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Chemotherapy-induced peripheral neuropathy (CIPN) remains a pressing clinical problem, however our understanding of sexual dimorphism in CIPN remains unclear. Emerging studies indicate a sex-dimorphic role of Toll-like receptor 4 (TLR4) in driving neuropathic pain. In this study we examined the role of TLR9 in CIPN induced by paclitaxel in wild-type and mutant mice of both sexes. Baseline pain sensitivity was not affected in either mutant male or female mice. Intraplantar and intrathecal injection of the TLR9 agonist ODN 1826 induced mechanical allodynia in both sexes of wild-type and knockout mice but failed to do so in mutant mice. Moreover, knockout or C-fiber blockade by resiniferatoxin failed to affect intraplantar ODN 1826-induced mechanical allodynia. Interestingly, the development of paclitaxel-evoked mechanical allodynia was attenuated by TLR9 antagonism or mutation only in male mice. Paclitaxel-induced CIPN caused macrophage infiltration to dorsal root ganglia (DRG) in both sexes, and this infiltration was not affected by mutation. Paclitaxel treatment also upregulated TNF and CXCL1 in macrophage cultures and DRG tissues in both sexes, but these changes were compromised by mutation in male animals. Intraplantar adoptive transfer of paclitaxel-activated macrophages evoked mechanical allodynia in both sexes, which was compromised by mutation or by treatment with TLR9 inhibitor only in male animals. Finally, TLR9 antagonism reduced paclitaxel-induced mechanical allodynia in female nude mice (T cell and B cell deficient). Together, these findings reveal sex-dimorphic macrophage TLR9 signaling in chemotherapy-induced neuropathic pain.Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect in cancer patients undergoing clinical chemotherapy treatment regimens. The role of sex-dimorphism with regards to the mechanisms of CIPN and analgesia against CIPN remains unclear. Previous studies have found that the infiltration of immune cells such as macrophages into dorsal root ganglia (DRG) and their subsequent activation promote CIPN. Interestingly, the contribution of microglia to CIPN appears to be limited. Here, we show that macrophage TLR9 signaling promotes CIPN in male mice only. This study suggests that pathways in macrophages may be sex-dimorphic in CIPN. Our findings provide new insights into the role of macrophage signaling mechanisms underlying sex-dimorphism in CIPN, which may inspire the development of more precise and effective therapies.
Learn More >Nociceptors located in the TG and DRG are the primary sensors of damaging or potentially damaging stimuli for the head and body, respectively, and are key drivers of chronic pain states. While nociceptors in these two tissues show a high degree of functional similarity, there are important differences in their development lineages, their functional connections to the central nervous system, and recent genome-wide analyses of gene expression suggest that they possess some unique genomic signatures. Here, we used translating ribosome affinity purification (TRAP) to comprehensively characterize and compare mRNA translation in -positive nociceptors in the TG and DRG of male and female mice. This unbiased method independently confirms several findings of differences between TG and DRG nociceptors described in the literature but also suggests preferential utilization of key signaling pathways. Most prominently, we provide evidence that translational efficiency in mechanistic target of rapamycin (mTOR)-related genes is higher in the TG compared to DRG while several genes associated with the negative regulator of mTOR, AMPK activated protein kinase (AMPK), have higher translational efficiency in DRG nociceptors. Using capsaicin as a sensitizing stimulus we show that behavioral responses are greater in the TG region and this effect is completely reversible with mTOR inhibition. These findings have implications for the relative capacity of these nociceptors to be sensitized upon injury. Altogether, our data provide a comprehensive, comparative view of transcriptome and translatome activity in TG and DRG nociceptors that enhances our understanding of nociceptor biology.The DRG and TG provide sensory information from the body and head, respectively. Nociceptors in these tissues are critical first neurons in the pain pathway. Injury to peripheral neurons in these tissues can cause chronic pain. Interestingly, clinical and preclinical findings support the conclusion that injury to TG neurons is more likely to cause chronic pain and chronic pain in the TG area is more intense and more difficult to treat. We used TRAP technology to gain new insight into potential differences in the translatomes of DRG and TG neurons. Our findings demonstrate previously unrecognized differences between TG and DRG nociceptors that provide new insight into how injury may differentially drive plasticity states in nociceptors in these two tissues.
Learn More >Dorsal root ganglion (DRG) sensory neuron subtypes defined by their in vivo properties display distinct intrinsic electrical properties. We used bulk RNA sequencing of genetically labeled neurons and electrophysiological analyses to define ion channel contributions to the intrinsic electrical properties of DRG neuron subtypes. The transcriptome profiles of eight DRG neuron subtypes revealed differentially expressed and functionally relevant genes, including voltage-gated ion channels. Guided by these data, electrophysiological analyses using pharmacological and genetic manipulations as well as computational modeling of DRG neuron subtypes were undertaken to assess the functions of select voltage-gated potassium channels (Kv1, Kv2, Kv3, and Kv4) in shaping action potential (AP) waveforms and firing patterns. Our findings show that the transcriptome profiles have predictive value for defining ion channel contributions to sensory neuron subtype-specific intrinsic physiological properties. The distinct ensembles of voltage-gated ion channels predicted to underlie the unique intrinsic physiological properties of eight DRG neuron subtypes are presented.
Learn More >Piezo channels are mechanically activated ion channels that confer mechanosensitivity to a variety of different cell types. Piezos oligomerize as propeller-shaped homotrimers that are thought to locally curve the membrane into spherical domes that project into the cell. While several studies have identified domains and amino acids that control important properties such as ion permeability and selectivity as well as inactivation kinetics and voltage sensitivity, only little is known about intraprotein interactions that govern mechanosensitivity-the most unique feature of PIEZOs. Here we used site-directed mutagenesis and patch-clamp recordings to investigate the mechanogating mechanism of PIEZO2. We demonstrate that charged amino acids at the interface between the beam domain-i.e., a long α-helix that protrudes from the intracellular side of the "propeller" blade toward the inner vestibule of the channel-and the C-terminal domain (CTD) as well as hydrophobic interactions between the highly conserved Y2807 of the CTD and pore-lining helices are required to ensure normal mechanosensitivity of PIEZO2. Moreover, single-channel recordings indicate that a previously unrecognized intrinsically disordered domain located adjacent to the beam acts as a cytosolic plug that limits ion permeation possibly by clogging the inner vestibule of both PIEZO1 and PIEZO2. Thus, we have identified several intraprotein domain interfaces that control the mechanical activation of PIEZO1 and PIEZO2 and which might thus serve as promising targets for drugs that modulate the mechanosensitivity of Piezo channels.
