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There is strong evidence that spinoparabrachial neurons in the superficial dorsal horn contribute to persistent pain states, and that the lateral parabrachial complex (PB) conveys relevant nociceptive information to higher structures. The role of PB itself in hyperalgesia and how it recruits descending facilitation has nevertheless received significantly less attention. The current study is a first step towards delineating the functional dynamics of PB and its link to descending control in acute and persistent inflammatory pain. In lightly anesthetized rats, we recorded behavioral withdrawal evoked by mechanical stimulation of the hindpaw, and simultaneously, activity of identified pain-modulating neurons, "ON-cells" and "OFF-cells," in the rostral ventromedial medulla (RVM). This was done before and after inactivation of PB, or to an inflamed paw (1 h, 1 d, or 5-6 d after intraplantar injection of Complete Freund's adjuvant, CFA). Inactivation of but not PB interfered with nociceptive input to RVM under basal conditions, as well as in acute inflammation. By contrast, blocking , but not , PB in established inflammation interfered with behavioral hyperalgesia and ON- and OFF-cell responses. Lesion of PB prior to CFA injection prevented this recruitment of PB in persistent inflammation. These experiments show that PB is required to initiate hyperalgesia, which is then maintained by PB, most likely in both cases via engagement of pain-modulating neurons of the RVM.The lateral parabrachial complex (PB) relays nociceptive information to brain circuits important for transmission and modulation of pain, but its specific role in persistent pain and engagement of descending control mechanisms has received relatively little attention. We show here that PB and to an inflammatory insult demonstrate different functions as inflammation persists, likely by engaging pain-facilitating neurons of the rostral ventromedial medulla. While the PB, the target of the major spinoparabrachial pathway, relays acute nociceptive information, the PB is recruited or unmasked in persistent inflammation to maintain hyperalgesia. These data point to plasticity in the PB itself or its direct and indirect connections with pain-modulating systems as central to development and maintenance of persistent pain.
Learn More >Pain memories are hypothesized to be critically involved in the transition of pain from an acute to a chronic state. To help elucidate the underlying neurobiological mechanisms of pain memory, we developed novel paradigms to study context-dependent pain hypersensitivity in mouse and human subjects, respectively. We find that both mice and people become hypersensitive to acute, thermal nociception when tested in an environment previously associated with an aversive tonic pain experience. This sensitization persisted for at least 24 hr and was only present in males of both species. In mice, context-dependent pain hypersensitivity was abolished by castrating male mice, pharmacological blockade of the hypothalamic-pituitary-adrenal axis, or intracerebral or intrathecal injections of zeta inhibitory peptide (ZIP) known to block atypical protein kinase C (including the protein kinase Mζ isoform). In humans, men, but not women, self-reported higher levels of stress when tested in a room previously associated with tonic pain. These models provide a new, completely translatable means for studying the relationship between memory, pain, and stress.
Learn More >Individuals exhibit considerable and unpredictable variability in painful percepts in response to the same nociceptive stimulus. Previous work has found neural responses that, while not necessarily responsible for the painful percepts themselves, can still correlate well with intensity of pain perception within a given individual. However, there is no reliable neural response reflecting the variability in pain perception across individuals. Here, we use an electrophysiological approach in humans and rodents to demonstrate that brain oscillations in the gamma band [gamma-band event-related synchronization (γ-ERS)] sampled by central electrodes reliably predict pain sensitivity across individuals. We observed a clear dissociation between the large number of neural measures that reflected subjective pain ratings at within-subject level but not across individuals, and γ-ERS, which reliably distinguished subjective ratings within the same individual but also coded pain sensitivity across different individuals. Importantly, the ability of γ-ERS to track pain sensitivity across individuals was selective because it did not track the between-subject reported intensity of nonpainful but equally salient auditory, visual, and nonnociceptive somatosensory stimuli. These results also demonstrate that graded neural activity related to within-subject variability should be minimized to accurately investigate the relationship between nociceptive-evoked neural activities and pain sensitivity across individuals.
Learn More >In this issue of Neuron, Royal et al. (2018) find that a mutant form of the TRESK ion channel linked to migraine undergoes alternative translation to produce an inhibitory protein that blocks TREK channels, leading to neuronal hyperexcitability and migraine in rodents.
Learn More >Sensory problems, such as neuropathic pain, are common and debilitating symptoms in multiple sclerosis (MS), an autoimmune inflammatory disorder of the central nervous system (CNS). Regulatory T (Treg) cells are critical for maintaining immune homeostasis, however, their role in MS-associated pain remains unknown. Here, we demonstrate that Treg cell ablation is sufficient to trigger experimental autoimmune encephalomyelitis (EAE) and facial allodynia in immunised female mice. In EAE-induced female mice, adoptive transfer of Treg cells and spinal delivery of the Treg cell cytokine interleukin (IL)-35 significantly reduced facial stimulus-evoked pain and spontaneous pain independent of disease severity, and increased myelination of the facial nociceptive pathway. The effects of intrathecal IL-35 therapy were Treg cell-dependent, and were associated with upregulated IL-10 expression in CNS-infiltrating lymphocytes, and reduced monocyte infiltration in the trigeminal afferent pathway. Taken together, we present evidence for a beneficial role of Treg cells and IL-35 in attenuating pain associated with EAE, independently of motor symptoms, by decreasing neuroinflammation and increasing myelination.Pain is a highly prevalent symptom affecting the majority of multiple sclerosis (MS) patients and dramatically affects overall health-related quality-of-life, yet represents a research area that has been largely ignored. Here we identify, for the first time, a role for regulatory T cells and interleukin-35 in suppressing facial allodynia and facial grimacing in animals with experimental autoimmune encephalomyelitis (EAE). We demonstrate that spinal delivery of regulatory T cells and interleukin-35 reduces pain associated with EAE by decreasing neuroinflammation and increasing myelination, independently of motor symptoms. These findings increase our understanding of the mechanisms underlying pain in EAE, and suggest potential treatment strategies for pain relief in MS.
Learn More >Multiple sclerosis (MS) is a neurodegenerative autoimmune disease with many known structural and functional changes in the central nervous system (CNS). A well-recognized, but poorly understood, complication of MS is chronic pain. Little is known regarding the influence of sex on the development and maintenance of MS-related pain. This is important to consider, as MS is a predominantly female disease. Using the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we demonstrate sex differences in measures of spinal cord inflammation and plasticity that accompany tactile hypersensitivity. While we observed substantial inflammatory activity in both sexes, only male EAE mice exhibit robust staining of axonal injury markers and increased dendritic arborisation in morphology of deep dorsal horn neurons. We propose that tactile hypersensitivity in female EAE mice may be more immune-driven, while pain in male mice with EAE may rely more heavily on neurodegenerative and plasticity-related mechanisms. Morphological and inflammatory differences in the spinal cord associated with pain early in EAE progression supports the idea of differentially regulated pain pathways between the sexes. Results from this study may indicate future sex-specific targets that are worth investigating for their functional role in pain circuitry.
Learn More >Dysfunctions of genes transcription and translation in the nociceptive pathways play the critical role in development and maintenance of chronic pain. Circular RNAs (circRNAs) are emerging as new players in regulation of gene expression, but whether and how circRNAs are involved in chronic pain remains elusive. We showed here that complete Freund's adjuvant (CFA)-induced chronic inflammation pain significantly increased circRNA-Filip1l (filamin A interacting protein 1-like) expression in spinal neurons of mice. Blockage of this increase attenuated CFA-induced nociceptive behaviors, and overexpression of spinal circRNA-Filip1l in naïve mice mimicked the nociceptive behaviors as evidenced by decreased thermal and mechanical nociceptive threshold. Furthermore, we found that mature circRNA-Filip1l expression was negatively regulated by miRNA-1224 via binding and splicing of precursor of circRNA-Filip1l (pre-circRNA-Filip1l) in the Argonaute-2 (Ago2)-dependent manner. Increase of spinal circRNA-Filip1l expression resulted from the decrease of miRNA-1224 expression under chronic inflammation pain state. MiRNA-1224 knockdown or Ago2 overexpression induced nociceptive behaviors in naïve mice, which was prevented by the knockdown of spinal circRNA-Filip1l. Finally, we demonstrated that an ubiquitin protein ligase E3 component n-recognin 5 (Ubr5), validated as a target of circRNA-Filip1l, plays a pivotal role in regulation of nociception by spinal circRNA-Filip1l. These data suggest that miRNA-1224-mediated and Ago2-dependent modulation of spinal circRNA-Filip1l expression regulates nociception via targeting Ubr5, revealing a novel epigenetic mechanism of interaction between miRNA and circRNA in chronic inflammation pain.CircRNAs are emerging as new players in regulation of gene expression. Here, we found that the increase of circRNA-Filip1l mediated by miRNA-1224 in Ago2-dependent way in the spinal cord is involved in regulation of nociception via targeting Ubr5. Our study reveals a novel epigenetic mechanism of interaction between miRNA and circRNA in chronic inflammation pain.
Learn More >The taste of sucrose is commonly used to provide pain relief in newborn humans and is innately analgesic to neonatal rodents. In adulthood, sucrose remains a strong motivator to feed, even in potentially hazardous circumstances (i.e. threat of tissue damage). However, the neurobiological mechanisms of this endogenous reward-pain interaction are unclear. We have developed a simple model of sucrose drinking-induced analgesia in Sprague-Dawley rats (6-10 weeks old) and have undertaken a behavioral and pharmacological characterization using the Hargreaves' test of hind paw thermal sensitivity. Our results reveal an acute, potent and robust inhibitory effect of sucrose drinking on thermal nociceptive behaviour that unlike the phenomenon in neonates is independent of endogenous opioid signalling and does not appear to operate via classical descending inhibition of the spinal cord circuitry. Experience of sucrose drinking had a conditioning effect whereby the apparent expectancy of sucrose enabled water alone (in euovolaemic animals) to elicit a short-lasting placebo-like analgesia. Sweet taste alone, however, was insufficient to elicit analgesia in adult rats intraorally perfused with sucrose. Instead, the sucrose analgesia phenomenon only appeared after conditioning by oral perfusion in chronically cannulated animals. This sucrose-analgesia was completely prevented by systemic dosing of the endocannabinoid CB1 receptor antagonist rimonabant. These results indicate the presence of an endogenous supra-spinal analgesic circuit that is recruited by the context of rewarding drinking and is dependent on endocannabinoid signalling. We propose that this hedonic sucrose-drinking model may be useful for further investigation of the supra-spinal control of pain by appetite and reward.
Learn More >Symptomatic treatment of neuropathic pain in small fibre neuropathy is often disappointing. The finding of voltage-gated sodium channel mutations in small fibre neuropathy (with mutations in SCN9A, encoding for Nav1.7) being most frequently reported suggest a specific target for therapy. The anticonvulsant lacosamide acts on Nav1.3, Nav1.7, and Nav1.8. The aim of this study was to evaluate the efficacy, safety, and tolerability of lacosamide as a potential treatment for pain in Nav1.7-related small fibre neuropathy. The Lacosamide-Efficacy-'N'-Safety in SFN (LENSS) was a randomized, placebo-controlled, double-blind, crossover-design study. Subjects were recruited in the Netherlands between November 2014 and July 2016. Patients with Nav1.7-related small fibre neuropathy were randomized to start with lacosamide followed by placebo or vice versa. In both 8-week treatment phases, patients received 200 mg two times a day (BID), preceded by a titration period, and ended by a tapering period. The primary outcome was efficacy, defined as the proportion of patients with 1-point average pain score reduction compared to baseline using the Pain Intensity Numerical Rating Scale. The trial is registered with ClinicalTrials.gov, number NCT01911975. Twenty-four subjects received lacosamide, and 23 received placebo. In 58.3% of patients receiving lacosamide, mean average pain decreased by at least 1 point, compared to 21.7% in the placebo group [sensitivity analyses, odds ratio 5.65 (95% confidence interval: 1.83-17.41); P = 0.0045]. In the lacosamide group, 33.3% reported that their general condition improved versus 4.3% in the placebo group (P-value = 0.0156). Additionally, a significant decrease in daily sleep interference, and in surface pain intensity was demonstrated. No significant changes in quality of life or autonomic symptoms were found. Lacosamide was well tolerated and safe in use. This study shows that lacosamide has a significant effect on pain, general wellbeing, and sleep quality. Lacosamide was well tolerated and safe, suggesting that it can be used for pain treatment in Nav1.7-related small fibre neuropathy.
Learn More >Accumulating evidence has demonstrated that the enhanced synaptic plasticity of nociceptive interneurons in the spinal dorsal horn is the basis of central sensitization in neuropathic pain. Our previous results demonstrate that Sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase, alleviates neuropathic pain in type 2 diabetes mellitus (T2DM) rats. SIRT1 has also been reported to regulate synaptic plasticity in different brain neurons. However, the role of SIRT1 in synaptic plasticity of spinal dorsal horn neurons remains unknown. In this study, we found that in the spinal dorsal horn of diabetic neuropathic pain (DNP) rats and db/db mice, decreased SIRT1 expression was accompanied by enhanced structural synaptic plasticity. The levels of post-synaptic density protein 95 (PSD-95), growth associated protein 43 (GAP43) and synaptophysin (SYP) increased in the spinal dorsal horn of DNP rats and db/db mice and in high glucose (HG)-cultured primary spinal neurons. Upregulation of spinal SIRT1 by SIRT1 activator SRT1720 relieved pain behavior, inhibited the enhanced structural synaptic plasticity in DNP rats and db/db mice, and decreased the levels of synapse-associated proteins in DNP rats, db/db mice, and HG-cultured spinal neurons. SIRT1 shRNA induced pain behavior, enhanced structural synaptic plasticity in normal rats, and increased synapse-associated proteins levels in normal rats and spinal neurons. Intrathecal AAV-Cre-EGFP into SIRT1 mice also induced pain behavior and enhanced synaptic plasticity of the spinal dorsal horn neurons. These results suggest that SIRT1 plays an important role in the progression of DNP by regulating synaptic plasticity of spinal dorsal horn neurons.
Learn More >It is widely accepted that neuroinflammation in the spinal cord contribute to the development of central sensitization in neuropathic pain. MAPKs activation plays an vital role in the development of neuroinflammation in the spinal cord. In this study, we investigated the effect of bexarotene, a RXR agonist, on MAPKs activation in CCI-induced neuropathic pain. The data showed that daily treatment with bexarotene 50mg/kg significantly alleviated CCI-induced nociceptive hypersensitivity in rats. Bexarotene 50mg/kg/day inhibited CCI-induced MAPKs (p38MAPK, ERK1/2, and JNK) activation and upregulation of proinflammatory factors(IL-1β, TNF-α and IL-6). Bexarotene also reversed CCI-induced microglia activation in the ipsilateral spinal cord. Furthermore, bexarotene treatment significantly upregulated MKP-1 in the spinal cord. These effects were completely abrogated by MKP-1 inhibitor BCI. These results indicated that bexarotene relieved CCI-induced neuroinflammation and neuropathic pain by targeting MKP-1. Therefore, bexarotene might be a potential agent for the treatment of neuropathic pain.
Learn More >Drug overdose is the leading cause of unintentional injury-associated death in the United States. Among 70,237 fatal drug overdoses in 2017, prescription opioids were involved in 17,029 (24.2%) (1). Higher rates of opioid-related deaths have been recorded in nonmetropolitan (rural) areas (2). In 2017, 14 rural counties were among the 15 counties with the highest opioid prescribing rates.* Higher opioid prescribing rates put patients at risk for addiction and overdose (3). Using deidentified data from the Athenahealth electronic health record (EHR) system, opioid prescribing rates among 31,422 primary care providers in the United States were analyzed to evaluate trends from January 2014 to March 2017. This analysis assessed how prescribing practices varied among six urban-rural classification categories of counties, before and after the March 2016 release of CDC's Guideline for Prescribing Opioids for Chronic Pain (Guideline) (4). Patients in noncore (the most rural) counties had an 87% higher chance of receiving an opioid prescription compared with persons in large central metropolitan counties during the study period. Across all six county groups, the odds of receiving an opioid prescription decreased significantly after March 2016. This decrease followed a flat trend during the preceding period in micropolitan and large central metropolitan county groups; in contrast, the decrease continued previous downward trends in the other four county groups. Data from EHRs can effectively supplement traditional surveillance methods for monitoring trends in opioid prescribing and other areas of public health importance, with minimal lag time under ideal conditions. As less densely populated areas appear to indicate both substantial progress in decreasing opioid prescribing and ongoing need for reduction, community health care practices and intervention programs must continue to be tailored to community characteristics.
Learn More >Migraine is a debilitating disease that affects almost 15% of the population worldwide and is the first cause of disability in people under 50 years of age, yet its etiology and pathophysiology remain incompletely understood. Recently, small molecules and therapeutic antibodies that block the calcitonin gene-related peptide (CGRP) signaling pathway have reduced migraine occurrence and aborted acute attacks of migraine in clinical trials and provide prevention in patiens with episodic and chronic migraine. Heterogeneity is present within each diagnosis and a patient's response to treatment, suggesting migraine as a final common pathway potentially activated by multiple mechanisms, e.g. not all migraine attacks respond or are prevented by anti-CGRP pharmacological interventions. Consequently, other unique mechanisms central to migraine pathogenesis may present new targets for drug development. Pituitary adenylate cyclase-activating peptide (PACAP) is an attractive novel target for treatment of migraines. We generated a specific, high affinity, neutralizing monoclonal antibody (ALD1910) with reactivity to both PACAP38 and PACAP27. In vitro, ALD1910 effectively antagonizes PACAP38 signaling through the PAC1-R, VPAC1-R, and VPAC2-R. ALD1910 recognizes a non-linear epitope within PACAP and blocks its binding to the cell surface. To test ALD1910 antagonistic properties directed against endogenous PACAP, we developed an umbellulone-induced rat model of neurogenic vasodilation and parasympathetic lacrimation. In vivo, this model demonstrates that the antagonistic activity of ALD1910 is dose-dependent, retaining efficacy at doses as low as 0.3 mg/kg. These results indicate that ALD1910 represents a potential therapeutic antibody to address PACAP-mediated migraine.
Learn More >We have reported child anxiety sensitivity (CASI) predicts chronic post-surgical pain (CPSP). Here, we evaluated DNA methylation profiles to understand gene-environmental interactions underlying CPSP and CASI, in order to identify shared, enriched, genomic pathways. In 73 prospectively recruited adolescents undergoing spine fusion, preoperative CASI, and pain data over 12 months post-surgery were collected. DNA from peripheral blood of evaluable subjects with (n=16) and without CPSP (n=40) were analyzed using MethylationEPIC arrays. We identified 637 and 2,445 differentially methylated positions (DMPs) associated with CPSP and CASI respectively (p≤0.05). Ingenuity pathway analysis of 39 genes with DMPs for both CPSP and CASI revealed enrichment of several canonical pathways, including GABA receptor (p=0.00016 (CPSP); 0.0008 (CASI)) and Dopamine-DARPP32 Feedback in cAMP (p=0.004 (CPSP) and 0.00003 (CASI)) Signaling. Gene-gene interaction network enrichment analysis revealed participation of pathways in cell signaling, molecular transport, metabolism and neurological diseases (p-value <10-8). Bioinformatic approaches to identify histone marks and transcription factor (TF) binding events underlying DMPs, showed their location in active regulatory regions in pain pathway relevant brain cells. Using Enrichr/Pinet enrichment and Library of Integrated Network-Based Cellular Signatures (LINCS) knockdown signatures, we identified TFs regulating genes with DMPs in association with CPSP and CASI. In conclusion, we identified epigenetically enriched pathways associated with CPSP and anxiety sensitivity in children undergoing surgery. Our findings support GABA hypofunction and Dopamine-DARPP32 pathway's roles in emotion/reward and pain. This pilot study provides new epigenetic insights into the pathophysiology of CPSP, and a basis for future studies in biomarker development and targetable interventions. Perspective: Differential DNA methylation in regulatory genomic regions enriching shared neural pathways were associated with chronic post-surgical pain and anxiety sensitivity in adolescents undergoing spine surgery. Our findings support GABA hypofunction and Dopamine-DARPP32 pathway's roles in emotion/reward contributing to behavioral maintenance of pain 10-12 months after surgery.
Learn More >Mechanisms responsible for osteoarthritic pain remain poorly understood and current analgesic therapies are often insufficient. We have characterized and pharmacologically tested the pain phenotype of a non-invasive mechanical joint loading (MJL) model of osteoarthritis thus providing an alternative murine model for osteoarthritic pain.
Learn More >Both the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) are involved in affective control and reward-related behaviors. Moreover, the neuronal activities of the VTA and DRN are modulated by opioids. However, the precise circuits from the VTA to DRN and how opioids modulate these circuits remain unknown. Here, we found that neurons projecting from the VTA to DRN are primarily GABAergic. Rostral VTA (rVTA) GABAergic neurons preferentially innervate DRN GABAergic neurons, thus disinhibiting DRN serotonergic neurons. Optogenetic activation of this circuit induces aversion. In contrast, caudal VTA (cVTA) GABAergic neurons mainly target DRN serotonergic neurons, and activation of this circuit promotes reward. Importantly, μ-opioid receptors (MOPs) are selectively expressed at rVTA→DRN GABAergic synapses, and morphine depresses the synaptic transmission. Chronically elevating the activity of the rVTA→DRN pathway specifically interrupts morphine-induced conditioned place preference. This opioid-modulated inhibitory circuit may yield insights into morphine reward and dependence pathogenesis.
