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Neuropathic pain causes severe suffering, and most patients are resistant to current therapies. A core element of neuropathic pain is the loss of inhibitory tone in the spinal cord. Previous studies have shown that foetal GABAergic neuron precursors can provide relief from pain. However, the source of these precursor cells and their multipotent status make them unsuitable for therapeutic use. Here, we extend these findings by showing, for the first time, that spinally transplanted, terminally differentiated human induced pluripotent stem cell-derived GABAergic (iGABAergic) neurons provide significant, long-term, and safe relief from neuropathic pain induced by peripheral nerve injury in mice. Furthermore, iGABAergic neuron transplants survive long term in the injured spinal cord and show evidence of synaptic integration. Together, this provides the proof in principle for the first viable GABAergic transplants to treat human neuropathic pain patients.
Learn More >Efficient and homogeneous in vitro generation of peripheral sensory neurons may provide a framework for novel drug screening platforms and disease models of touch and pain. We discover that, by overexpressing NGN2 and BRN3A, human pluripotent stem cells can be transcriptionally programmed to differentiate into a surprisingly uniform culture of cold- and mechano-sensing neurons. Although such a neuronal subtype is not found in mice, we identify molecular evidence for its existence in human sensory ganglia. Combining NGN2 and BRN3A programming with neural crest patterning, we produce two additional populations of sensory neurons, including a specialized touch receptor neuron subtype. Finally, we apply this system to model a rare inherited sensory disorder of touch and proprioception caused by inactivating mutations in PIEZO2. Together, these findings establish an approach to specify distinct sensory neuron subtypes in vitro, underscoring the utility of stem cell technology to capture human-specific features of physiology and disease.
Learn More >A recent study with Ca-sensitive-dyes in neurons in whole DRGs (Table 5) found that much lower percentages of nociceptors were polymodal-nociceptors (PMNs) (Emery , 2016), than the 50-80% values in many electrophysiological fiber studies. This conflict highlighted the lack of knowledge about percentages of nociceptor-subtypes in the DRG. This was analysed from intracellularly-recorded neurons in rat lumbar DRGs stimulated from outside the skin. Polymodal nociceptors (PMNs) were 11% of all neurons and 19% of all nociceptors. Most PMNs had C-fibers (CPMNs). Percentages of C-nociceptors that were CPMNs varied with receptive field (RF) depths, whether superficial (∼80%), dermal (25%), deep (0%) or cutaneous (superficial + dermal) (40%). This explains CPMN percentages 40-90%, being highest, in electrophysiological studies using cutaneous nerves, and lowest in studies that also include deep RFs, including ours, and the recent Ca-imaging studies in whole DRGs. Despite having been originally described in 1967 (Burgess and Perl), both Aβ-nociceptors and Aβ-moderate pressure receptors (MPRs) remain overlooked. Most A-fiber nociceptors in rodents have Aβ-fibers. Of rat lumbar Aβ-nociceptors with superficial RFs, 50% were MPRs with variable medium-low trkA-expression. Despite having conduction velocities at the two extremes for nociceptors, both CPMNs and MPRs have relatively low thresholds, superficial/epidermal RFs and low trkA-expression. For abbreviations used see Table 5.
Learn More >The transient receptor potential (TRP) superfamily of ion channels has garnered significant attention by the pharmaceutical industry. In particular, TRP channels showing high levels of expression in sensory neurons such as TRPV1, TRPA1, and TRPM8, have been considered as targets for indications where sensory neurons play a fundamental role, such as pain, itch, and asthma. Modeling these indications in rodents is challenging, especially in mice. The rat is the preferred species for pharmacological studies in pain, itch, and asthma, but until recently, genetic manipulation of the rat has been technically challenging. Here, using CRISPR technology, we have generated a TRPA1 KO rat to enable more sophisticated modeling of pain, itch, and asthma. We present a detailed phenotyping of the TRPA1 KO rat in models of pain, itch, and asthma that have previously only been investigated in the mouse. With the exception of nociception induced by direct TRPA1 activation, we have found that the TRPA1 KO rat shows apparently normal behavioral responses in multiple models of pain and itch. Immune cell infiltration into the lung in the rat OVA model of asthma, on the other hand, appears to be dependent on TRPA1, similar to was has been observed in TRPA1 KO mice. Our hope is that the TRPA1 KO rat will become a useful tool in further studies of TRPA1 as a drug target.
Learn More >C-LTMRs are known to convey affective aspects of touch and to modulate injury-induced pain in humans and mice. However, a role for these neurons in temperature sensation has been suggested, but not fully demonstrated. Here, we report that deletion of C-low-threshold mechanoreceptor (C-LTMR)-expressed bhlha9 causes impaired thermotaxis behavior and exacerbated formalin-evoked pain in male, but not female, mice. Positive modulators of GABA receptors failed to relieve inflammatory formalin pain and failed to decrease the frequency of spontaneous excitatory post-synaptic currents (sEPSCs) selectively in bhlha9 knockout (KO) males. This could be explained by a drastic change in the GABA content of lamina II inner inhibitory interneurons contacting C-LTMR central terminals. Finally, C-LTMR-specific deep RNA sequencing revealed more genes differentially expressed in male than in female bhlha9 KO C-LTMRs. Our data consolidate the role of C-LTMRs in modulation of formalin pain and provide in vivo evidence of their role in the discriminative aspects of temperature sensation.
Learn More >To identify and validate an fMRI-based neural marker for migraine without aura (MwoA) and to examine its association with treatment response.
Learn More >Improved understanding of brain mechanisms regulating endogenous analgesia is important from a fundamental physiological perspective and for identification of novel therapeutic strategies for pain. The endocannabinoid system plays a key role in stress-induced analgesia, including fear-conditioned analgesia (FCA), a potent form of endogenous analgesia. Here we studied the role of the endocannabinoid 2-arachidonoyl glycerol (2-AG) within the anterior cingulate cortex (ACC; a brain region implicated in the affective component of pain) in FCA in rats.
Learn More >Migraine with aura (MwA) is associated with increased brain hyper-responsiveness to visual stimuli and increased visual network connectivity relative to migraine without aura (MwoA). Despite this, prior studies have provided conflicting results regarding whether MwA is associated with higher photophobia symptom scores compared to MwoA. The relationships between MwA and other types of sensory hypersensitivity, such as phonophobia and cutaneous allodynia (CA), have not been previously investigated. The purpose of this cross-sectional observational study was to investigate whether MwA is associated with greater symptoms of photophobia, phonophobia, and CA compared to MwoA.
Learn More >Piezo1 ion channels are activated by mechanical stimuli and mediate the sensing of blood flow. Although cryo-electron microscopy (cryo-EM) structures have revealed the overall architecture of Piezo1, the precise domains involved in activation and subsequent inactivation have remained elusive. Here, we perform a targeted chimeric screen between Piezo1 and the closely related isoform Piezo2 and use electrophysiology to characterize their inactivation kinetics during mechanical stimulation. We identify three small subdomains within the extracellular cap that individually can confer the distinct kinetics of inactivation of Piezo2 onto Piezo1. We further show by cysteine crosslinking that conformational flexibility of these subdomains is required for mechanical activation to occur and that electrostatic interactions functionally couple the cap to the extensive blades, which have been proposed to function as sensors of membrane curvature and tension. This study provides a demonstration of internal gating motions involved in mechanotransduction by Piezo1.