Learn More >In this issue of Neuron, Pagani et al. (2019) find that itch signaling occurs only when GRP neurons fire action potentials in bursts. This enables GRP release and the activation of GRPR neurons, which help carry the itch signal to the brain.
Learn More >To evaluate changes from baseline in patient-reported outcomes for measures of functioning and disability among patients with migraine treated with galcanezumab or placebo.
Learn More >Migraine is a prevalent disorder, affecting 15.1% of the world's population. In most cases, the migraine attacks are sporadic; however, some individuals experience a gradual increase in attack frequency over time, and up to 2% of the general population develop chronic migraine. The mechanisms underlying this chronicity are unresolved but are hypothesized to involve a degree of inflammation. In this article, we review the relevant literature related to inflammation and migraine, from the initiation of attacks to chronification. We propose that the increase in migraine frequency leading to chronic migraine involves neurogenic neuroinflammation, possibly entailing increased expression of cytokines via activation of protein kinases in neurons and glial cells of the trigeminovascular system. We present evidence from preclinical research that supports this view and discuss the implications for migraine therapy.
Learn More >Migraine is a common neurological problem associated with the highest burden amongst neurological conditions in terms of years lived with disability. Medications can be used as prophylaxis or rescue medicines, but are costly and not always effective. A range of psychological interventions have been developed to manage migraine.
Learn More >Vincristine, oxaliplatin, and cisplatin are commonly prescribed chemotherapeutic agents for the treatment of many tumors. However, a main side-effect is chemotherapy-induced peripheral neuropathy (CIPN), which may lead to changes in chemotherapeutic treatment. Although symptoms associated with CIPN are recapitulated by mouse models, there is limited knowledge of how these drugs affect the expression of genes in sensory neurons. The present study carried out a transcriptomic analysis of dorsal root ganglia (DRG) following vincristine, oxaliplatin, and cisplatin treatment with a view to gain insight into the comparative pathophysiological mechanisms of CIPN. RNA-Seq revealed 368, 295 and 256 differential expressed genes (DEGs) induced by treatment with vincristine, oxaliplatin and cisplatin, respectively and only five shared genes were dysregulated in all three groups. Cell type enrichment analysis and gene set enrichment analysis showed predominant effects on genes associated with the immune system after treatment with vincristine, while oxaliplatin treatment affected mainly neuronal genes. Treatment with cisplatin resulted in a mixed gene expression signature. Perspective: These results provide insight into the recruitment of immune responses to DRG and indicate enhanced neuro-inflammatory processes following administration of vincristine, oxaliplatin, and cisplatin. These gene expression signatures may provide insight into novel drug targets for treatment of CIPN.
Learn More >This systematic review analyzed available literature on functional brain alterations in low back pain (LBP) measured with electroencephalography (EEG), as until now evidence thereof was unclear. Four electronic databases were systematically searched the 10 of March 2018, resulting in 12 included studies. Studies showed a risk of bias of 37.5%-75% using the Newcastle-Ottawa Scale for case-control studies. Limited evidence reported higher amplitudes of balance-related potentials and early components of somatosensory evoked potentials (SEP) to noxious stimuli, and altered feedback-related negativity and P300 potentials during decision-making in chronic LBP (CLBP). These findings suggest postural strategies requiring a higher cortical attention-demand, increased sensory-discriminative processing of noxious input, and altered decision-making in CLBP. However, further research is warranted as these inferences were based on single studies. Moderate evidence for unaltered amplitude of late-phase SEPs to noxious stimuli and auditory evoked potentials in LBP implies that the affective-emotional processing of stimuli might be unaffected in LBP. Furthermore, moderate evidence indicated disturbed habituation of somatosensory stimuli in LBP. Most studies examined non-specific or mixed CLBP populations, hence EEG-quantified brain activity in (sub)acute or recurrent LBP still needs to be explored. Perspective: This review presents an overview of the current understanding of the functional LBP brain measured with EEG. The limited evidence in current research suggests altered cortical function regarding balance control, somatosensory processing and decision making in LBP, and highlights opportunities for future EEG-research.
Learn More >Gain-of-function missense mutations in the α subunit of neuronal Ca2.1 channels, which define Familial Hemiplegic Migraine Type 1 (FHM1), result in enhanced cortical glutamatergic transmission and a higher susceptibility to cortical spreading depolarization. It is now well established that neurons signal to surrounding glial cells, namely astrocytes and microglia, in the central nervous system, which in turn become activated and in pathological conditions can sustain neuroinflammation. We and others previously demonstrated an increased activation of pro-algogenic pathways, paralleled by augmented macrophage infiltration, in both isolated trigeminal ganglia and mixed trigeminal ganglion neuron-satellite glial cell cultures of FHM1 mutant mice. Hence, we hypothesize that astrocyte and microglia activation may occur in parallel in the central nervous system.
Learn More >Research in adult populations indicates that several sociodemographic and environmental variables increase risk for pain and poor outcomes. There is little research exploring the impact of household income, health insurance coverage, barriers to health care, neighborhood and school safety, violence experienced, and neighborhood isolation on pediatric chronic pain. Data from the Add Health Study, a longitudinal examination of a nationally-representative adolescent sample were analyzed. The relationships between demographic variables, risk factors, chronic pain, and long-term health outcomes were examined. Adolescents with chronic pain had lower income, more health care barriers, greater safety concerns, and experienced more violence compared to those without pain. In a model together, female sex, White race/ethnicity, and greater health care barriers, safety concerns, and violence exposure conferred significant risk for chronic pain. Additional analyses revealed nuances in the strength of risk factors between racial/ethnic groups. Systemic health care barriers were significantly associated with chronic pain and may delay symptom alleviation and return to functioning. Considering access to care is necessary in prevention efforts. Among adolescents with chronic pain, greater safety concerns predicted poor mental health outcomes, particularly for White females. The cumulative stress of environmental concerns, such as safety, and managing chronic pain may worsen functioning. PERSPECTIVE: Adolescents with chronic pain had lower income, and more health care barriers, safety concerns, and violence exposure compared to those without chronic pain. Access to care is a significant problem in youth with chronic pain. The relationships between race/ethnicity, risk factors, and health outcomes is complex and requires additional research.
Learn More >This study examined psychosocial pain treatment moderation in a secondary analysis of a trial that compared cognitive therapy (CT), mindfulness-meditation (MM), and mindfulness-based cognitive therapy (MBCT) for chronic low back pain (CLBP). The Limit, Activate and Enhance (LA&E) model of moderation provided a framework for testing a priori hypotheses. Adult participants (N=69) with CLBP completed a pre-treatment assessment of hypothesized moderators: pain catastrophizing, brain state as assessed by electroencephalogram, mindful observing, and non-reactivity. Outcomes were pain interference, characteristic pain intensity, physical function, and depression, assessed at pre- and post-treatment. Moderation analyses found significant interaction effects, specifically: (1) higher and lower baseline pain catastrophizing was associated with greater improvement in pain intensity in MM and MBCT, respectively; (2) higher baseline theta power was associated with greater improvement in depression in MBCT and interfered with response to CT; (3) lower baseline non-reactivity was associated with greater improvement in physical function in MM while higher non-reactivity was associated with greater improvement in MBCT. The findings support the possibility that different patients are more or less likely to benefit from various treatments. Theory-driven moderation research has the capacity to inform the development of patient-treatment matching algorithms to optimize outcome. Perspective: This study presents preliminary findings from theory-driven tests of the moderators of mindfulness meditation, cognitive therapy and mindfulness-based cognitive therapy for chronic low back pain. The results of such analyses may inform the understanding of for whom various evidence-based psychosocial pain treatments may engender the most meaningful benefits.
Learn More >To determine whether high placebo effects observed in recently published clinical noninvasive vagal nerve stimulation (nVNS) trials can be attributed to an active modulation of the trigeminal-autonomic reflex by the sham device.
Learn More >Pain is among the most common symptoms in cancer and approximately 90% of patients experience end-stage cancer pain. The management of cancer pain is challenging due to the significant side effects associated with opioids, and novel therapeutic approaches are needed. MMG22 is a bivalent ligand containing MOR agonist and mGluR antagonist pharmacophores joined by a 22-atom spacer. MMG22 exhibited extraordinary analgesia following intrathecal administration in a mouse model of bone cancer pain. Here, we assessed the effectiveness of systemic administration of MMG22 in reducing cancer pain and evaluated whether MMG22 displays side effects associated with opioids. Fibrosarcoma cells were injected into and around the calcaneus bone in C3H mice. Mechanical hyperalgesia was defined as an increase in the paw withdrawal frequencies (PWFs) evoked by application of a von Frey monofilament (3.9 mN bending force) applied to the plantar surface of the hind paw. Subcutaneous (s.c.), intramuscular (i.m.), and oral (p.o.) administration of MMG22 produced robust dose-dependent antihyperalgesia, whose ED was orders of magnitude lower than morphine. Moreover, the ED for MMG22 decreased with disease progression. Importantly, s.c. administration of MMG22 did not produce acute (24 h) or long-term (9 days) tolerance, was not rewarding (conditioned place preference test), and did not produce naloxone-induced precipitated withdrawal or alter motor function. A possible mechanism of action of MMG22 is discussed in terms of inhibition of spinal NMDAR via antagonism of its co-receptor, mGluR, and concomitant activation of neuronal MOR. We suggest that MMG22 may be a powerful alternative to traditional opioids for managing cancer pain.
Learn More >Neural responses to incentives are altered in chronic pain and by opioid use. To understand how opioid use modulates the neural response to reward/value in chronic pain, we compared brain functional magnetic resonance imaging (fMRI) responses to a monetary incentive delay (MID) task in patients with fibromyalgia taking opioids (N = 17), patients with fibromyalgia not taking opioids (N = 17), and healthy controls (N = 15). Both groups of patients with fibromyalgia taking and not taking opioids had similar levels of pain, psychological measures, and clinical symptoms. Neural responses in the nucleus accumbens to anticipated reward and non-loss outcomes did not differ from healthy controls in either fibromyalgia group. However, neural responses in the medial prefrontal cortex differed, such that patients with fibromyalgia not taking opioids demonstrated significantly altered responses to anticipated rewards and non-loss outcomes compared to healthy controls, but patients with fibromyalgia taking opioids did not. Despite limitations including the use of additional non-opioid medications by fibromyalgia patients taking opioids, these preliminary findings suggest relatively "normalized" neural responses to monetary incentives in chronic pain patients who take opioids versus those who do not.
Learn More >In this review, we discuss the most recent evidence on mechanisms underlying pathological nociceptive processing in Parkinson's disease patients, as well as novel treatment strategies.
Learn More >: There is a strong association between chronic pain and unhelpful pain cognitions. Educating patients on pain neuroscience has been shown to reduce pain catastrophization, kinesiophobia, and self-perceived disability. This study investigated whether a group-based pain neuroscience education (PNE) session influenced pain-related outcomes, and whether readiness to change moderated these outcomes. : In a pragmatic pre-post-intervention study using a convenience sample, adults with chronic pain participated in one, 90-120 minute PNE session. Pain-related outcomes (i.e. pain catastrophization, kinesiophobia, disability, and pain neuroscience knowledge) and the Pain Stage of Change Questionnaire (PSOCQ) were assessed at baseline and immediately post-intervention. Paired t-tests evaluated pre-post changes in outcomes, and linear regression examined the impact of PSOCQ score changes on PNE-induced changes in clinical outcomes. : Sixty-five participants were recruited. All outcomes showed positive intervention effects ( < .01). Relationships between changes in PSOCQ subscale scores and change in post-intervention pain-related outcomes were found; 'Pre-Contemplation' was positively associated with pain catastrophization ( = .01), and 'Action' was negatively associated with kinesiophobia ( = .03). : Consistent with previous research, there were improvements in outcomes associated with chronic pain after PNE. Some of these improvements were predicted by changes in PSOCQ scores, however, these findings are preliminary and require further investigation using controlled research designs.
Learn More >Unremitting head and neck pain (UHNP) is a commonly encountered phenomenon in Headache Medicine and may be seen in the setting of many well-defined headache types. The prevalence of UHNP is not clear, and establishing the presence of UHNP may require careful questioning at repeated patient visits. The cause of UHNP in some patients may be compression of the lesser and greater occipital nerves by the posterior cervical muscles and their fascial attachments at the occipital ridge with subsequent local perineural inflammation. The resulting pain is typically in the sub-occipital and occipital location, and, via anatomic connections between extracranial and intracranial nerves, may radiate frontally to trigeminal-innervated areas of the head. Migraine-like features of photophobia and nausea may occur with frontal radiation. Occipital allodynia is common, as is spasm of the cervical muscles. Patients with UHNP may comprise a subgroup of Chronic Migraine, as well as of Chronic Tension-Type Headache, New Daily Persistent Headache and Cervicogenic Headache. Centrally acting membrane-stabilizing agents, which are often ineffective for CM, are similarly generally ineffective for UHNP. Extracranially-directed treatments such as occipital nerve blocks, cervical trigger point injections, botulinum toxin and monoclonal antibodies directed at calcitonin gene related peptide, which act primarily in the periphery, may provide more substantial relief for UHNP; additionally, decompression of the occipital nerves from muscular and fascial compression is effective for some patients, and may result in enduring pain relief. Further study is needed to determine the prevalence of UHNP, and to understand the role of occipital nerve compression in UHNP and of occipital nerve decompression surgery in chronic head and neck pain.
Learn More >Sustained pain freedom is an important attribute of acute migraine therapies for patients and physicians. Here we report efficacy of the centrally penetrant, highly selective, 5-HT agonist lasmiditan on sustained pain freedom and other outcomes at 24 and 48 hours post-dose.
Learn More >Avoidance of physical activity is a common migraine management strategy. Anxiety sensitivity (i.e. fear of anxiety and bodily sensations due to physical, cognitive, or social consequences) is a potential correlate of physical activity avoidance and may strengthen beliefs about physical activity's detrimental effect on migraine.
Learn More >In this study, we focused on several itch‑related molecules and receptors in the spinal cord with the goal of clarifying the specific mediators that regulate itch sensation. We investigated the involvement of serotonin receptors, opioid receptors, glia cell markers and chemokines (ligands and receptors) in models of acetone/ether/water (AEW)‑ and diphenylcyclopropenone (DCP)‑induced chronic itch. Using reverse transcription‑quantitative polymerase chain reaction, we examined the expression profiles of these mediators in the lower cervical spinal cord (C5‑8) of two models of chronic itch. We found that the gene expression levels of opioid receptor mu 1 (Oprm1), 5‑hydroxytryptamine receptor 1A (Htr1a) and 5‑hydroxytryptamine receptor 6 (Htr6) were upregulated. Among the chemokines, the expression levels of C‑C motif chemokine ligand (Ccl)21, Cxcl3 and Cxcl16 and their receptors, Ccr7, Cxcr2 and Cxcr6, were simultaneously upregulated in the spinal cords of the mice in both models of chronic itch. By contrast, the expression levels of Ccl2, Ccl3, Ccl4 and Ccl22 were downregulated. These findings indicate that multiple mediators, such as chemokines in the spinal cord, are altered and may be central candidates in further research into the mechanisms involved in the development of chronic itch.
Learn More >Patients with high-frequency episodic migraine (HFEM) have a greater disease burden than those with low-frequency episodic migraine (LFEM). Acute treatment overuse increases the risk of migraine chronification in patients with HFEM. Galcanezumab, a humanized monoclonal antibody binding calcitonin gene-related peptide (CGRP), is effective for migraine prevention with a favorable safety profile. Here, we investigate whether there are differences in galcanezumab efficacy in patients with LFEM or with HFEM.
Learn More >MicroRNAs (miRs) have emerged as biomarkers of migraine disease in both adults and children. In this study we evaluated the expression of hsa-miR-34a-5p and hsa-miR-375 in serum and saliva of young subjects (age 11 ± 3.467 years) with migraine without aura (MWA), while some underwent pharmacological treatment, and healthy young subjects were used as controls. miRs were determined using the qRT-PCR method, and gene targets of hsa-miR-34a-5p and hsa-miR-375 linked to pain-migraine were found by in silico analysis. qRT-PCR revealed comparable levels of hsa-miRs in both blood and saliva. Higher expression of hsa-miR-34a-5p and hsa-miR-375 was detected in saliva of untreated MWAs compared to healthy subjects (hsa-miR-34a-5p: < 0.05; hsa-miR-375 < 0.01). Furthermore, in MWA treated subjects, a significant decrease of hsa-miR-34a-5p and of hsa-miR-375 was documented in saliva and blood compared to MWA untreated ones. Altogether, these findings suggested thathsa-miR-34a-5p and hsa-miR-375 are expressed equally in blood and saliva and that they could be a useful biomarker of disease and of drug efficacy in patients with MWA.
Learn More >To inform feasibility and design of a future randomised controlled trial (RCT) using brain functional MRI (fMRI) to determine the mechanism of action of gabapentin in managing chronic pelvic pain (CPP) in women.
Learn More >Antidepressant medications offer an effective treatment for depression, yet nearly 50% of patients either do not respond or have side-effects rendering them unable to continue the course of treatment. Mechanistic studies might help advance the pharmacology of depression by identifying pathways through which treatments exert their effects. Toward this goal, we aimed to identify the effects of antidepressant treatment on neural connectivity, the relationship with symptom improvement, and to test whether these effects were reproducible across two studies.
Learn More >When patients first develop a painful temporomandibular disorder (TMD) and seek care, 1 priority for clinicians is to assess prognosis. The authors aimed to develop a predictive model by using biopsychosocial measures from the Diagnostic Criteria for Temporomandibular Disorders (DC-TMD) to predict risk of developing TMD symptom persistence.
Learn More >Infants spending extended time in the neonatal intensive care unit are at greater risk of developing a variety of mental health problems later in life, possibly due to exposure to painful/stressful events. We used a rodent model of inflammatory neonatal pain to explore effects on fear conditioning, somatosensory function and maternal behavior. Hindpaw injections of 2% λ-carrageenan on postnatal days 1 and 4 produced an attenuation in conditioned freezing during the postweaning period, similar to our previous work with acute pain, but did not cause lasting impacts on contextual freezing nor somatosensory function. Additionally, we assessed maternal behavior to observe dam-pup interactions during the neonatal period. Results showed dams of litters which experienced pain spent similar amounts of time with pups as undisturbed controls. However, the specific behaviors differed per condition. Dams of pain litters exhibited less time licking/grooming, but more time nursing than controls. These results suggest changes in maternal care following pain could be a contributing factor underlying the long-term effects of neonatal trauma. Furthermore, our laboratory has previously shown acute, but not inflammatory pain, disrupted conditioned freezing; the current experiment observed the long-term effects of neonatal inflammatory pain on conditioned fear using a weak conditioning protocol.
Learn More >Bone cancer pain (BCP), which is induced by primary or metastatic bone cancer, remains a clinically challenging problem due to the poor understanding of its mechanisms. Sirtuin 1 (SIRT1) plays an important role in various pain models. Intrathecal administration of SRT1720, a SIRT1 activator, attenuates BCP in a rat model. However, the expression and activity of SIRT1 during the development and maintenance of BCP remain unknown. Furthermore, the underlying mechanism of SIRT1 in BCP remains ambiguous. In this study, we detected the time course of SIRT1 expression and activity in the spinal cord of mice with BCP and examined whether SRT1720 alleviated BCP by inhibiting metabotropic glutamatergic receptor (mGluR) 1/5 expression. In addition, we downregulated spinal SIRT1 expression in normal mice through an intrathecal injection of AAV-SIRT1-shRNA and then assessed pain behavior and mGluR1/5 expression. Mice with BCP developed significant mechanical allodynia and spontaneous flinching, accompanied by decreased levels of the SIRT1 protein, mRNA, and activity in the spinal cord. The SRT1720 treatment produced an analgesic effect on tumor-bearing mice and decreased the spinal levels of the mGluR1/5 protein and mRNA. In contrast, the AAV-SIRT1-shRNA treatment induced pain behavior in normal mice and increased the spinal levels of the mGluR1/5 protein and mRNA. The results suggested a critical role for SIRT1 in the development and maintenance of BCP and further indicated that activation of SIRT1 in the spinal cord by SRT1720 functionally reverses BCP in mice by inhibiting mGluR1/5.
Learn More >Opioids remain the standard of care in the provision of analgesia in the patient undergoing cancer surgery preoperatively. The effects of opioids on tumor growth and metastasis have been discussed for many years. In recent years their use as part of the perioperative pain management bundle in the patients undergoing cancer surgery has been thought to promote cancer recurrence and metastasis. This narrative review highlights earlier and more recent in vitro, in vivo and human retrospective studies that yield conflicting results as to their immune modulatory effects of morphine on tumor biology. The article examines and explains the discrepancies with regards to the seemingly opposite results of morphine in the tumor milieu. The results of both, earlier studies that demonstrated procarcinogenic effects versus the data of more recent refined rodent studies that more adequately reflect de novo metastasis that yielded neutral or even anti-carcinogenic effects are presented here. Until the results of prospective randomized controlled trials are available to clarify this important question, it is currently not warranted to support opiophobia and opioids continue to constitute a pivotal role in the pain management of cancer patients.
Learn More >To explore the association of peripheral neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) use in patients with cancer.
Learn More >Sigma-1 (σ) receptor antagonists are promising tools for neuropathic pain treatment, but it is unknown whether σ receptor inhibition ameliorates the neuropathic signs induced by nerve transection, in which the pathophysiological mechanisms and response to drug treatment differ from other neuropathic pain models. In addition, σ antagonism ameliorates inflammatory pain through modulation of the endogenous opioid system, but it is unknown whether this occurs during neuropathic pain. We investigated the effect of σ inhibition on the painful hypersensitivity associated with the spared nerve injury (SNI) model in mice. Wild-type (WT) mice developed prominent cold (acetone test), mechanical (von Frey test), and heat hypersensitivity (Hargreaves test) after SNI. σ receptor knockout (ခσ-KO) mice did not develop cold allodynia and showed significantly less mechanical allodynia, although they developed heat hyperalgesia after SNI. The systemic acute administration of the selective σ receptor antagonist S1RA attenuated all three types of SNI-induced hypersensitivity in WT mice. These ameliorative effects of S1RA were reversed by the administration of the σ agonist PRE-084, and were absent in σ-KO mice, indicating the selectivity of S1RA-induced effects. The opioid antagonist naloxone and its peripherally restricted analog naloxone methiodide prevented S1RA-induced effects in mechanical and heat hypersensitivity, but not in cold allodynia, indicating that opioid-dependent and -independent mechanisms are involved in the effects of this σ antagonist. The repeated administration of S1RA twice a day during 10 days reduced SNI-induced cold, mechanical, and heat hypersensitivity without inducing analgesic tolerance during treatment. These effects were observed up to 12 h after the last administration, when S1RA was undetectable in plasma or brain, indicating long-lasting pharmacodynamic effects. These data suggest that σ antagonism may have therapeutic value for the treatment of neuropathic pain induced by the transection of peripheral nerves.
Learn More >Sigma-1 receptors (S1R) and sigma-2 receptors (S2R) may modulate nociception without the liabilities of opioids, offering a promising therapeutic target to treat pain. The purpose of this study was to investigate the analgesic and anti-allodynic activity of two novel sigma receptor antagonists, the S1R-selective CM-304 and its analog the non-selective S1R/S2R antagonist AZ-66. Inhibition of thermal, induced chemical or inflammatory pain, as well as the allodynia resulting from chronic nerve constriction injury (CCI) and cisplatin exposure as models of neuropathic pain were assessed in male mice. Both sigma receptor antagonists dose-dependently (10-45 mg/kg, i.p.) reduced allodynia in the CCI and cisplatin neuropathic pain models, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg, i.p.), although AZ-66 demonstrated a much longer duration of action. Both CM-304 and AZ-66 produced antinociception in the writhing test [0.48 (0.09-1.82) and 2.31 (1.02-4.81) mg/kg, i.p., respectively] equivalent to morphine [1.75 (0.31-7.55) mg/kg, i.p.]. Likewise, pretreatment (i.p.) with either sigma-receptor antagonist dose-dependently produced antinociception in the formalin paw assay of inflammatory pain. However, CM-304 [17.5 (12.7-25.2) mg/kg, i.p.) and AZ-66 [11.6 (8.29-15.6) mg/kg, i.p.) were less efficacious than morphine [3.87 (2.85-5.18) mg/kg, i.p.] in the 55°C warm-water tail-withdrawal assay. While AZ-66 exhibited modest sedative effects in a rotarod assay and conditioned place aversion, CM-304 did not produce significant effects in the place conditioning assay. Overall, these results demonstrate the S1R selective antagonist CM-304 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, supporting the use of S1R antagonists as potential treatments for chronic pain.
Learn More >The incidence of bortezomib-induced neuropathic pain hampers the progress of therapy for neoplasia, and also negatively affects the quality of life of patients. However, the molecular mechanism underlying bortezomib-induced neuropathic pain remains unknown. In the present study, we found that the application of bortezomib significantly increased the expression of GATA binding protein 3 (GATA3) in the spinal dorsal horn, and intrathecal administration of GATA3 siRNA attenuated mechanical allodynia. Furthermore, ChIP-sequencing showed that bortezomib treatment induced the redistribution of GATA3 to transcriptional relevant regions. Notably, combined with the results of mRNA microarray, we found that C-C motif chemokine ligand 21 (CCL21) had an increased GATA3 binding and upregulated mRNA expression in the dorsal horn after bortezomib treatment. Next, we found that bortezomib treatment induced CCL21 upregulation in the spinal neurons, which was significantly reduced upon GATA3 silencing. Blockade of CCL21 using the neutralizing antibody or special siRNA ameliorated mechanical allodynia induced by bortezomib. In addition, bortezomib treatment increased the acetylation of histone H3 and the interaction between GATA3 and CREB-binding protein (CBP). GATA3 siRNA suppressed the CCL21 upregulation by decreasing the acetylation of histone H3. Together, these results suggested that activation of GATA3 mediated the epigenetic upregulation of CCL21 in dorsal horn neurons, which contributed to the bortezomib-induced neuropathic pain.
Learn More >Pain at any age is related to pain experienced at younger ages, but not much is known on how pain develops over the adult life course. We studied long-term individual trajectories of pain over 15 years of the life course and evaluated the role of baseline sociodemographic factors, lifestyle factors and health characteristics.
Learn More >Recent studies have reported structural and functional abnormalities in multiple brain regions of classical trigeminal neuralgia (CTN) patients. Differences in spontaneous neuronal activity between CTN patients and healthy subjects, however, remain unknown. The aim of the present study was to investigate alterations in brain activity by application of amplitude of low frequency fluctuation (ALFF), thus analyzing the correlation between durations of spontaneous pain intensity and ALFF values in CTN patients. A total of 28 CTN patients (male, n=12; female, n=16) and 28 healthy controls (HCs; male, n=12; female, n=16) matched for age and sex were enrolled. All subjects underwent resting‑state functional magnetic resonance imaging and changes in spontaneous brain activity were investigated using an ALFF method. Receiver operating characteristic (ROC) curve analysis was applied to differentiate ALFF values of CTN patients from HCs. Altered ALFF values and clinical manifestations were evaluated using Pearson's correlation analysis. ALFF values of the bilateral inferior cerebellum, bilateral fusiform gyrus, right precentral gyrus, left inferior temporal gyrus, right superior cerebellum, left inferior occipital gyrus and right superior occipital gyrus were significantly higher in CTN patients when compared to HCs. ROC curve analysis of each brain revealed a near‑perfect AUC accuracy. Pearson's correlation analysis revealed the visual analog scale of the right eye to be positively correlated with both left inferior temporal and occipital gyral findings, while episode duration likewise was positively associated with left inferior temporal gyral findings. CTN patients exhibited abnormal spontaneous activity in multiple brain regions closely related to pain regulation and perception, while VAS and CTN episode duration were positively correlated with ALFF signal values in some brain regions. The present findings provide further insight into the pathological mechanisms underlying CTN.
Learn More >Central pain associated with changes in sensory thresholds is one of the most enduring consequences of major trauma. Yet it remains sparsely studied among community-dwelling survivors of moderate-to-severe traumatic brain injury (TBI).
Learn More >Atopic dermatitis (AD) is an inflammatory skin disease with a chronic, relapsing course. Clinical features of AD vary by age, duration, and severity but can include papules, vesicles, erythema, exudate, xerosis, scaling, and lichenification. However, the most defining and universal symptom of AD is pruritus. Pruritus or itch, defined as an unpleasant urge to scratch, is problematic for many reasons, particularly its negative impact on quality of life. Despite the profoundly negative impact of pruritus on patients with AD, clinicians and researchers lack standardized and validated methods to objectively measure pruritus. The purpose of this review is to discuss emerging methods to assess pruritus in AD by describing objective patient-centered tools developed or enhanced over the last decade that can be utilized by clinicians and researchers alike.
Learn More >Several tools can provide a reliable and accurate evaluation of pruritus, including the visual analogue scale (VAS), numeric rating scale (NRS), verbal rating scale (VRS), and multidimensional questionnaires such as the itch severity scale (ISS). However, no single method is considered a gold standard.
Learn More >Liver X receptors (LXRs), including LXRα and LXRβ, are key regulators of transcriptional programs for both cholesterol homeostasis and inflammation in the brain. Here, the modes of action of LXRs and the epigenetic mechanisms regulating LXRβ expression in anterior cingulate cortex (ACC) of chronic inflammatory pain (CIP) are investigated.
Learn More >Although opioids and pregabalin are widely used for cancer-related neuropathic pain (CNP), no clinical trials exist to determine which medications are effective when an opioid-pregabalin combination therapy fails.
Learn More >The most debilitating symptoms during oxaliplatin-based chemotherapy in patients with colorectal cancer (CRC) are neuropathy and fatigue. Inflammation has been suggested to contribute to these symptoms, and the anti-inflammatory agent minocycline is safe and readily available.
Learn More >The long-term use of opioid analgesics is limited by the development of unwanted side-effects, such as tolerance. The molecular mechanisms of morphine anti-nociceptive tolerance are still unclear. The mitochondrial calcium uniporter (MCU) is involved in painful hyperalgesia, but the role of MCU in morphine tolerance has not been uncharacterised.
Learn More >Experimental models of pain in humans are crucial for understanding pain mechanisms. The most often used muscle pain models involve the injection of algesic substances, such as hypertonic saline solution or nerve growth factor, or the induction of delayed onset muscle soreness (DOMS) by an unaccustomed exercise routine. However, these models are either invasive or take substantial time to develop, and the elicited level of pain/soreness is difficult to control. To overcome these shortcomings, we propose to elicit muscle pain by a localized application of short-wave diathermy (SWD).
Learn More >Opioids are highly effective analgesics, however their therapeutic use is limited by adverse effects that include respiratory depression, dependence, and tolerance. Inflammation has been implicated as a significant driver for the development of tolerance to opioids. Recent studies show that chronic morphine in mice results in gut microbial dysbiosis and inflammation in the colon. In the present study we examined whether colonic inflammation results in tolerance to the antinociceptive effects of morphine. Colonic inflammation was induced in mice by intrarectal administration of 2,4,6-trinitro-benzene sulfonic acid (TNBS). The development of antinociceptive tolerance was determined by warm-water tail-immersion assay in mice implanted with 25 mg, 50 mg or 75 mg morphine pellet. Colonic inflammation significantly enhanced the rate at which tolerance developed in each cohort of chronic morphine treated mice. At the lowest dose of morphine pellet (25 mg), antinociceptive tolerance only developed in the presence of colonic inflammation; whereas, in 50 mg and 75 mg pelleted mice, tolerance developed faster in the inflamed animals than the non-inflamed mice. The enhanced antinociceptive tolerance was attenuated with daily administration of peripheral opioid receptor antagonist, 6β-N-heterocyclic substituted naltrexamine derivative (NAP), irrespective of colonic inflammation. Collectively, these findings show that the rate of tolerance to morphine antinociception is exaggerated in the presence of colonic inflammation and tolerance is prevented by a peripheral mu-opioid receptor antagonist. These studies suggest a peripheral component to the development of antinociceptive tolerance to opioids. Furthermore, peripherally selective opioid antagonists may be useful adjuncts in opioid based pain management. SIGNIFICANCE STATEMENT: Our study supports the notion that inflammation influences the development of antinociceptive tolerance to chronic morphine exposure. We found that as the dose of morphine increased in the presence of colonic inflammation, the more tolerant the mice became to the antinociceptive effects of morphine. We also found that treatment with a peripheral opioid receptor antagonist prevented morphine antinociceptive tolerance. By increasing opioid intake during an inflammatory state would result in decreased analgesia and enhanced analgesic tolerance, which puts patients with inflammatory bowel diseases, inflammatory joint diseases, and sickle cell anemia at risk for a heavy opioid use.
Learn More >Patients having chronic musculoskeletal pain (CMP) face challenges as mismatches often exist between the complexity of patient's pain problem and the rehabilitation treatment offered. This can result in less efficient care for the patient and increased medical shopping. The Network Pain Rehabilitation Limburg (NPRL), a transmural integrated healthcare network, will be designed to improve daily care for patients with CMP. NPRL focusses on improving patient's level of functioning despite pain by stimulating a biopsychosocial approach given by all involved healthcare professionals. A feasibility study will be performed which will give insight into the barriers and facilitators, perceived value, acceptability and implementation strategies for NPRL.
Learn More >We conducted a cohort study of adult patients presenting for orthopaedic trauma surgery at a statewide trauma centre, with the aims of determining (i) the incidence and risk factors for severe acute pain in the PACU, and (ii) the incidence and risk factors for persistent post-surgical pain at 3 months.
Learn More >To study the possible associations of various clinically assessed painful signs of temporomandibular disorders (TMD) with the presence of migraine using a large population-based dataset.
Learn More >In western countries, lower back pain (LBP) is one of the most common disorders, experienced by more than 80% of the population. Chronic LBP due to disc degeneration has been linked to ongoing inflammatory processes in the disc and endplates. Pain effects the body in different ways, inducing a general stress response in which the body responds by releasing the stress hormone cortisol. Little is known about the impact of pain-induced stress on the progression of disc degeneration. Thus, the effects of cortisol on disc cells (DCs) and human mesenchymal stem cells (hMSCs) were explored in vitro with the objective of investigating the repercussions of cortisol on these cell types involved in de- and regenerative mechanisms of the disc. DC and hMSC pellet cultures were exposed to cortisol at two concentrations (150 and 300 ng/mL) for 28 days to simulate pain-induced stress. Cell viability, histological staining, and GAG DNA, along with apo-ptotic assays were conducted. Detection of OCT4, SOX9, IL-1R, and CXCR2 expressions was performed by immunohistochemistry. With cortisol treatment, restricted cell proliferation and less GAG production in both DCs and hMSCs were observed. Suppression of the differentiation and immunomodulatory efficacy of hMSCs was also detected. Moreover, elevated expressions of IL-1R and CXCR2 were detected in both cell types. To conclude, constant exposure to cortisol even at a physiological level enhanced pathological cellular processes in both DCs and hMSCs, which further jeopardized chondrogenesis. This suggests that cortisol resulting from pain-induced stress is a contributing component of intervertebral disc degeneration and may negatively affect regenerative attempts of the disc.
Learn More >Chronic pain is one of the commonest reasons individuals seek medical attention. It is a major issue because of the wide inter-individual variability in the analgesic response. This might be partly explained by the presence of variants in genes encoding molecules involved in pharmacodynamics and pharmacokinetics. The aim was to analyze opioid effectiveness in chronic low-back pain (CLBP) relief after opioid titration, unveiling the impact of pharmacogenetics.
Learn More >Exercise therapy (ET) is advocated as a treatment for chronic nonspecific low back pain (CNSLBP). However, therapy effect sizes remain low. In other chronic disorders, training at higher intensity has resulted in greater improvements on both general health related and disease specific outcomes compared to lower intensity ET. Possibly, high intensity training also improves effect sizes in CNSLBP.
Learn More >Patient and Disease Characteristics Associates With Sensory Testing Results in Chronic Pancreatitis.
Abdominal pain is the most common symptom in chronic pancreatitis and has extensive impact on patients' lives. Quantitative sensory testing (QST) provides information on sensitivity to pain and mechanisms which can help quantify pain and guide treatment. The aims of this study were (1) to explore sensitivity to pain in patients with chronic pancreatitis using QST, and (2) to associate patient- and disease characteristics with QST results.
Learn More >: While migraine with aura is a complex neurological syndrome with a well-characterized clinical phenotype, its pathophysiology still has grey areas which could be partially clarified by microstructural and functional neuroimaging investigations. : This article, summarizing the most significant findings from advanced neuroimaging studies, aims to achieve a unifying pathophysiological model of the migraine aura. A comprehensive review has been conducted of PubMed citations by entering the key word 'neuroimaging' combined with 'migraine with aura' AND/OR 'MRI.' Other keywords included 'grey matter' OR 'white matter', 'structural' OR 'functional'. : Converging evidence from advanced neuroimaging investigations underlined the critical role of the extrastriate visual cortex, and in particular the lingual gyrus, in the genesis of the aura phenomenon. However, the relationship between the aura and the headache phase of migraine attacks has not been completely clarified, to date, and underlying pathophysiological mechanisms need to be further elucidated.
Learn More >Operant methods that allow animals to avoid painful stimuli are interpreted to assess the aversive quality of pain; however, such measurements require investigator-initiated stimuli to animals. Here we developed a shuttle maze test to repeatedly assess activity associated nociception without forced stimulation. Rats ambulate back and forth between two treat feeders by taking either a short route with a prickly surfaced arch or a longer route with a smooth floor. L5-L6 spinal nerve ligation (SNL) reduced the preference for the short route with the arch, correlated with hypersensitivity in the hind paw. Oral gabapentin restored the short route preference and reduced hypersensitivity in SNL rats, and blockade of spinal α2-adrenoceptors reduced gabapentin's effects on hypersensitivity but not on preference index. These results suggest that SNL injury alters behavior in the shuttle maze test and that the shuttle maze test shows comparable results to reflexive hypersensitivity after SNL in magnitude and response to gabapentin.
Learn More >Background Recent studies showed the possible association between inflammation-induced blood-brain barrier (BBB) structural changes followed by greater permeability of the BBB and chronic pain. Thus, measurement of BBB breakdown would be a valuable aid in the diagnosis in migraine. Dynamic contrast material-enhanced (DCE) MRI can determine perfusion and permeability properties related to the BBB. Purpose To evaluate the relationship between permeability of the BBB in migraine-associated brain regions by using DCE MRI. Materials and Methods In this prospective study, from September 2016 to December 2017, 56 study participants underwent DCE MRI after gadobutrol administration and were classified into migraine ( = 35) and healthy control ( = 21) groups. Automatic volumetric segmentation was performed on the pre-contrast-enhanced T1-weighted images by using FreeSurfer, and migraine-associated brain region masks were extracted by using the software NordicICE. The corresponding maps for pharmacokinetic parameters (the volume transfer constant) and (the fractional plasma volume) were coregistered with the region-of-interest masks, and their mean values of corresponding total volume of interest were calculated. For comparison analyses, the Mann-Whitney tests were used. Receiver operating characteristic curve analysis and Spearman rank correlation tests were used to identify correlations between clinical characteristics and the aforementioned perfusion parameters. Results Mean age was younger in the migraine group (mean ± standard deviation, 57 years ± 12) than in the healthy control group (mean, 71 years ± 8) ( < .001). In the migraine group, the mean value of in the left amygdala (median, 0.27 mL/100 g) was lower than that in the healthy control group (median, 0.39 mL/100 g) ( = .04). The mean value of in the left amygdala was correlated with the intensity of headache attack in participants with migraine (correlation coefficient, -0.34; = .04). Conclusion Lower fractional plasma volume in the left amygdala was observed in participants with migraine than in healthy participants. © RSNA, 2019 See also the editorial by Carroll and Ginat in this issue.
Learn More >Chronic neuropathic pain constitutes a serious public health problem, but the disease mechanisms are only partially understood. The involvement of different brain regions like the medial prefrontal cortex has already been established, but the comparison of the role of different subregions and layers is still inconclusive. In the current study, we performed patch-clamp recordings followed by anatomical reconstruction of pyramidal cells from different layers of the prelimbic and infralimbic subregions of the medial prefrontal cortex in neuropathic (spared nerve injury, SNI) and control mice. We found that in the prelimbic cortex, layer 2/3 pyramidal cells from SNI mice exhibited increased excitability compared to sham controls, whereas prelimbic layer 5 pyramidal neurons showed reduced excitability. Pyramidal cells in both layer 2/3 and layer 5 of the infralimbic subregion did not change their excitability, but layer 2/3 pyramidal cells displayed increased dendritic length and branching. Our findings support the view that chronic pain is associated with subregion- and layer-specific changes in the medial prefrontal cortex. They therefore provide new insights into the mechanisms underlying the chronification of pain.
Learn More >Perception of sensory stimulation is influenced by numerous psychological variables. One example is placebo analgesia, where expecting low pain causes a painful stimulus to feel less painful. Yet, because pain evolved to signal threats to survival, it should be maladaptive for highly-erroneous expectations to yield unrealistic pain experiences. Therefore, we hypothesised that a cue followed by a highly discrepant stimulus intensity, which generates a large prediction error, will have a weaker influence on the perception of that stimulus. To test this hypothesis we collected two independent pain-cueing datasets. The second dataset and the analysis plan were preregistered ( https://osf.io/5r6z7/ ). Regression modelling revealed that reported pain intensities were best explained by a quartic polynomial model of the prediction error. The results indicated that the influence of cues on perceived pain decreased when stimulus intensity was very different from expectations, suggesting that prediction error size has an immediate functional role in pain perception.
Learn More >MINI: In multivariate logistic regression analysis in 1,128 elderly people, NeP(+) (odds ratio (OR): 3.01), positive spinal inclination (OR: 1.14), and high VAS for LBP (OR: 1.04) were identified as risk factors for low physical QOL, and NeP(+) (OR: 5.32) was the only significant risk factor for low mental QOL.
Learn More >Opioids are the mainstay of pain management after burn injury. The United States currently faces an epidemic of opioid overuse and abuse, while simultaneously experiencing a nationwide shortage of intravenous narcotics. Adjunctive pain management therapies must be sought and utilized to reduce the use of opioids in burn care to prevent the long-term negative effects of these medications and to minimize the dependence on opioids for analgesia. The purpose of this review was to identify literature on adjunctive pain management therapies that have been demonstrated to reduce pain severity or opioid consumption in adult burn patients. Three databases were searched for prospective studies, randomized controlled trials, and systematic reviews that evaluated adjunctive pain management strategies published between 2008 and 2019 in adult burn patients. Forty-six studies were analyzed, including 24 randomized control trials, six crossover trials, and ten systematic reviews. