membrane, with a corresponding significant increase in neuronal excitability. Furthermore, using CRISPR-Cas9 engineering to correct the F139WfsX2 mutation, we show a reversal of the heightened neuronal excitability, linking the phenotype to the mutation. In contrast we find no change in excitability in induced pluripotent stem cell derived nociceptors with the C110R mutation and preserved TRESK current; thereby confirming that only the frameshift mutation is associated with loss of function and a migraine relevant cellular phenotype. We then demonstrate the importance of TRESK to pain states by showing that the TRESK activator, cloxyquin, can reduce the spontaneous firing of nociceptors in an in vitro human pain model. Using the chronic nitroglycerine rodent migraine model, we demonstrate that mice lacking TRESK develop exaggerated nitroglycerine-induced mechanical and thermal hyperalgesia, and furthermore, show that cloxyquin conversely is able to prevent sensitization. Collectively, our findings provide evidence for a role of TRESK in migraine pathogenesis and its suitability as a therapeutic target.
Learn More >Transcripts of noxious stimulus-detecting TrpA1 channels are alternatively spliced. Despite the importance of nociception for survival, the in vivo significance of expressing different TrpA1 isoforms is largely unknown. Here, we develop a novel genetic approach to generate Drosophila knockin strains expressing single TrpA1 isoforms. Drosophila TrpA1 mediates heat and UVC-triggered nociception. We show that TrpA1-C and TrpA1-D, two alternative isoforms, are co-expressed in nociceptors. When examined in heterologous cells, both TrpA1-C and TrpA1-D are activated by heat and UVC. By contrast, analysis of knockin flies reveals the striking functional specificity; TrpA1-C mediates UVC-nociception, whereas TrpA1-D mediates heat-nociception. Therefore, in vivo functions of TrpA1-C and TrpA1-D are different from each other and are different from their in vitro properties. Our results indicate that a given sensory stimulus preferentially activates a single TrpA1 isoform in vivo and that polymodal nociception requires co-expression of TrpA1 isoforms, providing novel insights of how alternative splicing regulates nociception.
Learn More >Fibromyalgia (FM) is characterized by pain and fatigue, particularly during physical activity. Transcutaneous electrical nerve stimulation (TENS) activates endogenous pain inhibitory mechanisms. We evaluated if using TENS during activity would improve movement-evoked pain and other patient-reported outcomes in women with FM.
Learn More >Pain following brain surgery can compromise recovery. Several pharmacological interventions have been used to prevent pain after craniotomy; however, there is currently a lack of evidence regarding which interventions are most effective.
Learn More >The proinflammatory cytokine interleukin-17 (IL-17) is implicated in pain regulation. However, the synaptic mechanisms by which IL-17 regulates pain transmission are unknown. Here, we report that glia-produced IL-17 suppresses inhibitory synaptic transmission in the spinal cord pain circuit and drives chemotherapy-induced neuropathic pain. We find that IL-17 not only enhances excitatory postsynaptic currents (EPSCs) but also suppresses inhibitory postsynaptic synaptic currents (IPSCs) and GABA-induced currents in lamina II somatostatin-expressing neurons in mouse spinal cord slices. IL-17 mainly expresses in spinal cord astrocytes, and its receptor IL-17R is detected in somatostatin-expressing neurons. Selective knockdown of IL-17R in spinal somatostatin-expressing interneurons reduces paclitaxel-induced hypersensitivity. Overexpression of IL-17 in spinal astrocytes is sufficient to induce mechanical allodynia in naive animals. In dorsal root ganglia, IL-17R expression in nociceptive sensory neurons is sufficient and required for inducing neuronal hyperexcitability after paclitaxel. Together, our data show that IL-17/IL-17R mediate neuron-glial interactions and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy.
Learn More >Pancreatitis-associated proteins (PAPs) display multiple functions in visceral diseases. Previous studies showed that the expression level of PAP-I was low in the dorsal root ganglion (DRG) of naïve rats but was expressed after peripheral nerve injury. However, its role in neuropathic pain remains unknown. We found that PAP-I expression was continuously up-regulated in the DRG neurons from rat spared nerve injury (SNI) models, and transported towards the spinal dorsal horn to act as a pro-inflammatory factor. Intrathecal delivery of PAP-I enhanced sensory hyperalgesia, whereas PAP-I deficiency by either gene knockout or antibody application alleviated tactile allodynia at the maintenance phase after SNI. Furthermore, PAP-I functioned by activating the spinal microglia via C-C chemokine receptor type 2 (CCR2) that participated in neuropathic pain. Inhibition of either microglial activation or CCR2 abolished the PAP-I-induced hyperalgesia. Thus, PAP-I mediates the neuron-microglial crosstalk after peripheral nerve injury, and contributes to the maintenance of neuropathic pain.Neuropathic pain is maladaptive pain condition and the maintaining mechanism is largely unclear. Here we reveal that after peripheral nerve injury, PAP-I can be transported to the spinal dorsal horn and is crucial in the progression of neuropathic pain. Importantly, we prove that PAP-I mainly functions through activating the spinal microglia via CCR2-p38 MAPK pathway. Furthermore, we confirm that the pro-inflammatory effect of PAP-I is more prominent after the establishment of neuropathic pain, thus indicating that microglia also participates in the maintenance phase of neuropathic pain.
Learn More >Voltage-gated T-type Ca (Cav3) channels regulate diverse physiological events including neuronal excitability and have been linked to several pathological conditions such as absence epilepsy, cardiovascular diseases, and neuropathic pain. It is also acknowledged that Ca/Calmodulin-dependent protein kinase II (CaMKII) and protein kinases A and C (PKA and PKC) regulate the activity of T-type channels. Interestingly, peripheral nerve injury induces tactile allodynia and up-regulates Cav3.2 channels and Cdk5 in dorsal root ganglia (DRG) and spinal dorsal horn (SDH). Here, we report that recombinant Cav3.2 channels expressed in HEK-293 cells are regulatory targets of cyclin-dependent kinase 5 (Cdk5). Site-directed mutagenesis showed that the relevant sites for this regulation are residues S561 and S1987. We also found that Cdk5 may regulate Cav3.2 channel functional expression in rats with mechanical allodynia induced by spinal nerve ligation (SNL). Consequently, the Cdk5 inhibitor olomoucine affected the compound action potential (cAP) recorded in the spinal nerves, as well as the paw withdrawal threshold. Likewise, Cdk5 expression was upregulated after SNL in the DRGs. These findings unveil a novel mechanism for how phosphorylation may regulate Cav3.2 channels and suggest that increased channel activity by Cdk5-mediated phosphorylation after SNL contributes nerve injury-induced tactile allodynia.Neuropathic pain is a current public health challenge. It can develop as a result of injury or nerve illness. It is acknowledged that the expression of various ion channels can be altered in neuropathic pain, including T-type Ca channels that are expressed in sensory neurons where they play a role in the regulation of cellular excitability. The present work shows that the exacerbated expression of Cdk5 in a preclinical model of neuropathic pain increases the functional expression of Cav3.2 channels. This finding is relevant for the understanding of the molecular pathophysiology of the disease. Additionally, this work may have a substantial translational impact, since it describes a novel molecular pathway that could represent an interesting therapeutic alternative for neuropathic pain.
Learn More >Preventing and treating opioid dependence and withdrawal is a major clinical challenge, and the underlying mechanisms of opioid dependence and withdrawal remain elusive. We hypothesized that prolonged morphine exposure or chronic inflammation-induced μ-opioid receptor activity serves as a severe stress that elicit neuronal alterations and recapitulates events during development. Here, we report that Wnt signaling, which is important in developmental processes of the nervous system, plays a critical role in withdrawal symptoms from opioid receptor activation in mice. Repeated exposures of morphine or peripheral inflammation produced by intraplantar injection of Complete Freund's Adjuvant significantly increases the expression of Wnt5b in the primary sensory neurons in dorsal root ganglion (DRG). Accumulated Wnt5b in DRG neurons quickly transmits to the spinal cord dorsal horn (DH) following naloxone treatment. In the DH, Wnt5b, acts through the atypical Wnt-Ryk receptor and alternative Wnt-YAP/TAZ signaling pathways, contributing to the naloxone-precipitated opioid withdrawal-like behavioral symptoms and hyperalgesia. Inhibition of Wnt synthesis and blockage of Wnt signaling pathways greatly suppress the behavioral and neurochemical alterations after naloxone-precipitated withdrawal. These findings reveal a critical mechanism underlying naloxone-precipitated opioid withdrawal, suggesting that targeting Wnt5b synthesis in DRG neurons and Wnt signaling in DH may be an effective approach for prevention and treatment of opioid withdrawal syndromes, as well as the transition from acute to chronic pain.
Learn More >Many genetic markers have been associated with variations in treatment response to analgesics, but none have been assessed in the context of combination therapies. In this study, the treatment effects of nortriptyline and morphine were tested for association with genetic markers relevant to pain pathways. Treatment effects were determined for single and combination therapies. A total of 24 functional Single Nucleotide Polymorphisms (SNPs) were tested within the gene loci of OPRM1, ABCB1, CYP2C19 and CYP2D6, COMT and HTR2A. Genotyping was performed in a population of neuropathic pain patients that previously participated in a clinical trial. For monotherapy, neither nortriptyline nor morphine responses were associated with SNPs. However, for nortriptyline + morphine combination therapy, the SNP rs1045642, within the drug efflux pump ABCB1 transporter significantly predicted analgesic response. The presence of the C allele accounted for 51% of pain variance in this subgroup in response to combination treatment. The T-allele homozygotes demonstrated only 20% improvement in pain scores, while the C-allele homozygotes 88%. There was no significant contribution of rs1045642 to the medication side-effects under all treatment conditions. The UK Biobank dataset was then used to validate this genetic association. Here, patients receiving similar combination therapy (opioid + tricyclic antidepressant) carrying the C allele of rs1045642 displayed 33% fewer body pain sites than patients without that allele, suggesting better pain control. In all, our results show a robust effect of the rs1045642 polymorphism on response to chronic pain treatment with a nortriptyline + morphine combination.
Learn More >Evidence supports but is inconclusive that sensitization contributes to chronic pain in some adults with sickle cell disease (SCD). We determined the prevalence of pain sensitization among adults with SCD pain compared with pain-free healthy adults. In a cross sectional, single session study of 186 African American outpatients with SCD pain (age 18-74 years, 59% female) and 124 healthy age, gender, and race matched control subjects (age 18-69 years, 49% female), we compared responses to standard thermal (Medoc TSA II) and mechanical stimuli (von Frey filaments). Although we observed no significant differences in thermal thresholds between controls and patients, patients with SCD had lower pain thresholds to mechanical stimuli and reported higher pain intensity scores to all thermal and mechanical stimuli at a non-painful body site. Compared with controls, about twice as many patients with SCD showed sensitization: 12% versus 23% at the anterior forearm site (p=.02), and 16% versus 32% across three tested sites (p=.004). Among patients with SCD, 18% exhibited some element of central sensitization. Findings indicate that persistent allodynia and hyperalgesia can be part of the SCD pain experience and should be considered when selecting therapies for SCD pain. Perspective: Compared with matched healthy controls, quantitative sensory testing in adults with pain and sickle cell disease (SCD) demonstrates higher prevalence of sensitization, including central sensitization. The findings of allodynia and hyperalgesia may indicate neuropathic pain and could contribute to a paradigm shift in assessment and treatment of SCD pain.
Learn More >The experience of pain relief arises from physiological and psychological factors, and attributes such as the commercial features of analgesic treatments have been shown to influence placebo analgesia by affecting treatment expectations. Therefore, treatment valuation from price information should influence the placebo analgesic effect. This hypothesis was tested in a functional magnetic resonance imaging (fMRI) study in which healthy subjects were enrolled in a two-day experiment. On day 1, the participants (n=19) had treatment experiences with two different placebo creams during a conditioning session without receiving information on treatment price. On day 2, placebo analgesia was tested after providing price information (high vs. low) while fMRI was performed. The results showed that the higher-priced placebo treatment lead to enhanced pain relief. Placebo analgesia in response to the higher priced treatment was associated with activity in the ventral striatum, ventromedial prefrontal cortex and ventral tegmental area. The behavioral results indicate that the experience of pain was influenced by treatment valuation from price. Our findings reveal that the context of values in pain control is associated with activity in expectation- and reward-related circuitry. Perspective: Treatment with higher price was associated with enhanced placebo analgesia, and this effect was influenced by activities in expectation and reward processing brain areas. The context of value such as medical cost influences cognitive evaluation processes to modulate pain. Our study may help evaluate a patient's preference toward high-priced drugs.
Learn More >Voltage-gated sodium (Nav) channels respond to changes in the membrane potential of excitable cells through the concerted action of four voltage-sensor domains (VSDs). Subtype Nav1.7 plays an important role in the propagation of signals in pain-sensing neurons and is a target for the clinical development of novel analgesics. Certain inhibitory cystine knot (ICK) peptides produced by venomous animals potently modulate Nav1.7; however, the molecular mechanisms underlying their selective binding and activity remain elusive. This study reports on the design of a library of photoprobes based on the potent spider toxin Huwentoxin-IV and the determination of the toxin binding interface on VSD2 of Nav1.7 through a photocrosslinking and tandem mass spectrometry approach. Our Huwentoxin-IV probes selectively crosslink to extracellular loop S1-S2 and helix S3 of VSD2 in a chimeric channel system. Our results provide a strategy that will enable mapping of sites of interaction of other ICK peptides on Nav channels.
Learn More >Expectation interacting with nociceptive input can shape the perception of pain. It has been suggested that reward-related expectations are associated with the activation of the ventral tegmental area (VTA), which projects to the striatum (e.g., nucleus accumbens [NAc]) and prefrontal cortex (e.g., rostral anterior cingulate cortex [rACC]). However, the role of these projection pathways in encoding expectancy effects on pain remains unclear. In this study, we leveraged a visual cue conditioning paradigm with a long pain anticipation period and collected magnetic resonance imaging (MRI) data from 30 healthy human subjects (14 females). At the within-subject level, whole brain functional connectivity (FC) analyses showed that the mesocortical pathway (VTA-rACC FC) and the mesolimbic pathway (VTA-NAc FC) were enhanced with positive expectation but inhibited with negative expectation during pain anticipation period. Mediation analyses revealed that cue-based expectancy effects on pain were mainly mediated by the VTA-NAc FC, and structural equation modeling showed that VTA-based FC influenced pain perception by modulating pain-evoked brain responses. At the between-subject level, multivariate pattern analyses demonstrated that gray matter volumes in the VTA, NAc, and rACC were able to predict the magnitudes of conditioned pain responses associated with positive and/or negative expectations across subjects. Our results therefore advance the current understanding of how the reward system is linked to the interaction between expectation and pain. Furthermore, they provide precise functional and structural information on mesocorticolimibic pathways that encode within-subject and between-subject variability of expectancy effects on pain.Studies have suggested that reward-related expectation is associated with the activation of the ventral tegmental area (VTA), which projects to the striatum and prefrontal cortex. However, the role of these projection pathways in encoding expectancy effects on pain remains unclear. Using multi-modality MRI and a visual cue conditioning paradigm, we found that the functional connectivity and gray matter volumes in key regions (the VTA, nucleus accumbens, and rostral anterior cingulate cortex) within the mesocorticolimbic pathways encoded expectancy effects on pain. Our results advance the current understanding of how the reward system is linked to the interaction between expectation and pain, and provide precise functional and structural information on mesocorticolimbic pathways that encode expectancy effects on pain.
Learn More >Neuropathic pain is a debilitating condition caused by the abnormal processing of somatosensory input. Synaptic inhibition in the spinal dorsal horn plays a key role in that processing. Mechanical allodynia – the misperception of light touch as painful – occurs when inhibition is compromised. Disinhibition is due primarily to chloride dysregulation caused by hypofunction of the potassium-chloride co-transporter KCC2. Here we show, in rats, that excitatory neurons are disproportionately affected. This is not because chloride is differentially dysregulated in excitatory and inhibitory neurons, but, rather, because excitatory neurons rely more heavily on inhibition to counterbalance strong excitation. Receptive fields in both cell types have a center-surround organization but disinhibition unmasks more excitatory input to excitatory neurons. Differences in intrinsic excitability also affect how chloride dysregulation affects spiking. These results deepen understanding of how excitation and inhibition are normally balanced in the spinal dorsal horn, and how their imbalance disrupts somatosensory processing.
Learn More >Many studies suggest a strong familial component to fibromyalgia (FM). However, these studies have nearly all been confined to individuals with "primary" FM, i.e. FM without any other accompanying disorder. The current 2011-16 criteria for diagnosing FM construct a score using a combination of the number of painful body sites and the severity of somatic symptoms (FM-score). We estimated the genetic heritability of FM-score across sex and age groups to identify subgroups of individuals with greater heritability, which may help in the design of future genetic studies.
Learn More >Background Acute pain is a warning mechanism that exists to prevent tissue damage, however pain can outlast its protective purpose and persist beyond injury, becoming chronic. Chronic Pain is maladaptive and needs addressing as available medicines are only partially effective and cause severe side effects. There are profound differences between acute and chronic pain. Dramatic changes occur in both peripheral and central pathways resulting in the pain system being sensitised, thereby leading to exaggerated responses to noxious stimuli (hyperalgesia) and responses to non-noxious stimuli (allodynia). Critical role for immune system cells in chronic pain Preclinical models of neuropathic pain provide evidence for a critical mechanistic role for immune cells in the chronicity of pain. Importantly, human imaging studies are consistent with preclinical findings, with glial activation evident in the brain of patients experiencing chronic pain. Indeed, immune cells are no longer considered to be passive bystanders in the nervous system; a consensus is emerging that, through their communication with neurons, they can both propagate and maintain disease states, including neuropathic pain. The focus of this review is on the plastic changes that occur under neuropathic pain conditions at the site of nerve injury, the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. At these sites both endothelial damage and increased neuronal activity result in recruitment of monocytes/macrophages (peripherally) and activation of microglia (centrally), which release mediators that lead to sensitisation of neurons thereby enabling positive feedback that sustains chronic pain. Immune system reactions to peripheral nerve injuries At the site of peripheral nerve injury following chemotherapy treatment for cancer for example, the occurrence of endothelial activation results in recruitment of CX3C chemokine receptor 1 (CX3CR1)-expressing monocytes/macrophages, which sensitise nociceptive neurons through the release of reactive oxygen species (ROS) that activate transient receptor potential ankyrin 1 (TRPA1) channels to evoke a pain response. In the DRG, neuro-immune cross talk following peripheral nerve injury is accomplished through the release of extracellular vesicles by neurons, which are engulfed by nearby macrophages. These vesicles deliver several determinants including microRNAs (miRs), with the potential to afford long-term alterations in macrophages that impact pain mechanisms. On one hand the delivery of neuron-derived miR-21 to macrophages for example, polarises these cells towards a pro-inflammatory/pro-nociceptive phenotype; on the other hand, silencing miR-21 expression in sensory neurons prevents both development of neuropathic allodynia and recruitment of macrophages in the DRG. Immune system mechanisms in the central nervous system In the dorsal horn of the spinal cord, growing evidence over the last two decades has delineated signalling pathways that mediate neuron-microglia communication such as P2X4/BDNF/GABAA, P2X7/Cathepsin S/Fractalkine/CX3CR1, and CSF-1/CSF-1R/DAP12 pathway-dependent mechanisms. Conclusions and implications Definition of the modalities by which neuron and immune cells communicate at different locations of the pain pathway under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction and provides opportunities for novel approaches for the treatment of chronic pain.
Learn More >To provide a narrative review of clinical development programs for non-oral, non-injectable formulations of dihydroergotamine (DHE) for the treatment of migraine.
Learn More >Surgery is often accompanied by scar formation, which results in a pathological state called fibrosis. Fibrosis is characterized by the excess depositionof extracellular matrix molecules in the connective tissue, leading to tissue contracture and chronic pain. To understand the molecular mechanisms underlying these processes and their causative relationships, we performed comprehensive analyses of gene expression changes in the hind paw tissue of a mouse model established by generating a scar in the sole. Subcutaneous tissue was extensively stripped from the sole of the operation group mice, while a needle was inserted in the sole of the sham group mice. Pain threshold, as evaluated by mechanical stimulation with von Frey fiber, decreased rapidly in the operated (ipsilateral) paw and a day later inthe non-operated (contralateral) paw. The reductions were maintained for more than 3 weeks, suggesting that chronic pain spread to the other tissues via the central nervous system. RNA from the paw and the dorsal root ganglion (L3-5) tissues were subjected to microarray analyses 1 and 2 weeks following the operation. The expressions of a number of genes, especially those coding for extracellular matrix molecules and peripheral perceptivenerve receptors, were altered in the operation group mice paw tissues. The expression of few genes was altered in the dorsal root ganglion tissues; distinct upregulation of some nociceptive genes such as cholecystokinin B receptor was observed. Results of real-time polymerase chain reaction, and immune and histochemical staining of some of the gene products confirmed the results of the microarray analysis. Analyses using a novel mouse model revealed the extensive involvement of extracellular matrix-related genes and peripheral perceptive nerve receptor genes resulting in scar formation with chronic pain. Future bioinformatics analyses will explore the association between these relationships.
Learn More >Chronic pain is a complex trait that is moderately heritable and genetically, as well as phenotypically, correlated with major depressive disorder (MDD). Use of the conditional false discovery rate (cFDR) approach, which leverages pleiotropy identified from existing GWAS outputs, has been successful in discovering novel associated variants in related phenotypes. Here, genome-wide association study outputs for both von Korff chronic pain grade and for MDD were used to identify variants meeting a cFDR threshold for each outcome phenotype separately, as well as a conjunctional cFDR (ccFDR) threshold for both phenotypes together. Using a moderately conservative threshold, we identified a total of 11 novel single nucleotide polymorphisms (SNPs), six of which were associated with chronic pain grade and nine of which were associated with MDD. Four SNPs on chromosome 14 were associated with both chronic pain grade and MDD. SNPs associated only with chronic pain grade were located within SLC16A7 on chromosome 12. SNPs associated only with MDD were located either in a gene-dense region on chromosome 1 harbouring LINC01360, LRRIQ3, FPGT and FPGT-TNNI3K, or within/close to LRFN5 on chromosome 14. The SNPs associated with both outcomes were also located within LRFN5. Several of the SNPs on chromosomes 1 and 14 were identified as being associated with expression levels of nearby genes in the brain and central nervous system. Overall, using the cFDR approach, we identified several novel genetic loci associated with chronic pain and we describe likely pleiotropic effects of a recently identified MDD locus on chronic pain.
Learn More >The proper identification of chronic migraine is one of the mainstays for general practitioners. This study therefore aims to assess the epidemiology and determinants of chronic migraine in primary care in Italy by testing five operational case definition algorithms.
Learn More >Chronic pain after major lower back surgery is frequent. We investigated in adults the effect of perioperative low-dose ketamine on neuropathic lower back pain, assessed by the DN4 questionnaire, six and 12 months after major lower back surgery.
Learn More >Ecological research suggests that increased access to cannabis may facilitate reductions in opioid use and harms, and medical cannabis patients describe the substitution of opioids with cannabis for pain management. However, there is a lack of research using individual-level data to explore this question. We aimed to investigate the longitudinal association between frequency of cannabis use and illicit opioid use among people who use drugs (PWUD) experiencing chronic pain.
Learn More >Pain and depression are highly prevalent symptoms in cancer patients. They tend to occur simultaneously and affect each other and share biological pathways and neurotransmitters. In this study, we investigated the roles of microglia in the hippocampus in the comorbidity of bone cancer pain and depressive-like behaviors in an animal model of bone cancer pain.
Learn More >This paper examines the development of and some logistical and methodological issues surrounding the use of animal models of chronic pain. The first section addresses the emergent move towards mechanism-based and disease-related animal models of chronic pain that has accelerated since the late 1980s following publication of Bennett and Xie's (Pain 33:87-107, 1998) paper on chronic constriction injury of the sciatic nerve and Stein et al.'s (Pharmacol Biochem Behav 31:445-451, 1988) paper on unilateral hind paw inflammation with complete Freund's adjuvant. The discussion covers vast areas of chronic pain models developed over the past 50 years, starting with the numerous neuropathic, inflammatory and central pain models, as well as the growing number of models developed to study various forms of chronic pain from chronic back pain to visceral pain. It also examines the advantages and disadvantages of tonic pain models, mechanism-based and disease-related models of chronic pain, including issues related to the novel discovery of injury- or disease-related pathophysiological processes, the expansion of testing repertoires, and the successes and failures in the translation of analgesic development from animal preclinical models to human chronic pain conditions. The second section addresses experimental design considerations in the implementation of one of the 3Rs for the use of animal models of chronic pain; that is methods employed to reduce the number of animals used. The discussion covers various issues including the advantages and disadvantages of repeated dose designs and within-group drug testing, including incremental dosing schedules, and crossover designs. It also examines concerns surrounding the stability of symptoms and measures, including varying durations of multiple symptoms and the potential development of nociceptive sensitization, as well as possible use-dependent alterations in drug sensitivity and time-dependent changes in pain processes in specific animal models.
Learn More >Ketamine is a drug largely used in clinical practice as an anesthetic and it can also be used as an analgesic to manage chronic pain symptoms. Despite its interactions with several other signaling systems such as cholinergic, serotoninergic and adrenergic, it is accepted that NMDA receptor antagonism is the main mechanism of action of this drug. In this study we investigated the actions of endogenous opioids in the mechanism of peripheral analgesia induced by ketamine. The nociceptive threshold for mechanical stimuli was measured in Swiss mice using the Randall and Selitto test. The drugs used in this study were administered via intraplantar injection. Our results demonstrated that non selective opioid receptor antagonism (naloxone), selective μ- and δ-opioid receptors antagonism (clocinamox and naltrindole, respectively) but not κ-opioid receptor antagonism (nor-binaltorphimine NORBNI) antagonized ketamine-induced peripheral antinociception in a dose-dependent manner. In addition, administration of aminopeptidase inhibitor bestatin significantly potentiated ketamine-induced peripheral antinociception. Ketamine injection in the right hind paw induced β-endorphine synthesis in the epithelial tissue of the hindpaw. Together these results indicate a role for μ- and δ-opioid receptors and for the endogenous opioid β-endorphine increased synthesis in ketamine-induced peripheral analgesia mechanism of action.
Learn More >Pain is a common distressing symptom in children receiving pediatric palliative care. Both in children with cancer, but especially in children with progressive neurodegenerative and chromosomal conditions with CNS impairment pain is common, and often under-recognized and undertreated. Multimodal analgesia for children with serious illness acts synergistically for more effective pediatric pain and symptom control with fewer side effects than a single analgesic or modality. Successful pain treatment and prevention usually include integrative 'nonpharmacological' therapies, rehabilitation, psychology and spirituality in addition to pharmacology and regional anesthesia. This review article will address these effective components of multimodal pediatric analgesia and present starting doses of basic analgesia, opioids and adjuvants analgesia in infants, children and adolescents with serious illness.