Learn More >For patients with painful chronic pancreatitis, surgical treatment is postponed until medical and endoscopic treatment have failed. Observational studies have suggested that earlier surgery could mitigate disease progression, providing better pain control and preserving pancreatic function.
Learn More >Galanin is a neuropeptide expressed by sensory neurones innervating the gastrointestinal (GI) tract. Galanin displays inhibitory effects on vagal afferent signaling within the upper GI tract, and the goal of this study was to determine the actions of galanin on colonic spinal afferent function. Specifically, we sought to evaluate the effect of galanin on lumbar splanchnic nerve (LSN) mechanosensitivity to noxious distending pressures and the development of hypersensitivity in the presence of inflammatory stimuli and colitis. Using ex vivo electrophysiological recordings we show that galanin produces a dose-dependent suppression of colonic LSN responses to mechanical stimuli and prevents the development of hypersensitivity to acutely administered inflammatory mediators. Using galanin receptor (GalR) agonists, we show that GalR1 activation, but not GalR2/3 activation, suppresses mechanosensitivity. The effect of galanin on colonic afferent activity was not observed in tissue from mice with dextran sodium sulfate-induced colitis. We conclude that galanin has a marked suppressive effect on colonic mechanosensitivity at noxious distending pressures and prevents the acute development of mechanical hypersensitivity to inflammatory mediators, an effect not seen in the inflamed colon. These actions highlight a potential role for galanin in the regulation of mechanical nociception in the bowel and the therapeutic potential of targeting galaninergic signaling to treat visceral hypersensitivity.
Learn More >Early life administration of vincristine (VNC), commonly used to treat pediatric leukemia, evokes peripheral neuropathy and mechanical pain hypersensitivity in rats that lasts into adolescence. However, the degree to which VNC-evoked neuropathic pain persists throughout adulthood has yet to be examined. It also remains unclear if pediatric VNC exposure can 'prime' developing nociceptive pathways and thereby exacerbate chronic pain following subsequent trauma later in life. To address these issues, rats received five total doses of VNC (60 µg/kg; or vehicle) on postnatal days (P) 11, 13, 17, 19 and 21 followed by a hindpaw surgical incision during adulthood. In addition, in order to model the clinical scenario where cancer relapse necessitates another round of chemotherapy, separate groups of rats that had been treated with VNC (or vehicle) as neonates were subsequently administered VNC as adults (five injections at 100 µg/kg). Intraepidermal nerve fiber density and baseline mechanical pain sensitivity were similar between the neonatal VNC and vehicle-treated littermate controls at 13-15 weeks of age, suggesting that the peripheral neuropathy, and resulting chronic pain, had resolved by adulthood. Importantly, there was no significant overall effect of early life VNC on the severity of post-operative pain following adult incision. Similarly, prior VNC exposure did not significantly influence the degree of mechanical pain hypersensitivity produced by adult VNC treatment. Collectively, these findings suggest that early life VNC administration does not increase the susceptibility to develop chronic pain as adults.
Learn More >The midbrain periaqueductal grey (PAG) plays a central role in modulating pain through a descending pathway that projects indirectly to the spinal cord via the rostroventral medial medulla (RVM). While opioids are potent analgesics that target the PAG, their cellular actions on descending projection neurons are unclear.
Learn More >To characterize phenotypes of a novel CACNA1A mutation causing familial hemiplegic migraine type 1.
Learn More >We explore factors that may have contributed to differences in treatment-emergent adverse events in the phase 2 and phase 3 lasmiditan clinical trials.
Learn More >The hypothalamus plays a key role in both migraine and cluster headache (CH). As brain region-to-region structural correlations are believed to reflect structural and functional brain connectivity patterns, we assessed the structural covariance patterns between the volume of the hypothalamic region and vertex-by-vertex measurements of cortical thickness in patients with migraine and in those with CH relative to healthy controls (HC).
Learn More >Nearly 100 000 primary total knee replacements (TKR) are performed in the UK annually. The primary aim of TKR is pain relief, but 10%-34% of patients report chronic pain. The aim of this systematic review was to evaluate the effectiveness of presurgical interventions in preventing chronic pain after TKR.
Learn More >Opioid drugs are highly valued as potent analgesics; however, there are significant risks associated with long-term use because of their abuse liability. Opioids cause changes in ventral tegmental area (VTA) gene expression and cell activity that have been linked to addiction-related behaviors in rodent models. Here, we focus on VTA dopamine (DA) neurons and review the cellular, structural, and synaptic plasticity changes induced by acute and chronic opioid exposure. We also discuss many avenues for future research including determination of whether opioid neuroadaptations are specific for subpopulations of VTA DA neurons. A better understanding of the molecular adaptations within the cells and circuits that drive opioid abuse is crucial for the development of better treatments for substance use disorders and to create novel, safer pain-relieving therapeutics.
Learn More >Measuring altered nociceptive processing involved in chronic pain is difficult due to a lack of objective methods. Potential methods to characterize human nociceptive processing involve measuring neurophysiological activity and psychophysical responses to well-defined stimuli. To reliably measure neurophysiological activity in response to nociceptive stimulation using EEG, synchronized activation of nerve fibers and a large number of stimuli are required. On the other hand, to reliably measure psychophysical detection thresholds, selection of stimulus amplitudes around the detection threshold and many stimulus-response pairs are required. Combining the two techniques helps in quantifying the properties of nociceptive processing related to detected and non-detected stimuli around the detection threshold.The two techniques were combined in an experiment including 20 healthy participants to study the effect of intra-epidermal electrical stimulus properties (i.e. amplitude, single- or double-pulse and trial number) on the detection thresholds and vertex potentials. Generalized mixed regression and linear mixed regression were used to quantify the psychophysical detection probability and neurophysiological EEG responses, respectively.It was shown that the detection probability is significantly modulated by the stimulus amplitude, trial number, and the interaction between stimulus type and amplitude. Furthermore, EEG responses were significantly modulated by stimulus detection and trial number. Hence, we successfully demonstrated the possibility to simultaneously obtain information on psychophysical and neurophysiological properties of nociceptive processing. These results warrant further investigation of the potential of this method to observe altered nociceptive processing.
Learn More >Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) have been implicated in the trafficking of postsynaptic glutamate receptors, including N-methyl-D-aspartate (NMDA)-subtype glutamate receptors (NMDARs) that are critical for nociceptive plasticity and behavioral sensitization. However, the components of SNAREs complex involved in spinal nociceptive processing remain largely unknown. Here we found that SNAP25, syntaxin4, VAMP2 and Munc18-1 were localized at postsynaptic sites and formed the complex in the superficial lamina of spinal cord dorsal horn of rats. The complex formation between these SNAREs components were accelerated after intraplantar injection of complete Freund's adjuvant (CFA), pharmacological removal of GABAergic inhibition or activation of NMDAR in intact rats. The increased SNAP25/syntaxin4/VAMP2/Munc18-1 interaction facilitated the surface delivery and synaptic accumulation of NMDAR during inflammatory pain. Disruption of the molecular interaction between SNAP25 with its SNARE partners by using a blocking peptide derived from the C-terminus of SNAP25 effectively repressed the surface and synaptic accumulation of GluN2B-containing NMDARs in CFA-injected rats. This peptide also alleviated inflammatory mechanical allodynia and thermal hypersensitivity. These data suggested that SNAREs complex assembly in spinal cord dorsal horn was involved in the inflammatory pain hypersensitivity through promoting NMDAR synaptic trafficking.
Learn More >Spinal cord injury (SCI) produces both locomotor deficits and sensory dysfunction that greatly reduce the overall quality of life. Mechanisms underlying chronic pain include increased neuro-inflammation and changes in spinal processing of sensory signals, with reduced inhibitory GABAergic signaling a likely key player. Our previous research demonstrated that spinal transplantation of GABAergic neural progenitor cells (NPCs) reduced neuropathic pain while intensive locomotor training (ILT) could reduce development of pain and partially reverse already established pain behaviors. Therefore, we evaluate the potential mutually beneficial anti-hypersensitivity effects of NPC transplants cells in combination with early or delayed ILT. NPC transplants were done at 4 weeks post-SCI. ILT, using a progressive ramping treadmill protocol, was initiated either 5 days post-SCI (early: pain prevention group) or at 5 weeks post-SCI (delayed: to reverse established pain) in male Sprague Dawley rats. Results showed that either ILT alone or NPCs alone could partially attenuate SCI neuropathic pain behaviors in both prevention and reversal paradigms. However, the combination of ILT with NPC transplants significantly enhanced neuropathic pain reduction on most of the outcome measures including tests for allodynia, hyperalgesia, and ongoing pain. Immunocytochemical and neurochemical analyses showed decreased pro-inflammatory markers and spinal pathology with individual treatments; these measures were further improved by the combination of either early or delayed ILT and GABAergic cellular transplantation. Lumbar dorsal horn GABAergic neuronal and process density were nearly restored to normal levels by the combination treatment. Together, these interventions may provide a less hostile and more supportive environment for promoting functional restoration in the spinal dorsal horn and attenuation of neuropathic pain following SCI. These findings suggest mutually beneficial effects of ILT and NPC transplants for reducing SCI neuropathic pain.
Learn More >A proposed mechanism of chronic pain is dysregulation between the main inhibitory (GABA) and excitatory (glutamate) neurometabolites of the central nervous system. The level of these neurometabolites appears to differ in individual studies of people with pain compared to pain-free controls across different pain conditions. However, this has yet to be systematically investigated.
Learn More >Toll-like receptors (TLRs) have been implicated in pain and itch regulation. TLR2, a TLR family member that detects microbial membrane components, has been implicated in pathologic pain. However, the role of TLR2 in pruritic and nociceptive responses has not been thoroughly investigated. In this study, we found that TLR2 was expressed in mouse dorsal root ganglia (DRG) and trigeminal ganglia (TG) neurons. Itch and pain behaviors, including histamine-dependent and histamine-independent acute itching, acetone/diethyl ether/water and 2,4-dinitrofluorobenzene-induced chronic itching and inflammatory pain, were largely attenuated in TLR2 knockout (KO) mice. The TLR2 agonist Pam3CSK4, which targets TLR2/1 heterodimers, evoked pain and itch behavior, whereas lipoteichoic acid (LTA) and zymosan, which recognize TLR2/6 heterodimers, produced only pain response. The TLR2 agonist-induced nociceptive and pruritic behaviors were largely diminished in transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) KO mice. Finally, Pam3Csk4 and zymosan increased the [Ca2] in DRG neurons from wild-type mice. However, the enhancement of [Ca2] was largely inhibited in the DRG neurons from TRPV1 and TRPA1 KO mice. Our results demonstrate that TLR2 is involved in different itch and pain behaviors through activating TLR1/TLR2 or TLR6/TLR2 heterodimers via TRPV1 and TRPA1 channels.
Learn More >Postoperative pain relief is crucial for full recovery. With the ongoing opioid epidemic and the insufficient effect of acetaminophen on severe pain; non-steroidal anti-inflammatory drugs (NSAIDs) are heavily used to alleviate this pain. However, NSAIDs are known to inhibit postoperative healing of connective tissues by inhibiting prostaglandin signaling. Pain intensity, inflammatory mediators associated with wound healing and the pharmacological action of NSAIDs vary throughout the day due to the circadian rhythm regulated by the clock genes. According to this rhythm, most of wound healing mediators and connective tissue formation occurs during the resting phase, while pain, inflammation and tissue resorption occur during the active period of the day. Here we show, in a murine tibia fracture surgical model, that NSAIDs are most effective in managing postoperative pain, healing and recovery when drug administration is limited to the active phase of the circadian rhythm. Limiting NSAID treatment to the active phase of the circadian rhythm resulted in overexpression of circadian clock genes, such as Period 2 (Per2) at the healing callus, and increased serum levels of anti-inflammatory cytokines interleukin-13 (IL-13), interleukin-4 (IL-4) and vascular endothelial growth factor. By contrast, NSAID administration during the resting phase resulted in severe bone healing impairment.
Learn More >Previous attempts to develop a pragmatic human model for testing new anti-migraine drugs, have failed. Calcitonin gene-related peptide (CGRP) induces a mild headache in healthy volunteers and migraine-like headache in migraine patients. The induced headache must respond to already established migraine treatment for validation. Thus, the objective of the study was to test the effect of sumatriptan against CGRP-induced symptoms in an attempt to validate CGRP-induced headache as a model for drug testing.
Learn More >Knee osteoarthritis (OA) pain is the most common joint pain. Currently, dysfunction in the central nervous system rather than knee joint degeneration is considered to be the major cause of chronic knee OA pain; however, the underlying mechanism remains unknown. The aim of this study was to explore whether spinal NF-κB plays a critical role in chronic knee OA pain. In this study, we used a model induced by the intra-articular injection of monosodium iodoacetate (MIA). Spinal NF-κB and the phosphorylation and activation status of NF-κB p65/RelA (p-p65) were inhibited by the intrathecal injection of the inhibitor PDTC in this model. After behavioral assessment, the knee was dissected for histopathology, and the spinal cord was dissected and examined for NF-κB, p-p65 and cytokine expression. Furthermore, the quantity and activity of neurons, astrocytes and microglial cells and their colocalization with p-p65 in the spinal dorsal horn were investigated. Our findings included the following: (1) histology, the pathological changes in the joints of the knee OA model were basically consistent with knee OA patients; (2) the protein and transcription levels of NF-κB/p65 and p-p65 increased before day 14, appeared to decrease on day 21 and increased again on day 28, and the tendency of weight bearing was similar; (3) on days 21 and 28, the intrathecal injection of PDTC markedly prevented the MIA-induced reduction in the PWT; (4) real-time PCR demonstrated that the expression of TNF-α and IL-33 was suppressed in the knee OA model by the intrathecal injection of PDTC; And (5) immunofluorescence revealed that astrocytes were activated and that p-p65 was mainly increased in astrocytes. Our findings indicate that the spinal NF-κB/p65 pathway in astrocytes modulates neuroimmunity in rat model of intra-articular MIA-induced advanced osteoarthritis.
Learn More >Whilst sensory and sympathetic neurons are known to innervate bone, previous studies have found it difficult to unequivocally identify and characterise only those that are of sensory origin. In this study, we have utilized an in vivo anterograde tracing technique to selectively label spinal afferent (sensory) nerve endings that innervate the periosteum and marrow cavity of murine long bones. Unilateral injections of dextran-biotin (anterograde tracer; 20% in saline, 50-100 nL) were made into L3-L5 dorsal root ganglia (DRG). After a 10-day recovery period to allow sufficient time for selective anterograde transport of the tracer to nerve terminal endings in bone, the periosteum (whole-mount) and underlying bone were collected, processed to reveal anterograde labelling, and immuno-labelled with antibodies directed against protein gene product (pan-neuronal marker; PGP9.5), tyrosine hydroxylase (sympathetic neuron marker; TH), calcitonin gene-related protein (peptidergic nociceptor marker; CGRP) and/or neurofilament 200 (myelinated axon marker; NF200). Anterograde labelled nerve endings were dispersed throughout the periosteum and marrow cavity, and could be identified in close apposition to blood vessels and at sites distant from them. The periosteum and the marrow cavity were each innervated by myelinated (NF200+) sensory neurons, and unmyelinated (NF200-) sensory neurons that were either peptidergic (CGRP+) or non-peptidergic (CGRP-). Spinal afferent nerve endings did not express TH, and lacked the cylindrical morphology around blood vessels characteristic of sympathetic innervation. This approach to selective labelling of sensory nerve terminal endings will help to better identify how different sub-populations of sensory neurons, and their peripheral nerve terminal endings, interact with bone. This article is protected by copyright. All rights reserved.
Learn More >Investigate the potential role of (mu-opioid receptor) and (catechol-O-methyltransferase enzyme) polymorphisms in postoperative acute, chronic and experimental thermal pain. A secondary analysis of 125 adult cardiac surgery patients that were randomized between fentanyl and remifentanil during surgery and genotyped. Patients in the fentanyl group with the high-pain sensitivity haplotype required less postoperative morphine compared with the average-pain sensitivity haplotype (19.4 [16.5; 23.0] vs 34.6 [26.2; 41.4]; p = 0.00768), but not to the low-pain sensitivity group (30.1 [19.1; 37.7]; p = 0.13). No association was found between haplotype and other pain outcomes or polymorphisms and the different pain modalities. haplotype appears to explain part of the variability in acute postoperative pain in adult cardiac surgery patients.
Learn More >Although astrocytes are known to regulate synaptic transmission and affect new memory formation by influencing long-term potentiation and functional synaptic plasticity, their role in pain modulation is poorly understood. Motor cortex stimulation (MCS) has been used to reduce neuropathic pain through the incertothalamic pathway, including the primary motor cortex (M1) and the zona incerta (ZI). However, there has been no in-depth study of these modulatory effects and region-specific changes in neural plasticity. In this study, we investigated the effects of MCS-induced pain modulation as well as the relationship between the ZI neuroplasticity and MCS-induced pain alleviation in neuropathic pain (NP). MCS-induced threshold changes were evaluated after daily MCS. Then, the morphological changes of glial cells were compared by tissue staining. In order to quantify the neuroplasticity, MAP2, PSD95, and synapsin in the ZI and M1 were measured and analyzed with western blot. In behavioral test, repetitive MCS reduced NP in nerve-injured rats. We also observed recovered GFAP expression in the NP with MCS rats. In the NP with sham MCS rats, increased CD68 level was observed. In the NP with MCS group, increased mGluR1 expression was observed. Analysis of synaptogenesis-related molecules in the M1 and ZI revealed that synaptic changes occured in the M1, and increased astrocytes in the ZI were more closely associated with pain alleviation after MCS. Our findings suggest that MCS may modulate the astrocyte activities in the ZI and synaptic changes in the M1. Our results may provide new insight into the important and numerous roles of astrocytes in the formation and function.
Learn More >Spinal cord injury (SCI) usually leads to acute neuronal death and delayed secondary degeneration, resulting in sensory dysfunction, paralysis, and chronic pain. Excessive excitation is one of the critical factors leading to secondary neural damage initiated by various insults. KCNQ/Kv7 channels are highly expressed in spinal neurons and axons, and play an important role in controlling their excitability. Enhancing KCNQ channel activity by using its specific opener retigabine could thus be a plausible treatment strategy to reduce the pathology following SCI. We produced contusive SCI at T10 in adult, male rats, which then received 10 consecutive days' treatment with retigabine or vehicle starting 3 hours or 3 days after contusion. Two different concentrations and two different delivery methods were applied. Delivery of retigabine via Alzet osmotic pumps, but not intraperitoneal injections 3 hours after contusion promoted recovery of locomotor function. Remarkably, retigabine delivery in both methods significantly attenuated the development of mechanical stimuli-induced hyperreflexia and spontaneous pain although no significant difference in the thermal threshold was observed. While retigabine delivered 3 days after contusion significantly attenuated the development of mechanical hypersensitivity and spontaneous pain, the locomotor function is not improved by the delayed treatments. Finally, we found that early application of retigabine attenuates the inflammatory activity in the spinal cord and increases the survival of white matter following SCI. Our results suggest that decreasing neuronal excitability by targeting KCNQ/Kv7 channels at acute stage aids the recovery of locomotor function and attenuates the development of neuropathic pain after SCI. SIGNIFICANCE STATEMENT: Several pharmacological interventions have been proposed for SCI treatment, but none have been shown to be both effective and safe in clinical trials. Necrotic neuronal death and chronic pain often are the cost of pathological neural excitation after SCI. We show that early brief application of retigabine could aid locomotor and sensory neurobehavioral recovery following SCI, supporting the use of this drug in the clinic to promote motor and sensory function in SCI patients.
Learn More >Neurons are an integral component of the immune system that functions to coordinate responses to bacterial pathogens. Sensory nociceptive neurons that can detect bacterial pathogens are found throughout the body with dense innervation of the intestinal tract. Here we assessed the role of these nerves in the coordination of host defenses to Citrobacter rodentium. Selective ablation of nociceptive neurons significantly increased bacterial burden 10 days post infection and delayed pathogen clearance. Since the sensory neuropeptide CGRP regulates host-responses during infection of the skin, lung, and small intestine, we assessed the role of CGRP receptor signaling during C. rodentium infection. Although CGRP receptor blockade reduced certain pro-inflammatory gene expression, bacterial burden and Il-22 expression was unaffected. Our data highlight that sensory nociceptive neurons exert a significant host protective role during C. rodentium infection, independent of CGRP receptor signaling.