Learn More >Recent technical advances in genetics made large-scale genome-wide association studies (GWAS) in migraine feasible and have identified over 40 common DNA sequence variants that affect risk for migraine types. Most of the variants, which are all single nucleotide polymorphisms (SNPs), show robust association with migraine as evidenced by the fact that the vast majority replicate in subsequent independent studies. However, despite thorough bioinformatic efforts aimed at linking the migraine risk SNPs with genes and their molecular pathways, there remains quite some discussion as to how successful this endeavour has been, and their current practical use for the diagnosis and treatment of migraine patients. Although existing genetic information seems to favour involvement of vascular mechanisms, but also neuronal and other mechanisms such as metal ion homeostasis and neuronal migration, the complexity of the underlying genetic pathophysiology presents challenges to advancing genetic knowledge to clinical use. A major issue is to what extent one can rely on bioinformatics to pinpoint the actual disease genes, and from this the linked pathways. In this Commentary, we will provide an overview of findings from GWAS in migraine, current hypotheses of the disease pathways that emerged from these findings, and some of the major drawbacks of the approaches used to identify the genes and pathways. We argue that more functional research is urgently needed to turn the hypotheses that emerge from GWAS in migraine to clinically useful information.
Learn More >Neuropathic pain is driven by abnormal peripheral and central processing, and treatments are insufficiently effective. Antibodies against nerve growth factor (anti-NGF) have been investigated as a potent analgesic treatment for numerous conditions. However, the peripheral and brain effects of anti-NGF in neuropathic pain remain unknown. We examined the effectiveness of anti-NGF in reducing chronic pain by local administration in a rat model of sciatic constriction injury (CCI). NGF and substance P in the dorsal root ganglion (DRG) and spinal cord were evaluated. Neuronal activation was measured using c-Fos in the anterior cingulate cortex and ventrolateral periaqueductal gray. At 14 days after CCI, anti-NGF promoted a significant dose-dependent improvement in mechanical threshold, thermal withdrawal latency, and cold sensitivity, lasting for 5 h. NGF upregulation in the DRG and spinal cord after CCI was decreased by anti-NGF, while substance P was increased only in the DRG, and the treatment reduced it. Anti-NGF induced a significant reduction of neuronal activation in the anterior cingulate cortex, but not in the ventrolateral periaqueductal gray. This study provides the first evidence of the anti-NGF effects on brain activity. Thus, our findings suggest that anti-NGF improves chronic neuropathic pain, acting directly on peripheral sensitization and indirectly on central sensitization.
Learn More >Taste and somatosensation both mediate protective behaviors. Bitter taste guides avoidance of ingestion of toxins while pain sensations, such as noxious heat, signal adverse conditions to ward off harm. Although brain pathways for taste and somatosensation are typically studied independently, prior data suggest they intersect, potentially reflecting their common protective role. To investigate this, we applied electrophysiologic and optogenetic techniques in anesthetized mice of both sexes to evaluate relationships between oral somatosensory and taste activity in the parabrachial nucleus (PbN), implicated for roles in gustation and pain. Spikes were recorded from taste-active PbN neurons tested with oral delivery of thermal and chemesthetic stimuli, including agonists of nocisensitive transient receptor potential (TRP) ion channels on somatosensory fibers. Gustatory neurons were also tested to follow electrical pulse stimulation of an oral somatosensory region of the spinal trigeminal subnucleus caudalis (Vc), which projects to the PbN. Neurons composed classic taste groups, including sodium, electrolyte, appetitive, or bitter cells. Across groups, most neurons spiked to Vc pulse stimulation, implying trigeminal projections reach PbN gustatory neurons. Among such cells, a subpopulation responsive to the bitter taste stimuli quinine and cycloheximide, and aversive concentrations of sodium, co-fired to agonists of nocisensitive TRP channels, including capsaicin, mustard oil, and noxious heat. Such neurons populated the lateral PbN. Further, nociceptive activity in PbN bitter taste neurons was suppressed during optogenetic-assisted inhibition of the Vc, implying convergent trigeminal input contributed to such activity. Our results reveal a novel role for PbN gustatory cells in cross-system signaling related to protection.Prior data suggest gustatory and trigeminal neural pathways intersect and overlap in the parabrachial area. However, no study has directly examined such overlap and why it may exist. Here we found that parabrachial gustatory neurons can receive afferent projections from trigeminal nuclei and fire to oral nociceptive stimuli that excite somatosensory receptors and fibers. Activation to aversive nociceptive stimuli in gustatory cells was associated with responding to behaviorally-avoided bitter tastants. We were further able to show that silencing trigeminal projections inhibited nociceptive activity in parabrachial bitter taste neurons. Our results imply that in the parabrachial area, there is predictable overlap between taste and somatosensory processing related to protective coding and that classically-defined taste neurons contribute to this process.
Learn More >Monoclonal antibodies acting on the calcitonin gene-related peptide or on its receptor are new drugs to prevent migraine. Four monoclonal antibodies have been developed: one targeting the calcitonin gene-related peptide receptor (erenumab) and three targeting the calcitonin gene-related peptide (eptinezumab, fremanezumab, and galcanezumab). The aim of this document by the European Headache Federation (EHF) is to provide an evidence-based and expert-based guideline on the use of the monoclonal antibodies acting on the calcitonin gene-related peptide for migraine prevention.
Learn More >To evaluate the safety and efficacy of l-serine in humans with hereditary sensory autonomic neuropathy type I (HSAN1).
Learn More >The Fear-Avoidance Model (FAM) is a leading theoretical paradigm for explaining persistent pain following musculoskeletal injury. The model suggests that as injuries heal, pain-related outcomes are increasingly determined by psychological, rather than physiological factors. Increasing literature, however, suggests that neurophysiological processes related to pain sensitivity also play an important role in chronicity. To date, there has been limited research that has specifically explored the role of pain sensitivity within the FAM. This study addresses this gap by evaluating whether clinical measures of pain sensitivity help explain FAM-related outcomes, beyond model-relevant psychological predictors.
Learn More >Migraine is a prevalent, disabling neurological disorder involving the trigeminovascular system. Previous treatments were either originally intended for other conditions and/or associated with intolerable adverse effects. Calcitonin gene-related peptide (CGRP) is the most prevalent neuropeptide in the trigeminal afferent neurons and plays a significant role in pain sensitization central to migraine. The CGRP antagonists (gepants and monoclonal antibodies) are the first treatments created specifically for migraine, modulating pain signaling pathways and alleviating migraine attacks and recurrences. With their efficacy in several clinical trials and relatively fewer adverse effects, the CGRP antagonists show great promise for use in episodic migraine. This article is protected by copyright. All rights reserved.
Learn More >To investigate differences in clinical, psychological and psychophysical outcomes according to use of prophylactic medication (amitriptyline) in tension type headache (TTH).