Learn More >Bone Morphogenetic Protein-2/4 (BMP2/4) have been recognized as promoters of astrocyte activity. Substantial evidence suggests BMP2/4 may be elevated and play a critical role in astrocyte activation upon spinal cord injury. Although neuropathic pain (NP) is similarly associated with astrocyte activation, the participation of BMP2/4 in this regard still remains unclear. A rat model of NP achieved by spinal nerve ligation (SNL) at L5 was used to evaluate the expression of glial fibrillary acidic protein (GFAP) and BMP2/4 in the spinal cord in days 1, 4, 7, 10 and 14. Next, normal rats received intrathecal exogenous BMP2/4 and the antagonist Noggin to assess the effect of BMP2/4 on astrocyte activation. In both experiments, von Frey filaments were used to evaluate changes in paw withdrawal threshold (PWT). In addition, Western blotting and immunofluorescence were performed to assess the expression of glial fibrillary acidic protein (GFAP), BMP2/4, p-Smad 1/5/8, p-STAT3 in the spinal cord. Firstly, SNL caused a significant increase in the expression of BMP4, while BMP2 levels remained unchanged. Secondly, exogenous BMP4 but not BMP2 induced a significant decrease in PWT, along with upregulation of GFAP. Moreover, exogenous BMP4 stimulated both p-Smad 1/5/8 and p-STAT3, while BMP2 only upregulated p-Smad 1/5/8. Finally, exogenous Noggin alleviated the decrease in PWT induced by BMP4, and reduced astrocyte activation, as well as p-STAT3 upregulation. Our results indicate only BMP4-and not BMP2-intervened in allodynia in rats by eliciting glial activation, probably through both p-Smad 1/5/8 andp-STAT3 signaling.
Learn More >Small fiber neuropathies (SFN) are associated with a reduction in quality of life. In adults, epidermal nerve fiber density (END) analysis is recommended for the diagnosis of SFN. In children, END assessment is not often performed. We analyzed small nerve fiber innervation to elucidate the potential diagnostic role of skin biopsies in young patients with pain.
Learn More >Headache associated with ischemic stroke is poorly understood. To gain further insight, we systematically reviewed studies examining the prevalence and characteristics of new-onset poststroke headache.
Learn More >Mounting evidence suggests that antiretroviral therapy (ART) drugs may contribute to the prevalence of HIV-associated neurological dysfunction. The HIV envelope glycoprotein (gp120) is neurotoxic and has been linked to alterations in mitochondrial function and increased inflammatory gene expression, which are common neuropathological findings in HIV+ cases on ART with neurological disorders. Tenofovir disproxil fumarate (TDF) has been shown to affect neurogenesis in brains of mice and mitochondria in neurons. In this study, we hypothesized that TDF contributes to neurotoxicity by modulating mitochondrial biogenesis and inflammatory pathways. TDF administered to wild-type (wt) and GFAP-gp120 transgenic (tg) mice caused peripheral neuropathy, as indicated by nerve conduction slowing and thermal hyperalgesia. Conversely TDF protected gp120-tg mice from cognitive dysfunction. In the brains of wt and gp120-tg mice, TDF decreased expression of mitochondrial transcription factor A (TFAM). However, double immunolabelling revealed that TFAM was reduced in neurons and increased in astroglia in the hippocampi of TDF-treated wt and gp120-tg mice. TDF also increased expression of GFAP and decreased expression of IBA1 in the wt and gp120-tg mice. TDF increased tumor necrosis factor (TNF) α in wt mice. However, TDF reduced interleukin (IL) 1β and TNFα mRNA in gp120-tg mouse brains. Primary human astroglia were exposed to increasing doses of TDF for 24 hours and then analyzed for mitochondrial alterations and inflammatory gene expression. In astroglia, TDF caused a dose-dependent increase in oxygen consumption rate, extracellular acidification rate and spare respiratory capacity, changes consistent with increased metabolism. TDF also reduced IL-1β-mediated increases in IL-1β and TNFα mRNA. These data demonstrate that TDF causes peripheral neuropathy in mice and alterations in inflammatory signaling and mitochondrial activity in the brain.
Learn More >Chronic low back pain (CLBP) is a highly prevalent and significant cause of disability which is often resistant to pharmacological management. Virtual reality (VR) is an emerging technology with the potential to influence CLBP, and has been suggested as an alternative to opioids for pain management. VR is a goalfocused, computer-simulated reality allowing modification of the user's experience of their perceived world. A narrative review of peer-reviewed literature using a systematic search strategy, and sole reviewer for data extraction. VR has demonstrated effectiveness in reducing acute, experimental and chronic pain. This review describes the theoretical basis of the therapeutic effects of VR on CLBP via three distinct mechanisms: distraction, neuromodulation and graded exposure therapy. Furthermore, clinical application will be considered, including discussion of ethical issues associated with the technology.Implications for rehabilitationVirtual reality (VR) is suggested as an alternative for opioids in the management of acute and chronic pain.The therapeutic mechanisms of VR in chronic low back pain (CLBP) are equivocal but include distraction, neuromodulation of body perception and graded exposure therapy.VR may show greater efficacy in patients with CLBP with associated kinesiophobia.VR may show greater effect with increased immersion.
Learn More >The present study investigated the role and molecular mechanism of long non‑coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript (MALAT)1 in neuropathic pain in rat chronic constriction injury (CCI) model. Reverse transcription‑quantitative PCR and western blot analysis were used to detect the expression levels of MALAT1, microRNA (miR)‑154‑5p and aquaporin (AQP)9 in spinal cord tissue and microglia of CCI rats. ELISA and pain behavioral assays were used to observe the effect of MALAT1 on neuropathic pain and neuroinflammation in model rats, and to verify its molecular mechanism through bioinformatics and luciferase experiments. The results of the present study identified that the expression levels of MALAT1 and AQP9 were upregulated, while miR‑154‑5p was downregulated in spinal cord tissue and microglia of CCI rats. MALAT1 knockdown in CCI model rats significantly induced the occurrence of neuropathic pain, while the upregulation of miR‑154‑5p could reverse this process. The present study also identified that miR‑154‑5p was the target gene of MALAT1, and AQP9 was the target gene of miR‑154‑5p. AQP9 knockdown promoted the occurrence of neuropathic pain. In conclusion, lncRNA MALAT1 promotes the progression of neuropathic pain in rats by reducing miR‑154‑5p and increasing AQP9. The MALAT1/miR‑154‑5p/AQP9 axis can be used as a new therapeutic target for neuropathic pain.
Learn More >Lasmiditan demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed Phase 3 trials, SAMURAI and SPARTAN. Post-hoc integrated analyses evaluated the efficacy of lasmiditan in patients who reported a good or insufficient response to triptans and in those who were triptan naïve.
Learn More >Resting state (RS) functional connectivity (FC) abnormalities of brain networks involved in pain- and multisensory processing have been disclosed in adult-migraine patients. We explored RS FC of large-scale brain networks in pediatric-migraine patients and their correlation with patients' clinical characteristics. RS functional MRI data was acquired from 13 pediatric-migraine patients and 14 age- and sex-matched controls. Intra- and inter-network RS FC differences between patients and controls were evaluated. Correlations between RS FC abnormalities and patients' clinical characteristics were also assessed. Compared to controls, pediatric-migraine patients had a decreased RS FC of the left parieto-occipital junction of the default mode network (DMN) and left-dorsolateral prefrontal cortex of the executive control network (ECN). They also experienced an increased RS FC of the right frontopolar cortex of the right frontoparietal network (FPN) and the right-middle occipital gyrus of the secondary visual network. A significant stronger connectivity between the ECN and primary visual network and between the right FPN and primary sensorimotor, primary visual and auditory networks were found in migraine patients compared to controls. A significant weaker connectivity between the DMN and right FPN was revealed in migraineurs compared to controls. No correlation was found between intra- and inter-network RS FC abnormalities and patients' clinical characteristics. Pediatric-migraine patients harbor significant RS FC abnormalities in brain networks involved in multisensory processing and in the cognitive control of pain. An early dysregulation of multisensory processing, including pain, might represent a phenotypic biomarker of the disease.