Learn More >Chronic itch can be extremely devastating and, in many cases, difficult to treat. One challenge in treating itch disorders is the limited understanding of the multitude of chemical players involved in the communication of itch sensation from the peripheral to central nervous system. Neuropeptides are intercellular signaling molecules that are known to be involved in the transmission of itch signals from primary afferent neurons, which detect itch in the skin, to higher-order circuits in the spinal cord and brain. To investigate the role neuropeptides play in transmitting itch signals, we generated two mouse models of chronic itch-Acetone-Ether-Water (AEW, dry skin) and calcipotriol (MC903, atopic dermatitis). For peptide identification and quantitation, we analyzed the peptide content of dorsal root ganglia (DRG) and dorsal horn (DH) tissues from chronically itchy mice using liquid chromatography coupled to tandem mass spectrometry. De novo-assisted database searching facilitated the identification and quantitation of 335 peptides for DH MC903, 318 for DH AEW, 266 for DRG MC903, and 271 for DRG AEW. Of these quantifiable peptides, we detected 30 that were differentially regulated in the tested models, after accounting for multiple testing correction (q<0.1). These include several peptide candidates derived from neuropeptide precursors, such as proSAAS, protachykinin-1, proenkephalin and calcitonin gene-related peptide, some of them previously linked to itch. The peptides identified in this study may help elucidate our understanding about these debilitating disorders. Data are available via ProteomeXchange with identifier PXD015949.
Learn More >A systematic literature search was performed to identify studies that reported risk factors for persistent pain after childbirth. Many studies have sought to identify risk factors for post-delivery pain in different populations, using different methodologies and different outcome variables. Studies of several different but interrelated post-partum pain syndromes have been conducted. Factors strongly and specifically associated with persistent incisional scar pain after Caesarean delivery include a coexisting persistent pain problem in another part of the body and severe acute postoperative pain. For persistent vaginal and perineal pain, operative vaginal delivery and the magnitude of perineal trauma have been consistently linked. History of pregnancy-related and pre-pregnancy back pain and heavier body weight are robust risk factors for persistent back pain after pregnancy. Unfortunately, limitations, particularly small samples and lack of a priori sample size calculation designed to detect specific effect sizes for risk of persistent pain outcomes, preclude definitive conclusions about many other predictors and the strength of outcome associations. In future studies, assessments of specific phenotypes using a rigorous analysis with appropriate predetermined sample sizes and validated instruments are needed to allow elucidation of stronger and reliable associations. Interventional studies targeting the most robustly associated, modifiable risk factors, such as acute post-partum pain, may lead to solutions for the prevention and treatment of these common problems that impact a large population.
Learn More >Mu opioid receptor (MOPr) agonists are thought to produce analgesia via modulation of G-protein-coupled intracellular signalling pathways whereas the β-arrestin2 pathway is proposed to mediate opioid-related adverse effects. Here, we report the antinociception, constipation and respiratory depressant profile of CYX-6, a potent MOPr agonist that is also a delta and a kappa opioid receptor (DOPr/KOPr) antagonist and that lacks β-arrestin2 recruitment at each of the MOPr, DOPr and the KOPr. In anaesthetised male Sprague Dawley rats, an intracerebroventricular (i.c.v.) guide cannula was stereotaxically implanted. After 5-7 days post-surgical recovery, rats received a single i.c.v. bolus dose of CYX-6 (3-30 nmol), morphine (100 nmol) or vehicle. Antinociception was assessed using the warm water tail flick test (52.5 ± 0.5 °C). Constipation was assessed using the charcoal meal gut motility test and the castor oil-induced diarrhoea test. Respiratory depression was measured by whole-body plethysmography in awake, freely moving animals, upon exposure to a hypercapnic gas mixture (8% CO, 21% O and 71% N). The intrinsic pharmacology of CYX-6 given by the i.c.v. route in rats showed that it produced dose-dependent antinociception. It also produced respiratory stimulation rather than depression and it had a minimal effect on intestinal motility in contrast to the positive control, morphine. CYX-6 is an endomorphin-2 analogue that dissociates antinociception from constipation and respiratory depression in rats. Our findings provide useful insight to inform the discovery and development of novel opioid analgesics with a superior tolerability profile compared with morphine.
Learn More >Spinal cord injury (SCI) causes maladaptive changes to nociceptive synaptic circuits within the injured spinal cord. Changes also occur at remote regions including the brain stem, limbic system, cortex, and dorsal root ganglia. These maladaptive nociceptive synaptic circuits frequently cause neuronal hyperexcitability in the entire nervous system and enhance nociceptive transmission, resulting in chronic central neuropathic pain following SCI. The underlying mechanism of chronic neuropathic pain depends on the neuroanatomical structures and electrochemical communication between pre- and postsynaptic neuronal membranes, and propagation of synaptic transmission in the ascending pain pathways. In the nervous system, neurons are the only cell type that transmits nociceptive signals from peripheral receptors to supraspinal systems due to their neuroanatomical and electrophysiological properties. However, the entire range of nociceptive signaling is not mediated by any single neuron. Current literature describes regional studies of electrophysiological or neurochemical mechanisms for enhanced nociceptive transmission post-SCI, but few studies report the electrophysiological, neurochemical, and neuroanatomical changes across the entire nervous system following a regional SCI. We, along with others, have continuously described the enhanced nociceptive transmission in the spinal dorsal horn, brain stem, thalamus, and cortex in SCI-induced chronic central neuropathic pain condition, respectively. Thus, this review summarizes the current understanding of SCI-induced neuronal hyperexcitability and maladaptive nociceptive transmission in the entire nervous system that contributes to chronic central neuropathic pain.
Learn More >Neuromodulation therapies offer a treatment option that has minimal side effects and is relatively safe and potentially reversible. Spinal cord stimulation (SCS) has been used to treat various pain conditions for many decades. High-frequency SCS (HFSCS) involves the application of a single waveform at 10,000 Hz at a subthreshold level, therefore providing pain relief without any paresthesia.
Learn More >The TRPV1 ion channel is a neuronal sensor that plays an important role in nociception and neuropathic as well as inflammatory pain. In clinical trials, hyperthermia and thermo-hypoaesthesia turned out as major side effects of TRPV1 antagonists, preventing successful development of such molecules as analgesics. In vitro studies demonstrated that the TRPV1 ion channel is a polymodal sensor integrating stimuli from molecular modulators with temperature, pH and transmembrane potential. Temperature dependent gating is suggested to constitute the molecular basis for its role in heat sensation and body temperature regulation. Drug discovery scientists since many years seek to obtain "thermoneutral" TRPV1 inhibitors, blocking the channels sensitivity for painful stimuli while keeping its temperature mode of activation unaffected. Aiming for a screening rational for the identification of thermoneutral TRPV1 antagonists, we broadly characterized the prototypic small molecule TRPV1 inhibitors GRT12360V and GRTE16523. In vitro, GRT12360V demonstrated pan-modality inhibition on human, cynomolgus and rodent TRPV1, whereas GRTE16523 selectively bypassed the channels temperature mode on human and cynomolgus TRPV1 and revealed partial agonism on rodent channels. Strikingly, in vivo, GRT12360V induced hyperthermia in all species tested whereas GRTE16523 proved thermoneutral in cynomolgus monkeys and induced hypothermia in rodents. Hence, working out the different in vitro to in vivo correlations of two compounds, we suggest temperature dependent voltage gating as key parameter when screening for thermoneutral TRPV1 inhibitors. We highlight a species difference of molecular TRPV1 pharmacology between primates and rodents and provide a methodological breakthrough to engineer thermoneutral TRPV1 antagonists with improved therapeutic safety.
Learn More >Nausea and vomiting are often associated with opioid analgesia in cancer patients; however, only a subset of patients develop such side effects. Here, we tested the hypothesis that the occurrence of nausea and vomiting is modulated by the genetic background of the patients. Whole exome sequencing of DNA pools from patients with either low (n = 937) or high (n = 557) nausea and vomiting intensity, recruited in the European Pharmacogenetic Opioid Study, revealed a preliminary association of 53 polymorphisms. PCR-based genotyping of 45 of these polymorphisms in the individual patients of the same series confirmed the association for six SNPs in AIM1L, CLCC1, MUC16, PDE3A, POM121L2, and ZNF165 genes. Genotyping of the same 45 polymorphisms in 264 patients of the Italian CERP study, also treated with opioids for cancer pain, instead confirmed the association for two SNPs in ZNF568 and PDE3A genes. Only one SNP, rs12305038 in PDE3A, was confirmed in both series, although with opposite effects of the minor allele on the investigated phenotype. Overall, our findings suggest that genetic factors are indeed associated with nausea and vomiting in opioid-treated cancer patients, but the role of individual polymorphisms may be weak.
Learn More >Galcanezumab, a humanized monoclonal antibody that selectively binds to calcitonin gene-related peptide, has demonstrated a significant reduction in monthly migraine headache days in phase 2 and 3 trials. In these analyses, we aimed to evaluate the safety and tolerability of galcanezumab compared with placebo for prevention of episodic or chronic migraine.
Learn More >Pain is the vital sense preventing tissue damage by harmful noxious stimuli. The capsaicin receptor TRPV1 is activated by noxious temperatures, however, acute heat pain is only marginally affected in mice after TRPV1 knockout but completely eliminated in mice lacking TRPV1 positive fibers. Exploring contribution of candidate signal transduction mechanisms to heat pain in humans needs translational models.
Learn More >Endometriosis is chronic disorder with high socioeconomic impact defined by the presence of endometrial-like tissue ("lesions") outside the uterus. Genetic, hormonal, and immunological factors as well as endometrial progenitor cells are implicated in development of lesions. A hallmark of the disorder is chronic pain associated with neuroinflammation and changes in the CNS. Women with endometriosis are at increased risk of infertility. Current therapies are inadequate. To view this SnapShot, open or download the PDF.
Learn More >Multidisciplinary pain management programs (MPMP) for patients suffering from chronic back pain include a variety of treatment modalities. The patients' perceived helpfulness of these treatment modalities remains unclear. The aims of this prospective observational cohort study were to assess (i) the patients' perceived helpfulness of different treatment modalities, (ii) the influence of sociodemographic characteristics on the patient's perspective and (iii) whether treatment outcomes are affected by helpfulness ratings. Treatment modalities of this three-week MPMP consisted of individual physiotherapy, group-based physiotherapy, relaxation therapy, aquatic therapy, back education, medical training therapy, biofeedback, psychological pain therapy and music therapy. The study comprised 395 patients. The main outcome was the patients' perceived treatment helpfulness at the end of the program measured by a self-reported questionnaire ranging from 1 (not at all helpful) to 6 (extremely helpful). Secondary outcomes were treatment effects on pain, pain related disability, functional ability and level of depressive symptoms measured by self-reported questionnaires (NRS, PDI, FFbH-R, ADS-L). A total of 276 patients (22-64 years, 57% female) were available for overall analysis. Multivariate-analysis-of-variance- (MANOVA-) related results revealed that perceived treatment helpfulness (range 1-6) differed significantly between treatment modalities: individual physiotherapy (M = 5.00), group-based physiotherapy (M = 4.87), relaxation therapy (M = 4.6), aquatic therapy (M = 4.54), back education (M = 4.43), medical training therapy (M = 3.38), biofeedback (M = 3.31), psychological pain therapy (M = 3.15), music therapy (M = 3.02). Pain, pain related disability and levels of depressive symptoms significantly improved after the program ( < 0.001) whereas functional ability decreased ( < 0.01). Significant correlations were found between helpfulness ratings and sociodemographic data indicating that perceived treatment helpfulness was influenced by patient-related factors. Importantly, the degree of pain-related improvements was affected by the patients' perceived treatment helpfulness. In conclusion, patients' perceived treatment helpfulness differs significantly between treatment modalities and corresponds to treatment outcome.
Learn More >Cortical spreading depression (CSD) is a wave of transient network hyperexcitability leading to long lasting depolarization and block of firing, which initiates focally and slowly propagates in the cerebral cortex. It causes migraine aura and it has been implicated in the generation of migraine headache. Cortical excitability can be modulated by cholinergic actions, leading in neocortical slices to the generation of rhythmic synchronous activities (UP/DOWN states). We investigated the effect of cholinergic activation with the cholinomimetic agonist carbachol on CSD triggered with 130 mM KCl pulse injections in acute mouse neocortical brain slices, hypothesizing that the cholinergic-induced increase of cortical network excitability during UP states could facilitate CSD. We observed instead an inhibitory effect of cholinergic activation on both initiation and propagation of CSD, through the action of muscarinic receptors. In fact, carbachol-induced CSD inhibition was blocked by atropine or by the preferential M1 muscarinic antagonist telenzepine; the preferential M1 muscarinic agonist McN-A-343 inhibited CSD similarly to carbachol, and its effect was blocked by telenzepine. Recordings of spontaneous excitatory and inhibitory post-synaptic currents in pyramidal neurons showed that McN-A-343 induced overall a decrease of the excitatory/inhibitory ratio. This inhibitory action may be targeted for novel pharmacological approaches in the treatment of migraine with muscarinic agonists.
Learn More >The underlying mechanism of interstitial cystitis/bladder pain syndrome (IC/BPS) is not well understood and evaluation of current therapeutic interventions has not identified any generally effective treatments. Physical activity has shown beneficial effects on individuals suffering from chronic pain. Anxiety-prone rats exposed to water avoidance stress (WAS) develop urinary frequency and lower bladder sensory thresholds with high face and construct validity for the study of IC/BPS. The aim of this study was to evaluate the role of chronic voluntary exercise on urinary frequency, voiding function, and hyperalgesia in animals exposed to WAS.
Learn More >Epidermal keratinocytes express semaphorin (Sema) 3A, which is involved in the regulation of cutaneous innervation. However, the mechanisms underlying the intracellular signaling of Sema3A expression in keratinocytes remain unknown. We herein investigated signaling mechanisms for the induction of Sema3A expression in normal human epidermal keratinocytes (NHEKs). Sema3A expression transiently increased in calcium-stimulated NHEKs, but markedly decreased in terminally differentiated NHEKs. Sema3A mRNA mainly localized in the stratum basale and stratum suprabasale of the epidermis. The 5'-flanking region of the Sema3A gene was cloned, and a critical region for Sema3A promoter activity within -134 bp of the start codon was identified. Transcription factor binding sites, including that for activator protein (AP)-1, were found in this region. Sema3A expression was increased by the co-overexpression of JunB and Fra-2 in the presence of 0.1 or 1.4 mM calcium. The calcium-mediated transient up-regulation of Sema3A expression was significantly suppressed by mitogen-activated protein kinase [MAPK]/extracellular signal-regulated kinase [ERK] (MEK) 1/2 or AP-1 inhibitors. These results demonstrate that the calcium-mediated transient up-regulation of Sema3A in NHEKs is involved in the MEK/ERK and AP-1 signaling axis. Therefore, Sema3A mRNA may be expressed in the lower epidermis under controlled conditions by calcium via the MAPK-AP1 axis.