Learn More >Chronic pain is a pathological manifestation of neuronal plasticity supported by altered gene transcription in spinal cord neurons that results in long-lasting hypersensitivity. Recently, the concept that epigenetic regulators might be important in pathological pain has emerged, but a clear understanding of the molecular players involved in the process is still lacking. In this study we linked Dnmt3a2, a synaptic activity-regulated de novo DNA methyltransferase, to chronic inflammatory pain. We observed that Dnmt3a2 levels are increased in the spinal cord of adult mice following plantar injection of Complete Freund's Adjuvant (CFA), an in vivo model of chronic inflammatory pain. In vivo knockdown of Dnmt3a2 expression in dorsal horn neurons blunted the induction of genes triggered by CFA injection. Among the genes whose transcription was found to be influenced by Dnmt3a2 expression in the spinal cord is Ptgs2, encoding for Cox-2, a prime mediator of pain processing. Lowering the levels of Dnmt3a2 prevented the establishment of long-lasting inflammatory hypersensitivity. These results identify Dnmt3a2 as an important epigenetic regulator needed for the establishment of central sensitization. Targeting expression or function of Dnmt3a2 may be suitable for the treatment of chronic pain.
Learn More >Cannabis elicits its mood-enhancing and analgesic effects through the cannabinoid receptor 1 (CB1), a G protein-coupled receptor (GPCR) that signals primarily through the adenylyl cyclase-inhibiting heterotrimeric G protein G. Activation of CB1-G signaling pathways holds potential for treating a number of neurological disorders and is thus crucial to understand the mechanism of G activation by CB1. Here, we present the structure of the CB1-G signaling complex bound to the highly potent agonist MDMB-Fubinaca (FUB), a recently emerged illicit synthetic cannabinoid infused in street drugs that have been associated with numerous overdoses and fatalities. The structure illustrates how FUB stabilizes the receptor in an active state to facilitate nucleotide exchange in G. The results compose the structural framework to explain CB1 activation by different classes of ligands and provide insights into the G protein coupling and selectivity mechanisms adopted by the receptor.
Learn More >To assess the effectiveness and adverse effects of acute cluster headache medications in a large international sample, including recommended treatments such as oxygen, commonly used medications such as opioids, and emerging medications such as intranasal ketamine. Particular focus is paid to a large subset of respondents 65 years of age or older.
Learn More >Postherpetic itch (PHI), or herpes zoster itch, is an intractable and poorly understood disease. We targeted 94 herpes zoster patients to investigate their pain and itch intensities at three separate stages of the condition (acute, subacute, and chronic). We used painDETECT questionnaire (PDQ) scores to investigate the correlation between PHI and neuropathic pain. Seventy-six patients were able to complete follow-up surveys. The prevalence of PHI was 47/76 (62%), 28/76 (37%), and 34/76 (45%) at the acute, subacute, and chronic stages, respectively. PHI manifestation times and patterns varied. We investigated the relationship of PHI with neuropathic pain using the visual analog scale (VAS), which is a measure of pain intensity, and the PDQ, which is a questionnaire used to evaluate the elements of neuropathic pain. The VAS and PDQ scores did not differ significantly between PHI-positive and PHI-negative patients. A large neuropathic component was not found for herpes zoster itch, suggesting that neuropathic pain treatments may not able to adequately control the itch. Accordingly, we suggest that a more PHI-focused therapy is required to address this condition.
Learn More >GABA receptors containing the α6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 μM enhanced GABA currents at recombinant rat α6β3γ2, α6β3δ and α6β3 receptors whereas it was inactive at most GABA receptor subtypes containing other α subunits. DK-I-87-1 at concentrations below 1 μM was inactive at α6-containing receptors and only weakly modulated other GABA receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 h and 13 h, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-h period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery, or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy was already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. This article is protected by copyright. All rights reserved.
Learn More >Piezo1 and Piezo2 belong to a family of mechanically-activated ion channels implicated in a wide range of physiological processes. Mechanical stimulation triggers Piezo channels to open, but their characteristic fast inactivation process results in rapid closure. Several disease-causing mutations in Piezo1 alter the rate of inactivation, highlighting the importance of inactivation to the normal function of this channel. However, despite the structural identification of two physical constrictions within the closed pore, the mechanism of inactivation remains unknown. Here we identify a functionally conserved inactivation gate in the pore-lining inner helix of mouse Piezo1 and Piezo2 that is distinct from the two constrictions. We show that this gate controls the majority of Piezo1 inactivation via a hydrophobic mechanism and that one of the physical constrictions acts as a secondary gate. Our results suggest that, unlike other rapidly inactivating ion channels, a hydrophobic barrier gives rise to fast inactivation in Piezo channels.
Learn More >Sensitivity to different pain modalities has a genetic basis that remains largely unknown. Employing closely related inbred mouse substrains can facilitate gene mapping of nociceptive behaviors in preclinical pain models. We previously reported enhanced sensitivity to acute thermal nociception in C57BL/6J (B6J) versus C57BL/6N (B6N) substrains. Here, we expanded on nociceptive phenotypes and observed an increase in formalin-induced inflammatory nociceptive behaviors and paw diameter in B6J versus B6N mice (Charles River Laboratories). No strain differences were observed in mechanical or thermal hypersensitivity or in edema following the Complete Freund's Adjuvant (CFA) model of inflammatory pain, indicating specificity in the inflammatory nociceptive stimulus. In the chronic nerve constriction injury (CCI), a model of neuropathic pain, no strain differences were observed in baseline mechanical threshold or in mechanical hypersensitivity up to one month post-CCI. We replicated the enhanced thermal nociception in the 52.5°C hot plate test in B6J versus B6N mice from The Jackson Laboratory. Using a B6J x B6N-F2 cross (N=164), we mapped a major quantitative trait locus (QTL) underlying hot plate sensitivity to chromosome 7 that peaked at 26 Mb (LOD=3.81, p<0.01; 8.74 Mb-36.50 Mb) that was more pronounced in males. Genes containing expression QTLs (eQTLs) associated with the peak nociceptive marker that are implicated in pain and inflammation include Ryr1, Cyp2a5, Pou2f2, Clip3, Sirt2, Actn4, and Ltbp4 (FDR < 0.05). Future studies involving positional cloning and gene editing will determine the quantitative trait gene(s) and potential pleiotropy of this locus across pain modalities.
Learn More >Central sensitization is a condition in which there is an abnormal responsiveness to nociceptive stimuli. As such, the process may contribute to the development and maintenance of pain. Factors influencing the propensity for development of central sensitization have been a subject of intense debate and remain elusive. Injury-induced secondary hyperalgesia can be elicited by experimental pain models in humans, and is believed to be a result of central sensitization. Secondary hyperalgesia may thus reflect the individual level of central sensitization. The objective of this study was to investigate possible associations between increasing size of secondary hyperalgesia area and brain connectivity in known resting-state networks. We recruited 121 healthy participants (male, age 22, SD 3.35) who underwent resting-state functional magnetic resonance imaging. Prior to the scan session, areas of secondary hyperalgesia following brief thermal sensitization (3 min. 45 °C heat stimulation) were evaluated in all participants. 115 participants were included in the final analysis. We found a positive correlation (increasing connectivity) with increasing area of secondary hyperalgesia in the sensorimotor- and default mode networks. We also observed a negative correlation (decreasing connectivity) with increasing secondary hyperalgesia area in the sensorimotor-, fronto-parietal-, and default mode networks. Our findings indicate that increasing area of secondary hyperalgesia is associated with increasing and decreasing connectivity in multiple networks, suggesting that differences in the propensity for central sensitization, assessed as secondary hyperalgesia areas, may be expressed as differences in the resting-state central neuronal activity.
Learn More >Early detection and rapid intervention can prevent death from opioid overdose. At high doses, opioids (particularly fentanyl) can cause rapid cessation of breathing (apnea), hypoxemic/hypercarbic respiratory failure, and death, the physiologic sequence by which people commonly succumb from unintentional opioid overdose. We present algorithms that run on smartphones and unobtrusively detect opioid overdose events and their precursors. Our proof-of- concept contactless system converts the phone into a short-range active sonar using frequency shifts to identify respiratory depression, apnea, and gross motor movements associated with acute opioid toxicity. We develop algorithms and perform testing in two environments: (i) an approved supervised injection facility (SIF), where people self-inject illicit opioids, and (ii) the operating room (OR), where we simulate rapid, opioid-induced overdose events using routine induction of general anesthesia. In the SIF ( = 209), our system identified postinjection, opioid-induced central apnea with 96% sensitivity and 98% specificity and identified respiratory depression with 87% sensitivity and 89% specificity. These two key events commonly precede fatal opioid overdose. In the OR, our algorithm identified 19 of 20 simulated overdose events. Given the reliable reversibility of acute opioid toxicity, smartphone-enabled overdose detection coupled with the ability to alert naloxone-equipped friends and family or emergency medical services (EMS) could hold potential as a low-barrier, harm reduction intervention.
Learn More >The purpose of this study was to investigate the HCRTR2 gene variants rs3122156, rs2653342, and rs2653349 in a large homogenous Swedish case-control cohort in order to further evaluate the possible contribution of HCRTR2 to cluster headache.
Learn More >To identify and describe back pain (BP) trajectory groups and to compare indicators of health status, medication, and healthcare use by these groups.
Learn More >Cohort/psychometric study.
Learn More >To assess the effects of onabotulinumtoxinA treatment for chronic migraine (CM) on comorbid symptoms of depression, anxiety, fatigue and poor sleep quality.
Learn More >T-type calcium channels serve an essential role in the functioning of the nervous system. They exhibit unique properties among voltage-gated calcium channels, and mediate specific roles in brain function. Over the recent years, it has come to light that a number of chronic neurological disorders arise from defects in T-type channel function. The question then arises as to whether T-type channels could represent a relevant druggable target. In this review, we introduce the diversity, molecular structure, and principal electrophysiological properties of T-type channels. Then, we highlight their role in neuronal development, and their pathophysiological role in the nervous system. Finally, we discuss the potential of T-type channels as therapeutic targets in light of recent advances in their pharmacopoeia.
Learn More >Pregabalin is commonly used as an analgesic for neuropathic pain. But pregabalin as an adjunct to a multimodal analgesic regimen – although standard clinical protocol in some settings – has remained controversial. This meta-analysis was conducted to identify the efficacy of pregabalin for management of postoperative pain in thoracotomy.
Learn More >Chronic pain is one of the most prevalent chronic diseases in the world. The plastic changes of sensory neurons in dorsal root ganglia (DRG) have been extensively studied as the underlying periphery mechanism. Recent studies revealed that satellite cells, the major glial cells in DRG, also played important roles in the development/modulation of chronic pain. Whether DRG satellite glial cells generate new neurons as their counterparts in enteric nerve ganglia and carotid body do under pathological conditions remains poorly investigated. Here, we report that chronic pain induces proliferation and upregulation of progenitor markers in the sex-determining region Y-box 2 (Sox2)- and platelet-derived growth factor receptor alpha (PDGFRα)-positive satellite glial cells. BrdU incorporation assay revealed the generation of IB4- and CGRP-positive neurons, but not NF200-positive neurons in DRG ipsilateral to injury. Genetic fate tracings showed that PDGFRα-positive cells did not generate neurons, whereas Sox2-positive cells produced both IB4- and CGRP-positive neurons. Interestingly, glial fibrillary acidic protein-positive cells, a subpopulation of Sox2-positive satellites, only gave birth to IB4-positive neurons. Local persistent delivery of tetrodotoxin to the sciatic nerve trunk significantly reduced the pain-induced neurogenesis. Furthermore, patch-clamp studies demonstrated that these glia-derived new neurons could fire action potentials and respond to capsaicin. Taken together, our data demonstrated a chronic pain-induced nociceptive neurogenesis in DRG from Sox2-positive satellite cells, indicating a possible contribution of DRG neurogenesis to the pathology of chronic pain.
Learn More >OBJECTIVEFirst-line treatment for trigeminal neuralgia (TN) is pharmacological management using antiepileptic drugs (AEDs), e.g., carbamazepine (CBZ) and oxcarbazepine (OCBZ). Surgical intervention has been shown to be an effective and durable treatment for TN that is refractory to medical therapy. Despite the lack of evidence for efficacy in patients with TN, the authors hypothesized that patients with neuropathic facial pain are prescribed opioids at high rates, and that neurosurgical intervention may lead to a reduction in opioid use.METHODSThis is a retrospective study of patients with facial pain seen by a single neurosurgeon. All patients completed a survey on pain medications, medical comorbidities, prior interventions for facial pain, and a validated pain outcome tool (the Penn Facial Pain Scale). Patients subsequently undergoing neurosurgical intervention completed a survey at the 1-month follow-up in the office, in addition to telephone interviews using a standardized script between 1 and 6 years after intervention. Univariate and multivariate logistic regression were used to predict opioid use.RESULTSThe study cohort consisted of 309 patients (70% Burchiel type 1 TN [TN1], 18% Burchiel type 2 [TN2], 6% atypical facial pain [AFP], and 6% TN secondary to multiple sclerosis [TN-MS]). At initial presentation, 20% of patients were taking opioids. Of these patients, 55% were receiving concurrent opioid therapy with CBZ/OCBZ, and 84% were receiving concurrent therapy with at least one type of AED. Facial pain diagnosis (for diagnoses other than TN1, odds ratio [OR] 2.5, p = 0.01) and facial pain intensity at its worst (for each unit increase, OR 1.4, p = 0.005) were predictors of opioid use at baseline. Neurosurgical intervention led to a reduction in opioid use to 8% at long-term follow-up (p < 0.01, Fisher's exact test; n = 154). Diagnosis (for diagnoses other than TN1, OR 4.7, p = 0.002) and postintervention reduction in pain at its worst (for each unit reduction, OR 0.8, p < 10-3) were predictors of opioid use at long-term follow-up. On subgroup analysis, patients with TN1 demonstrated a decrease in opioid use to 5% at long-term follow-up (p < 0.05, Fisher's exact test), whereas patients with non-TN1 facial pain did not. In the nonsurgical group, there was no statistically significant decrease in opioid use at long-term follow-up (n = 81).CONCLUSIONSIn spite of its high potential for abuse, opioid use, mostly as an adjunct to AEDs, is prevalent in patients with facial pain. Opportunities to curb opioid use in TN1 include earlier neurosurgical intervention.
Learn More >Ketamine has been shown to reduce chronic pain; however, the adverse events associated with ketamine makes it challenging for use outside of the perioperative setting. The ketamine metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) has a therapeutic effect in mice models of depression, with minimal side effects. The objective of this study is to determine if (2R,6R)-HNK has efficacy in both acute and chronic mouse pain models.