Learn More >The array of end organ innervations of the vagus nerve, coupled with increased basic science evidence, has led to vagus nerve stimulation (VNS) being explored as a management option in a number of clinical disorders, such as heart failure, migraine and inflammatory bowel disease. Both invasive (surgically implanted) and non-invasive (transcutaneous) techniques of VNS exist. Transcutaneous VNS (tVNS) delivery systems rely on the cutaneous distribution of vagal afferents, either at the external ear (auricular branch of the vagus nerve) or at the neck (cervical branch of the vagus nerve), thus obviating the need for surgical implantation of a VNS delivery device and facilitating further investigations across a wide range of uses. The concept of electrically stimulating the auricular branch of the vagus nerve (ABVN), which provides somatosensory innervation to several aspects of the external ear, is relatively more recent compared with cervical VNS; thus, there is a relative paucity of literature surrounding its operation and functionality. Despite the increasing body of research exploring the therapeutic uses of auricular transcutaneous VNS (tVNS), a comprehensive review of the cutaneous, intracranial and central distribution of ABVN fibres has not been conducted to date. A review of the literature exploring the neuroanatomical basis of this neuromodulatory therapy is therefore timely. Our review article explores the neuroanatomy of the ABVN with reference to (1) clinical surveys examining Arnold's reflex, (2) cadaveric studies, (3) fMRI studies, (4) electrophysiological studies, (5) acupuncture studies, (6) retrograde tracing studies and (7) studies measuring changes in autonomic (cardiovascular) parameters in response to auricular tVNS. We also provide an overview of the fibre composition of the ABVN and the effects of auricular tVNS on the central nervous system. Cadaveric studies, of which a limited number exist in the literature, would be the 'gold-standard' approach to studying the cutaneous map of the ABVN; thus, there is a need for more such studies to be conducted. Functional magnetic resonance imaging (fMRI) represents a useful surrogate modality for discerning the auricular sites most likely innervated by the ABVN and the most promising locations for auricular tVNS. However, given the heterogeneity in the results of such investigations and the various limitations of using fMRI, the current literature lacks a clear consensus on the auricular sites that are most densely innervated by the ABVN and whether the brain regions secondarily activated by electrical auricular tVNS depend on specific parameters. At present, it is reasonable to surmise that the concha and inner tragus are suitable locations for vagal modulation. Given the therapeutic potential of auricular tVNS, there remains a need for the cutaneous map of the ABVN to be further refined and the effects of various stimulation parameters and stimulation sites to be determined.
Learn More >Sickle cell disease (SCD) is a group of inherited disorders of haemoglobin (Hb) structure in a person who has inherited two mutant globin genes (one from each parent), at least one of which is always the sickle mutation. It is estimated that between 5% and 7% of the world's population are carriers of the mutant Hb gene, and SCD is the most commonly inherited blood disorder. SCD is characterized by distorted sickle-shaped red blood cells. Manifestations of the disease are attributed to either haemolysis (premature red cell destruction) or vaso-occlusion (obstruction of blood flow, the most common manifestation). Shortened lifespans are attributable to serious comorbidities associated with the disease, including renal failure, acute cholecystitis, pulmonary hypertension, aplastic crisis, pulmonary embolus, stroke, acute chest syndrome, and sepsis. Vaso-occlusion can lead to an acute, painful crisis (sickle cell crisis, vaso-occlusive crisis (VOC) or vaso-occlusive episode). Pain is most often reported in the joints, extremities, back or chest, but it can occur anywhere and can last for several days or weeks. The bone and muscle pain experienced during a sickle cell crisis is both acute and recurrent. Key pharmacological treatments for VOC include opioid analgesics, non-opioid analgesics, and combinations of drugs. Non-pharmacological approaches, such as relaxation, hypnosis, heat, ice and acupuncture, have been used in conjunction to rehydrating the patient and reduce the sickling process.
Learn More >We previously demonstrated that acetaminophen (AcAP) has to be metabolized in the brain by fatty acid amide hydrolase enzyme (FAAH) into AM404 (N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide) to recruit CB1 and TRPV1 receptors, responsible for its analgesic effect. However, the brain mechanisms supporting AcAP-induced analgesia remain unknown.
Learn More >Remifentanil induces hyperalgesia, but the underlying mechanisms are not fully understood. Acid-sensing ion channel 3 (ASIC3) plays a regulatory role in the pain pathway. This study aimed to explore the effect of remifentanil administration on postoperative pain and on ASIC3 expression at the prespinal and supraspinal levels in a rat model.
Learn More >Lung cancer surgery is among the surgical procedures associated with the highest prevalence of pain, but prospective longitudinal studies following the pain trajectory are scarce.
Learn More >It has been demonstrated that smoking is associated with an increase in postoperative and chronic pain. The changes in the pain-related neural pathways responsible for these effects are unknown. Additionally, the effects of nicotine withdrawal, resulting from smoking abstinence preoperatively, has not been evaluated in terms of its impact on pain sensation. In this study, an animal model has been used to assess these effects. A rat model of long-term nicotine exposure was used. Von Frey mechanical sensory tests were performed. Western Blot and immunohistological analysis were conducted on spinal cord samples. Mechanical sensory thresholds increased in the initial period (1-3 weeks), indicating hyposensitivity. Long-term (4 -10 weeks) and under nicotine withdrawal, the mechanical sensory thresholds decreased, indicating hyperalgesia. During short-term nicotine exposure, glutamate decarboxylase 67 (GAD67), GAD65, and μ-opioid receptors (MOR) up-regulated. Beta-endorphins down-regulated. Increased γ -aminobutyric acid (GABA) and MOR appear responsible for the hyposensitivity since the GABA receptor antagonist, bicuculline and opioid receptor antagonist, naloxone decreased the mechanical thresholds of nicotine-induced hyposensitivity. In long-term nicotine exposure, the expression of GAD67, MOR, and GABA decreased. Baclofen, a derivative of GABA, reversed the hyperalgesia seen with nicotine withdrawal. Therefore, nicotine acts as an analgesic when used acutely or short-term. Long-term exposure or nicotine withdrawal (similar to smoking cessation) results in hyperalgesia. Nicotine appears to alter pain sensitivity by affecting the expression of GAD65, GAD67, MOR, endorphins, and GABA. This may partially explain the increased pain and opioid use seen in chronic smokers in the postoperative period.