Learn More >The primary outcome of this study was to assess the efficacy and safety of preventive treatment with amitriptyline on headache frequency and severity after mild traumatic brain injury (mTBI).
Learn More >This article reviews current headache disability measures and clinical need, as well as presenting the rationale for a new measure addressing work-related disability in migraine patients and the steps devoted to this aim.
Learn More >the ageing global population and concomitant increase in the use of opioid analgesia have highlighted the need to evaluate the effectiveness of opioids for chronic pain in older people.
Learn More >Patients with migraine have a co-morbidity with vascular diseases such as hypertension, coronary heart disease, and stroke.
Learn More >Dorsal root ganglion (DRG) neurons process pain signaling through specialized nociceptors located in their peripheral endings. It has long been established low voltage-activated (LVA) Ca3.2 calcium channels control neuronal excitability during sensory perception in these neurons. Silencing Ca3.2 activity with antisense RNA or genetic ablation results in anti-nociceptive, anti-hyperalgesic and anti-allodynic effects. Ca3.2 channels are regulated by many proteins (Weiss and Zamponi, 2017), including KLHL1, a neuronal actin-binding protein that stabilizes channel activity by recycling it back to the plasma membrane through the recycling endosome. We explored whether manipulation of KLHL1 levels and thereby function as a Ca3.2 modifier can modulate DRG excitability and mechanical pain transmission or sensitivity to pain. We first assessed the mechanical sensitivity threshold and DRG properties in the KLHL1 KO mouse model. KO DRG neurons exhibited smaller T-type current density compared to WT without significant changes in voltage dependence, as expected in the absence of its modulator. Western blot analysis confirmed Ca3.2 but not Ca3.1, Ca3.3, Ca2.1, or Ca2.2 protein levels were significantly decreased; and reduced neuron excitability and decreased pain sensitivity were also found in the KLHL1 KO model. Analogously, transient down-regulation of KLHL1 levels in WT mice with viral delivery of anti-KLHL1 shRNA also resulted in decreased pain sensitivity. These two experimental approaches confirm KLHL1 as a physiological modulator of excitability and pain sensitivity, providing a novel target to control peripheral pain.
Learn More >There is growing evidence to support Acceptance and Commitment Therapy (ACT) in the management of chronic pain. However, there is a need for further research evaluating ACT combined with physical exercise, and few studies have assessed the long-term impact of this type of intervention. This case series reports on the acceptability and impact of an ACT-based multidisciplinary pain management programme on a range of health outcomes in both the short and long-term.
Learn More >Although headaches have recognized impact, there are no public policies in Brazil addressing this problem.
Learn More >EpiFibro (Brazilian Epidemiological Study of Fibromyalgia) was created to study patients with fibromyalgia (FM). Patients were included since 2011 according to the classification criteria for FM of the American College of Rheumatology of 1990 (ACR1990).
Learn More >To examine the effect of a case manager-assisted rehabilitation programme as an add-on to usual physical rehabilitation in patients undergoing lumbar spinal fusion.
Learn More >Chronic pain conditions are complicated and challenging to live with. Electronic health (eHealth) interventions show promise in helping people cope with chronic illness, including pain. The success of these interventions depends not only on the technology and intervention content but also on the users' acceptance and adherence. Involving all stakeholders (eg, patients, spouses, health care providers, designers, software developers, and researchers) and exploring their input and preferences in the design and development process is an important step toward developing meaningful interventions and possibly strengthening treatment outcomes.
Learn More >Glucagon-like peptide-1 receptor has anti-apoptotic, anti-inflammatory, and neuroprotective effects. It is now recognized that the occurrence and development of chronic pain are strongly associated with anti-inflammatory responses; however, it is not clear whether glucagon-like peptide-1 receptor regulates chronic pain via anti-inflammatory mechanisms. We explored the effects of glucagon-like peptide-1 receptor on nociception, cognition, and neuroinflammation in chronic pain. A rat model of chronic pain was established using left L5 spinal nerve ligation. The glucagon-like peptide-1 receptor agonist exendin-4 was intrathecally injected into rats from 10 to 21 days after spinal nerve ligation. Electrophysiological examinations showed that, after treatment with exendin-4, paw withdrawal frequency of the left limb was significantly reduced, and pain was relieved. In addition, in the Morris water maze test, escape latency increased and the time to reach the platform decreased following exendin-4 treatment. Immunohistochemical staining and western blot assays revealed an increase in the numbers of activated microglia and astrocytes in the dentate gyrus of rat hippocampus, as well as an increase in the expression of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6. All of these effects could be reversed by exendin-4 treatment. These findings suggest that exendin-4 can alleviate pain-induced neuroinflammatory responses and promote the recovery of cognitive function via the glucagon-like peptide-1 receptor pathway. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Renmin Hospital of Wuhan University of China (approval No. WDRM 20171214) on September 22, 2017.
Learn More >Medical cannabis (MC) is increasingly being used for treatment of chronic pain symptoms. Among patients there is also a growing preference for the use of MC to manage sleep problems. The aim of the current study was to examine the associations between use of whole plant cannabis and sleep problems among chronic pain patients.
Learn More >According to clinical guidelines, advice to stay active despite experiencing pain is recommended to patients with non-specific low back pain (LBP). However, not all patients receive guideline-concordant information and advice, and some patients still believe that activity avoidance will help them recover. The purpose was to study whether guideline-concordant beliefs among patients and other explanatory variables were associated with recovery. The main aim was to investigate whether believing staying active despite having pain is associated with a better functional outcome.
Learn More >Individuals exposed to trauma, especially those who develop posttraumatic stress disorder (PTSD), are at a higher risk of suffering from chronic pain as well as altered pain perception and modulation. However, the underlying mechanisms of these processes are yet to be established. Recent findings have indicated that trauma survivors tend to personify chronic pain that is developed after the exposure, in a way that resonates with the traumatic experience. The aim of this study was to test whether pain personification plays a significant role in explaining the long-term links between trauma, PTSD and pain.
Learn More >This study was to assess the clinical efficacy of epidural injections with tumor necrosis factor-alpha (TNF-α) inhibitor in patients with chronic radicular pain caused by lumbar spinal stenosis (LSS). In a randomized controlled trial (RCT), patients diagnosed with mild-to-moderate LSS underwent epidural intervention with three different drugs and were allocated to TNF-α inhibitor group (Group A), steroid group (Group B) and lidocaine-only group (Group C). All patients were evaluated by visual analog scale (VAS) for leg pain and Oswestry disability index (ODI) to assess function. They all received a 6-month follow-up. Ninety patients were randomly assigned to three groups, for 30 cases in each group. A total of 82 participants (91.1%) completed the follow-up. Pain relief and improvement of movement function after epidural administration in Group A were more significant than those of groups B and C ( < .05) during the 6-month follow-up, while it showed no significant difference between groups B and C ( > .05). Our results indicated that epidural administration with TNF-α inhibitor may be a useful conservative method for the treatment of radicular pain caused by LSS. ClinicalTrials.gov Identifier: NCT04062474.
Learn More >Purinergic transmitters such as adenosine, ADP, ATP, UTP, and UDP-glucose play important roles in a wide range of physiological processes, including the sleep-wake cycle, learning and memory, cardiovascular function, and the immune response. Moreover, impaired purinergic signaling has been implicated in various pathological conditions such as pain, migraine, epilepsy, and drug addiction. Examining the function of purinergic transmission in both health and disease requires direct, sensitive, non-invasive tools for monitoring structurally similar purinergic transmitters; ideally, these tools should have high spatial and temporal resolution in in vivo applications. Here, we review the recent progress with respect to the development and application of new methods for detecting purinergic transmitters, focusing on optical tools; in addition, we provide discussion regarding future perspectives.
Learn More >The trigeminal nerve (TGN) is the largest cranial nerve and can be involved in multiple inflammatory, compressive, ischemic or other pathologies. Currently, imaging-based approaches to identify the TGN mostly rely on T2-weighted magnetic resonance imaging (MRI), which provides localization of the cisternal portion of the TGN where the contrast between nerve and cerebrospinal fluid (CSF) is high enough to allow differentiation. The course of the TGN within the brainstem as well as anterior to the cisternal portion, however, is more difficult to display on traditional imaging sequences. An advanced imaging technique, diffusion MRI (dMRI), enables tracking of the trajectory of TGN fibers and has the potential to visualize anatomical regions of the TGN not seen on T2-weighted imaging. This may allow a more comprehensive assessment of the nerve in the context of pathology. To date, most work in TGN tracking has used clinical dMRI acquisitions with a b-value of 1000 s/mm and conventional diffusion tensor MRI (DTI) tractography methods. Though higher b-value acquisitions and multi-tensor tractography methods are known to be beneficial for tracking brain white matter fiber tracts, there have been no studies conducted to evaluate the performance of these advanced approaches on nerve tracking of the TGN, in particular on tracking different anatomical regions of the TGN.
Learn More >Psoriasis is a chronic inflammatory skin disease presenting with an array of clinical phenotypes, often associated with pruritus. Environmental and psychological stressors can exacerbate psoriasis symptoms and provoke flares. Recent studies suggest a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis in some patients with psoriasis that can result in immune dysregulation. The immune system, in turn, can communicate with the nervous system to induce, maintain or aggravate psoriasis. In the skin, peripheral sensory as well as autonomic nerves control release of inflammatory mediators from dendritic cells, mast cells, T cells or keratinocytes, thereby modulating inflammatory responses and, in case of sensory nerves, pruritus. In response to the environment or stress, cytokines, chemokines, proteases, and neuropeptides fluctuate in psoriasis and influence immune responses as well as nerve activity. Furthermore, immune cells communicate with sensory nerves which control release of cytokines such as IL-23, that are ultimately involved in psoriasis pathogenesis. Nerves also communicate with keratinocytes to induce epidermal proliferation. Notably, in contrast to recent years the debilitating problem of pruritus in psoriasis has been increasingly appreciated. Thus, investigating neuroimmune communication in psoriasis will not only expand our knowledge about the impact of sensory nerves in inflammation and pruritus and give new insights into the impact of environmental factors activating neuroimmune circuits or of stress in psoriasis, but may also lead to novel therapies. This review summarizes the relevant literature on the role of neuroimmune circuits, stress and how the central HPA axis and its peripheral equivalent in the skin, impact psoriasis.
Learn More >Lasmiditan (LY573144/COL-144) is a high-affinity, centrally penetrant, selective 5-HT receptor agonist currently under investigation for acute treatment of migraine. Although lasmiditan is not known to induce vasoconstriction, it remains important to understand its effect on cardiovascular parameters because it is likely to be coadministered with β-adrenergic receptor antagonists used for migraine prophylaxis, such as propranolol. This phase 1, single-center, open-label, fixed-sequence study evaluated the cardiovascular and pharmacokinetic effects of 200 mg lasmiditan in 44 healthy subjects receiving repeated oral doses of twice-daily 80 mg propranolol under fasting conditions. Coadministration caused statistically significant decreases in mean hourly heart rate relative to propranolol alone, but the maximum magnitude of this effect was -6.5 bpm and recovered to predose levels by 3 to 4 hours before stabilizing. Additionally, short-lived (≤2.5 hours) statistically significant increases in systolic blood pressure (8.3 mm Hg) and diastolic blood pressure (6.4 mm Hg) were observed following coadministration. Consistent with the largely nonoverlapping metabolic pathways of lasmiditan and propranolol, exposure to either drug was not affected by coadministration. Overall, compared with administration of either drug alone, coadministration was generally well tolerated.
Learn More >Chronic widespread pain (CWP) has a negative impact on health status, but results have varied regarding gender-related differences and reported health status. The aim was to study the impact of CWP on health status in women and men aged 35-54 years in a sample of the general population. The aim was further to investigate lifestyle-related predictors of better health status in those with CWP in a 12- and 21-year perspective.
Learn More >Systematic review of topical diclofenac for the treatment of acute and chronic musculoskeletal pain.
The objective was to systematically review the efficacy and safety of topically applied diclofenac in both acute and chronic musculoskeletal pain in adults. We used standard Cochrane methods. Searches were conducted in MEDLINE, EMBASE, and the Cochrane Register of Studies; the date of the final search was November 2018. Included studies had to be randomised and double blinded, with ten or more participants per treatment arm. Risk of bias was assessed. The primary outcome of "clinical success" was defined as participant-reported reduction in pain of at least 50%. Details of adverse events (AE) and numbers of withdrawals due to lack of efficacy (LoE) or AE were recorded. For acute pain, 23 studies (5170 participants) were included. All participants were treated for at least 5 days; most were treated for 7-14 days. Compared to placebo, number needed to treat (NNT) for different formulations were as follows: diclofenac flector plaster, 4.7 (95%CI 3.7-6.5); diclofenac plaster with heparin, 7.4 (95%CI 4.6-19); and diclofenac emulgel, 1.8 (95%CI 1.5-2.1).4.7% (65/1373) participants reported a systemic AE; 4.1% (78/1919) reported a local AE; and 1.3% (14/1063) withdrew due to an AE. Few participants withdrew due to LoE.For chronic pain, 21 studies (26 publications) with 5995 participants were included. The majority of studies focused on knee osteoarthritis pain. Formulations of diclofenac included gel, solution with or without DMSO, emulsion, and plaster. A clinical success rate of approximately 60% (NNT 9.5 [95%CI 7-14.7]) was achieved with a variety of diclofenac formulations. Local AEs (approximately 14%) were similar for both diclofenac and placebo. Event rate for systemic events was approximately 10%. Few serious events were reported, and between 0% and 17% of participants withdrew due to AEs. AEs were likely higher in the chronic group because participants were exposed to treatment for weeks rather than days. This large systematic review of over 11,000 participants demonstrates that topical diclofenac is effective for acute pain, such as sprains and strains, with minimal AEs. The effectiveness of topical diclofenac was also demonstrated in chronic musculoskeletal pain, such as osteoarthritis, but with a higher NNT (worse) compared with acute pain. Again, the incidence of AEs was low. Formulation does play a part in effectiveness, and studies are needed to investigate this further. Studies of chronic pain outside of osteoarthritis would also be helpful.
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