Learn More >Dorsal root ganglion stimulation is an emerging therapy in the treatment of chronic pain. Compared with traditional spinal cord stimulation, it allows a discretely targeted stimulation profile and may act via differing mechanisms of action. Despite these advantages, little is known about the complications associated with this new modality.
Learn More >To expand the evidence base needed to enable personalized pain medicine, we evaluated whether self-reported cumulative exposure to medical opioids and subjective responses on first opioid use predicted responses to placebo-controlled opioid administration.
Learn More >Conventional opioids are widely used for acute pain management in the postoperative setting. However, a primary concern with conventional opioids is their therapeutic window-the range between doses that produce the desired therapeutic effect (analgesia) and doses that produce unwanted opioid-related adverse events (ORAEs). Conventional µ receptor opioids have a narrow therapeutic window in part because of their mechanism of action (MoA): they bind to µ receptors and non-selectively activate two intracellular signaling pathways, leading to analgesia and to ORAEs. This review explores the clinical potential of µ receptor ligands with differential signaling. Agents with a 'differential signaling" MoA represent an innovative approach that may enhance the therapeutic window. These agents modulate µ receptor activity to selectively engage downstream signaling pathways associated with analgesia while limiting activity in downstream signaling pathways that lead to ORAEs. Differential signaling may fulfill an unmet need in the management of postoperative pain.
Learn More >Regional anesthesia may mitigate the risk of persistent postoperative pain (PPP). This Cochrane review, published originally in 2012, was updated in 2017.
Learn More >Complex regional pain syndrome (CRPS) has been considered to be an autoimmune disease and there have been clinical trials with intravenous immunoglobulin. Often the etiology of the so-called CRPS diagnosis cannot be discerned and there are no validated instruments that provide functional metrics. The term complex regional pain syndrome (CRPS), coined in 1994 to describe patients in whom the pain is out of proportion to the injury, was actually a diagnosis proposed during the American Civil War, but was originally known as causalgia. Physicians have long observed similar sensitivity and inflammatory symptoms following periods of immobilization and disuse, which generally resolve within a few months of remobilization. Following the original description, persistent disproportionate pain would come to be known under many other names until researchers theorized that it was related to dysfunction in the sympathetic nervous system, after which it acquired the moniker, Reflex Sympathetic Dystrophy ("RSD"). In the latter quarter of the twentieth century, after researchers failed to prove the connection between the pain and the sympathetic nervous system, a small cadre of physicians-without rigorous science-invented CRPS. This new descriptor, CRPS, has become not only a diagnosis without objective data but with proposed criteria involving ambiguous signs and symptoms with low specificity. It has led to patients being treated erroneously with sympatholytic drugs, with or without pharmaceutical or surgical blockade of the sympathetic nervous system, unwarranted use of ketamine infusions, inappropriate use of narcotics and nerve stimulation. Intravenous immunoglobulin infusions have not been effective in the treatment of chronic pain. The indiscriminate use of pain medications to treat subjective symptoms of unclear diagnoses can be a risk factor for opioid and analgesic misuse or abuse.
Learn More >Migraine is a common neurologic disorder. This article will discuss a few factors that influence migraine (mostly episodic) and its treatment, such as sleep, obstructive sleep apnea (OSA), obesity, and affective disorders, as well as autoimmune diseases. Practitioners must be aware of these coexisting conditions (comorbidities) as they affect treatment. It is noted in literature that both the quantity (too much or too few hours) and the quality (OSA related) of sleep may worsen migraine frequency. An associated risk factor for OSA, obesity also increases migraine frequency in episodic migraine cases. A bidirectional relationship with migraine along with depression and anxiety is debated in the literature. Retrospective cohort studies are undecided and lack statistical significance, but prospective studies do show promising results on treatment of anxiety and depression as a means of improving migraine control. Finally, we address the topic of autoimmune diseases and migraine. While few studies exist at this time, there are cohort study groups looking into the association between rheumatoid arthritis, hypothyroidism, and antiphospholipid antibody. There is also evidence for the link between migraine and vascular diseases, including coronary and cerebral diseases. We suggest that these comorbid conditions be taken into account and individualized for each patient along with their pharmaceutical regimen. Physicians should seek a multifactorial treatment plan including diet, exercise, and healthy living to reduce migraine frequency.
Learn More >Differences in gene expression may provide insight into the biological pathways involved in chronic postsurgical pain (CPSP). We compared blood RNA microarrays preoperatively and postoperatively following total knee arthroplasty (TKA) in patients with and without CPSP.
Learn More >This controlled trial examined the benefit of a high-frequency transcutaneous electrical nerve stimulation (hfTENS) device (Quell ) for chronic low back pain (CLBP) patients. Thirty-five (N=35) participants were randomly assigned to use the device each day for 3 months (Experimental) and were compared with 33 subjects without the device (treatment-as-usual Control). All patients were instructed to complete baseline questionnaires and were assessed on thresholds of pressure pain and mechanical temporal summation as part of a standardized quantitative sensory test (QST) assessment. The subjects also uploaded smartphone applications (apps) for tracking use of the hfTENS and for daily pain assessment. Each participant completed weekly phone interviews, was prompted to complete daily pain app assessments, and was asked to repeat the baseline questionnaires again after 6 weeks and 3 months. Sixty percent of the subjects were female, 77.9% were Caucasian, and the average age was 46.2. Significant reductions in pain intensity (p<0.01) and activity interference (p<0.025) and significant improvements in pain catastrophizing (p<0.025) were noted in the Experimental subjects compared with the Controls. No group differences were found on depression, anxiety, or pain-related disability. Older subjects with a longer duration of pain tended to use the hfTENS more often. Subjects who showed greater sensitivity based on QST results revealed increased use of the hfTENS (p<0.025) and tended to believe that the hfTENS was more helpful in reducing their back pain, but these findings did not reach significance (p=0.09). Further trials designed to determine the mechanism of action of the hfTENS are needed. This article is protected by copyright. All rights reserved.
Learn More >Migraine-related intracerebral white matter lesions (WMLs) are likely to be microvascular in nature and can be found in all hemispheric lobes. The aim of this study was to investigate migraine patients with or without WMLs to see the effects of these tissue damages on cortical thickness and volume. The role of migraine characteristics (duration of headache, attack frequency, estimated lifetime attack number, aura) was also tested.
Learn More >Although the evidence of the attentional bias of chronic pain individuals toward pain-related information is established in the literature, few studies examined the time course of attention toward pain stimuli and the role of pain catastrophizing on attentional engagement toward pain-related information. This study examined the time course of attention to pain-related information and the role of pain catastrophizing on attentional engagement for pain-related information. Participants were fifty young adult participants with chronic pain (35% male, 65% female; M = 21.8 years) who completed self-report questionnaires assessing pain catastrophizing levels (Pain Catastrophizing Scale (PCS)), depression (the Center for Epidemiologic Studies Depression Scale (CES-D)), anxiety (State-Trait Anxiety Inventory (STAI)), and pain disability (the Pain Disability Index: (PDI)). Attentional engagements to pain- and anger-related information were measured by the eye tracker. Significant interaction effects were found between (1) time and stimulus type for pain-related information ( (5, 245) = 11.55, < 0.001) and (2) bias scores and pain catastrophizing ( (1, 48) = 6.736, < 0.05). These results indicated that the degree of increase for pain bias scores were significantly greater than anger bias scores as levels of pain catastrophizing increased. Results of the present study provided the evidence for the attentional bias and information processing model which has clinical implications; high levels of pain catastrophizing may impair individuals' ability to cope with chronic pain by increasing attentional engagement toward pain-related information. The present study can add knowledge to attentional bias and pain research as this study investigated the time course of attention and the role of pain catastrophizing on attentional engagement toward pain-related information for adults with chronic pain conditions.
Learn More >Low back pain (LBP) and neck pain are major causes of pain and disability that are experienced across all ages. The primary goals of treatment are to improve patient function and facilitate a return to the patient's desired level of daily activity. Therapeutic ultrasound is a noninvasive modality widely utilized in the management of musculoskeletal disorders, but there continues to be controversy regarding its use due to insufficient evidence of effectiveness. The objective of this systematic review was to evaluate the effectiveness of therapeutic ultrasound in the management of patients with chronic LBP and neck pain.
Learn More >Local infiltration analgesia (LIA) is an effective pain management technique following total knee arthroplasty (TKA).
Learn More >Background and aims Pain is a prevalent problem in many countries. Women are more often on sick-leave for pain than men. Such gender differences have been explained through biological factors, different demands for on the job market, and home conditions. Fewer studies have focused on how gender stereotypes may bias the medical assessment of pain patients. The aim of the present research was to investigate if a gender bias in medical students' evaluations of chronic pain patients can contribute to explaining the gender differences in sick-leave due to pain. Specifically, we investigated whether medical students' estimates of a patient's accuracy of their own work ability and amount of domestic work differed between female and male patients, and how such estimates influenced the medical students' judgments of the patient's work ability. Methods Medical students (n=137; 60 women; 74 men; three unspecified) read a vignette describing a patient with pain and filled out a questionnaire. The vignette was identical and gender neutral, except for the name of the patient signaling gender. A between-subjects experimental design was used in which participants were randomly assigned to an experimental condition. Participants then judged the patient's work ability, the accuracy of the patient's self-assessed work ability, and the amount of domestic work they believed was performed by the patient. All ratings were made on seven-point items. Results The results showed that there was no main effect of gender on perceived future work ability of the patient, F (1,131)=0.867, p=0.353. However, male patients were considered to be more accurate in their self-assessed work ability than female patients F (1,131)=5.925 p=0.016 (Mfemale=4.87, SDfemale=1.22, and Mmale=5.33, SDmale=1.02). Moreover, female patients were thought to perform more domestic work, F (1,131)=25.56, p<0.001 (Mfemale=4.14, SDfemale=1.41, and Mmale=3.07, SDmale=1.16). Finally, perceived amount of domestic work moderated the effects of perceived future work ability for female but not for male patients, B=0.42, p=0.005. Hence, there was a positive effect of amount of domestic work performed on work ability judgments for women, such that the more domestic work they were assumed to perform, the more they were perceived to be able to work. Conclusions Gender stereotypes influenced assessments of future work ability in pain patients, mainly because women were assumed to perform more domestic work which had a positive effect on perceived work ability. Because domestic work should have a negative effect on recovery, expectations from the physician that domestic work is expected by female patients may in fact have the opposite effect prolonging sick-leave. Moreover, the students trusted the male patients' ability to assess their own work capacity more than women's. Implications It is important that medical students receive education about gender biases and how they may influence medical assessment during their training. Such education may alleviate the influence of gender stereotypes.
Learn More >A prospective observational study with translation and psychometric analyses of a questionnaire.
Learn More >There is a substantial body of evidence indicating that corneal sensory innervation is affected by pathology in a range of diseases. However, there are no published studies that have directly assessed whether the nerve fiber density of the different subpopulations of corneal sensory neurons are differentially affected. The present study explored the possibility that the intraepithelial nerve fiber density of corneal polymodal nociceptors and cold thermoreceptors are differentially affected in mice fed with a high-fat high cholesterol (HFHC; 21% fat, 2% cholesterol) diet and in those that also have diabetes.
Learn More >Features suggestive of neuropathic pain (NP) have been described in RA in addition to nociceptive pain. We aimed to determine the clinical predictors of NP in RA patients and study its association with radiographic structural damage.
Learn More >To assess chronic potentially unsafe medication use among older adults using opioids chronically versus those who did not, to assess the likelihood of chronically using medications to treat adverse effects associated with chronic opioid use, and to characterize the differences in chronic potentially unsafe medication use at three morphine equivalent dose (MED) levels/day (<50MED, 50-90MED, and >90MED).
Learn More >The use of medical cannabis and cannabis-based medicines has received increasing interest in recent years; with a corresponding surge in the number of studies and reviews conducted in the field. Despite this growth in evidence, the findings and conclusions of these studies have been inconsistent. In this paper, we outline the current evidence for medical cannabis and cannabis-based medicines in the treatment and management of chronic non-cancer pain. We discuss limitations of the current evidence, including limitations of randomised control trials in the field, limits on generalisability of previous findings and common issues such as problems with measurements of dose and type of cannabinoids. We discuss future directions for medicinal cannabinoid research, including addressing limitations in trial design; developing frameworks to monitor for use disorder and other unintended outcomes; and considering endpoints other than 30% or 50% reductions in pain severity.
Learn More >A majority of the nearly two million Americans living with limb loss suffer from chronic pain in the form of neuroma-related residual limb and phantom limb pain (PLP). Targeted muscle reinnervation (TMR) surgically transfers amputated nerves to nearby motor nerves for prevention of neuroma. The objective of this study was to determine whether TMR at the time of major limb amputation decreases the incidence and severity of PLP and residual limb pain.
Learn More >Accumulating evidence shows that inhibition of glycogen synthase kinase-3beta (GSK-3β) ameliorates cognitive impairments caused by a diverse array of diseases. Our previous work show that spared nerve injury (SNI) that induces neuropathic pain causes short-term memory (STM) deficits.Here,we reported that GSK-3β activity was enhanced in hippocampus and reduced in spinal dorsal horn following SNI, and the changes persisted for at least 45 d. Repetitive applications of selective GSK-3β inhibitors (SB216763, 5 mg/kg, i.p., 3 times or AR-A014418, 400 ng/kg, i.t., 7 times) prevented STM deficits but did not affect neuropathic pain in SNI rats. Surprisingly, we found that the repetitive SB216763 or AR-A014418 induced a persistent pain hypersensitivity in sham animals. Mechanistically,both β-catenin and brain-derived neurotrophic factor (BDNF) were upregulated in spinal dorsal horn but downregulated in hippocampus following SNI. Injections of SB216763 prevented the BDNF downregulation in hippocampus but enhanced BDNF upregulation in spinal dorsal horn in SNI rats. In sham rats SB216763 upregulated both β-catenin and BDNF in spinal dorsal horn but not affect neither of them in hippocampus. Finally, intravenous injection of interleukin-1beta that induces pain hypersensitivity and memory deficits mimicked the SNI-induced the differential regulation of GSK-3β/β-catenin/BDNF in spinal dorsal horn and in hippocampus. Accordingly, the prolonged opposite changes of GSK-3β activity in hippocampus and in spinal dorsal horn induced by SNI may contribute to Molecular Pain memory deficits and neuropathic pain by differential regulation of BDNF in the two regions. GSK-3β inhibitors that treat cognitive disorders may result in a long-lasting pain hypersensitivity.
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