Learn More >Anterior midcingulate cortex (aMCC) has been shown to be involved in most of the functional imaging studies investigating acute pain. For 10-15 years, it has even been a main focus of interest for pain studies, considering that neurons in the aMCC could encode for pain intensity. This latter function is now presumed to occur in secondary somatosensory (SII) area and/or insular cortices, while anterior cingulate cortex (ACC) is supposed to sustain other functions such as pain-related attention, arousal, motor withdrawal reflex, pain modulations, and engagement of endogenous pain control system. The quantitative imaging studies have shown a rich density of opioid receptors in the ACC. Thus, the perigenual subdivision has been suggested to participate in top-down controls of pain, (including the placebo effects known to be opioid mediated), mainly (but not exclusively) through the connection between the orbitofrontal/subgenual ACC and the periaqueductal gray (PAG). From this rationale, this area may lead to neurosurgical targeting including electrical stimulation for intractable pain in the future. A number of imaging studies have also reported activity changes in the posterior cingulate cortex during pain and proposed its speculative involvement to modulate the conscious experience of pain according to elements from the context and awareness of the self and others.
Learn More >Familial hemiplegic migraine (FHM) is a group of genetic migraine, associated with hemiparesis and aura. Three causative different genes have been identified, all of which are involved in membrane ion transport. Among these, SCN1A encodes the voltage-gated Na channel Nav1.1, and FHM caused by mutations of SCN1A is named FHM3. For 7 of the 12 known FHM3-causing SCNA1 mutations functional consequences have been investigated, and even if gain of function effect seems to be a predominant phenotype, for several mutations conflicting results have been obtained and the available data do not reveal a univocal FHM3 pathomechanism.
Learn More >N-Acetylaspartylglutamate (NAAG) is the third most prevalent neurotransmitter in the mammalian nervous system, yet its therapeutic potential is only now being fully recognized. Drugs that inhibit the inactivation of NAAG by glutamate carboxypeptidase II (GCPII) increase its extracellular concentration and its activation of its receptor, mGluR3. These drugs warrant attention, as they are effective in animal models of several clinical disorders including stroke, traumatic brain injury and schizophrenia. In inflammatory and neuropathic pain studies, GCPII inhibitors moderated both the primary and secondary pain responses when given systemically, locally or in brain regions associated with the pain perception pathway. The finding that GCPII inhibition also moderated the motor and cognitive effects of ethanol intoxication led to the discovery of their procognitive efficacy in long-term memory tests in control mice and in short-term memory in a mouse model of Alzheimer's disease. NAAG and GCPII inhibitors respectively reduce cocaine self-administration and the rewarding effects of a synthetic stimulant. Most recently, GCPII inhibition also has been reported to be efficacious in a model of inflammatory bowel disease. GCPII was first discovered as a protein expressed by and released from metastatic prostate cells where it is known as prostate specific membrane antigen (PSMA). GCPII inhibitors with high affinity for this protein have been developed as prostate imaging and radiochemical therapies for prostate cancer. Taken together, these data militate in favor of the development and application of GCPII inhibitors in more advanced preclinical research as a prelude to clinical trials.
Learn More >Patients qualifying for Medicare disability have the highest rates of opioid use compared with older Medicare beneficiaries and commercial insurance beneficiaries. Research on opioid overdose deaths in this population can help identify appropriate interventions.
Learn More >Multiple sclerosis is an autoimmune disease with a distinct female bias, as well as a high prevalence of neuropathic pain in both sexes. The dorsal root ganglia (DRG) contain the primary sensory neurons that give rise to pain, and damage to these neurons may lead to neuropathic pain. Here, we investigate the sex differences of the DRG transcriptome in a mouse model of MS.
Learn More >Resting-state functional connectivity (FC) MRI has widely been used to understand migraine pathophysiology and to identify an imaging marker of the disorder. Here, we review what we have learned from FC studies.
Learn More >The purpose of this work is to determine the relationship between biomarkers of inflammation, structure, and pain with radiographic disc space narrowing (DSN) in community-based participants. A total of 74 participants (37 cases and 37 controls) enrolled in the Johnston County Osteoarthritis (OA) Project during 2006-2010 were selected. Cases had at least mild radiographic DSN and low back pain (LBP). Controls had neither radiographic evidence of DSN nor LBP. Measured analytes from human serum included N-cadherin, Keratin-19, Lumican, CXCL6, RANTES, IL-17, IL-6, BDNF, OPG and NPY. A standard dolorimeter measured pressure-pain threshold. Coefficients of variation (CVs) were used to evaluate inter- and intra-assay reliability. Participants with similar biomarker profiles were grouped together using cluster analysis. Binomial regression models were used to estimate risk ratios (RR) and 95% confidence intervals (CI) in propensity score matched models. Significant associations were found between radiographic DSN and OPG (RR=3.90 95% CI 1.83, 8.31), IL-6 (RR=2.54 95% CI 1.92, 3.36) and NPY (RR=2.06 95% CI 1.62, 2.63). Relative to a cluster with low levels of biomarkers, a cluster representing elevated levels of OPG, RANTES, Lumican, Keratin-19 and NPY (RR=3.04 95% CI 1.22, 7.54) and a cluster representing elevated levels of NPY (RR=2.91 95% CI 1.15, 7.39) were significantly associated with radiographic DSN. Clinical Significance: These findings suggest that individual and combinations of biochemical biomarkers may reflect radiographic DSN. This is just one step towards understanding the relationships between biochemical biomarkers and DSN that may lead to improved intervention delivery. This article is protected by copyright. All rights reserved.
Learn More >Chronic pain outcomes are traditionally defined in terms of ability and . A definition of adaptive functioning in the context of chronic pain beyond the mere absence of negative outcomes, is the ability to (i.e., experience emotional, psychological and social ; Keyes, 2002). We explored in two chronic pain samples the prevalence and sociodemographic, physical and psychological correlates of flourishing, and complemented this exploration with a similar examination of to help contextualize findings. Sample 1 ( = 1498) was a nationally representative sample. Subgroups included people with regular joint pain (1), regular joint pain and rheumatoid arthritis (2) and without chronic pain (3). Using chi-square tests we calculated the prevalence of both mental health outcomes and examined if people with or without chronic pain were more/less likely to flourish/at risk for psychopathology. Sample 2 ( = 238) concerned baseline data of a Randomized Controlled Trial on the effectiveness of Acceptance and Commitment Therapy for chronic pain (Trompetter et al., 2015b). We performed logistic regression analysis to identify flourishers/those at risk for depression. The Mental Health Continuum-Short Form was used to measure flourishing. The prevalence of flourishing was 34% (recurrent joint pain) and 38% (recurrent joint pain and arthritis) in sample 1, and 23% in sample 2. Compared to those without chronic pain, people with chronic pain were as likely to flourish, but more likely to be at risk for psychopathology. In sample 2, both flourishing and being at risk for depression were related foremost to correlates. While engaged living was the most important correlate of flourishing, pain catastrophizing and psychological inflexibility were most important correlates of being at risk for depression. In conclusion, people with chronic pain to flourish. Findings suggest that positive and negative chronic pain outcomes function on two different continua, with potentially unique protective and risk factors. The Psychological Flexibility model provides pathways to explain both poor and optimal functioning in the presence of chronic pain. A better understanding of people with chronic pain who are able to flourish can be a fruitful endeavor to improve chronic pain models and interventions.
Learn More >Previous research suggests that multisensory body illusions that alter the conscious bodily experience can modulate pain in osteoarthritis, which may be a result of modifying cortical misrepresentations of the painful body part. However, the longevity and underlying mechanisms of such illusion-induced analgesia is unknown.
Learn More >Lasmiditan is a centrally penetrant, highly selective 5-hydroxytryptamine (serotonin) receptor 1F (5HT ) agonist under development as a novel therapy for acute treatment of migraine. A phase 1 randomized, placebo- and positive-controlled crossover study assessed the abuse potential of lasmiditan in adult recreational polydrug users. Following a qualification phase, subjects were randomized into treatment sequences, each consisting of 5 study treatments: placebo, alprazolam 2 mg, lasmiditan 100, 200 (lasmiditan 100 and 200 mg are proposed therapeutic doses), and 400 mg (supratherapeutic). The abuse potential of lasmiditan was investigated and compared with alprazolam and with placebo using the maximal effect score (E ) of the Drug-Liking Visual Analog Scale as the primary end point. Lasmiditan was not similar to placebo in drug-liking scores at all doses tested, with a maximum difference observed with the lasmiditan 400-mg dose (upper 90% confidence limit on difference in least-squares [LS] means > 14 for all lasmiditan doses). Drug-liking scores for lasmiditan 400 mg were not significantly different from alprazolam (lower 90% confidence limit on difference in LS means < 5), but drug-liking scores at lower doses (100 and 200 mg) were significantly different from alprazolam. During the treatment phase, the incidence of treatment-emergent adverse events (TEAEs) increased with increasing dose of lasmiditan; all TEAEs reported with lasmiditan treatment were mild. Subjective drug-liking effects for lasmiditan versus placebo and versus alprazolam, and the safety and tolerability profile of lasmiditan suggest that lasmiditan has a low potential for abuse.
Learn More >Sepiapterin reductase has been identified as a potential drug target for neuropathic and inflammatory pain. Virtual screening was executed against a publicly available x-ray crystal structure of sepiapterin reductase. A set of structurally diverse and potent sepiapterin reductase inhibitors was identified. This set of compounds with favorable ligand efficiency and lipophilic efficiency are tractable for further optimization. An SAR follow-up library was synthesized based on one of the virtual screening hits exploring SAR.
Learn More >Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of N-cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaines were designed, synthesized and assayed, leading to the discovery of a benzylamine derivative (compound 4, SLL-039) as a highly selective and potent κ opioid agonist (κ, Ki=0.47 nM, κ/μ=682, κ/δ=283), which was confirmed by functional assays in vitro and antinociceptive assays in vivo. The in vivo effect could be blocked by pretreatment with the selective κ antagonist nor-BNI. Moreover, this compound did not induce sedation, a common dose limiting effect of κ opioid receptor agonists, at its analgesic dose compared to U50,488H. The dissociation of sedation/antinociception found in SLL-039 was assumed to be correlated with the occupation of its benzamide motif in a unique subsite involving V1182.63, W124EL1 and E209EL2.
Learn More >Aim of this study was to detect the expression of miR-15a in rats following chronic constriction injury (CCI) and to investigate the regulatory functions of miR-15a during neuropathic pain (NP) development.
Learn More >Neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) is a novel hypnotic and voltage-dependent blocker of T-type calcium channels. Here we examine its potential analgesic effects and adjuvant anesthetic properties using a post-surgical pain model in rodents.
Learn More >Hypnosis is a technique that induces changes in perceptual experience through response to specific suggestions. By means of functional neuroimaging, a large body of clinical and experimental studies has shown that hypnotic processes modify internal (self-awareness) as well as external (environmental awareness) brain networks. Objective quantifications of this kind permit the characterization of cerebral changes after hypnotic induction and its uses in the clinical setting. Hypnosedation is one such application, as it combines hypnosis with local anesthesia in patients undergoing surgery. The power of this technique lies in the avoidance of general anesthesia and its potential complications that emerge during and after surgery. Hypnosedation is associated with improved intraoperative comfort and reduced perioperative anxiety and pain. It ensures a faster recovery of the patient and diminishes the intraoperative requirements for sedative or analgesic drugs. Mechanisms underlying the modulation of pain perception under hypnotic conditions involve cortical and subcortical areas, mainly the anterior cingulate and prefrontal cortices as well as the basal ganglia and thalami. In that respect, hypnosis-induced analgesia is an effective and highly cost-effective alternative to sedation during surgery and symptom management.
Learn More >Ovarian hormones play an important role in pain perception, and are responsible, at least in part, for the pain threshold differences between the sexes. Modulation of pain and its perception are mediated by neurochemical changes in several pathways, affecting both the central and peripheral nervous systems. One of the most studied neurotransmitters related to pain disorders is serotonin. Estrogen can modify serotonin synthesis and metabolism, promoting a general increase in its tonic effects. Studies evaluating the relationship between serotonin and disorders such as irritable bowel syndrome, fibromyalgia, migraine, and other types of headache suggest a clear impact of this neurotransmitter, thereby increasing the interest in serotonin as a possible future therapeutic target. This literature review describes the importance of substances such as serotonin and ovarian hormones in pain perception and illustrates the relationship between those two, and their direct influence on the presentation of the aforementioned pain-related conditions. Additionally, we review the pathways and receptors implicated in each disorder. Finally, the objective was to stimulate future pharmacological research to experimentally evaluate the potential of serotonin modulators and ovarian hormones as therapeutic agents to regulate pain in specific subpopulations.
Learn More >Since it became available in the mid-2010s, dorsal root ganglion (DRG) stimulation has become part of the armamentarium to treat chronic pain. To date, one randomized controlled trial, and several studies of moderate sample size and various etiologies have been published on this topic. We conducted a pooled analysis to investigate the generalizability of individual studies and to identify differences in outcome between chronic pain etiologic subgroups and/or pain location.
Learn More >The transient receptor potential melastatin type 8 (TRPM8) receptor channel is expressed in primary afferent neurons where it is the main transducer of innocuous cold temperatures and also in a variety of tumors, where it is involved in progression and metastasis. Modulation of this channel by intracellular signaling pathways has therefore important clinical implications. We investigated the modulation of recombinant and natively expressed TRPM8 by the Src kinase, which is known to be involved in cancer pathophysiology and inflammation. Human TRPM8 expressed in HEK293T cells is constitutively tyrosine phosphorylated by Src which is expressed either heterologously or endogenously. Src action on TRPM8 potentiates its activity, as treatment with PP2, a selective Src kinase inhibitor, reduces both TRPM8 tyrosine phosphorylation and cold-induced channel activation. RNA interference directed against the Src kinase diminished the extent of PP2-induced functional downregulation of TRPM8, confirming that PP2 acts mainly through Src inhibition. Finally, the effect of PP2 on TRPM8 cold activation was reproduced in cultured rat dorsal root ganglion neurons, and this action was antagonized by the protein tyrosine phosphatase inhibitor pervanadate, confirming that TRPM8 activity is sensitive to the cellular balance between tyrosine kinases and phosphatases. This positive modulation of TRPM8 by Src kinase may be relevant for inflammatory pain and cancer signaling.
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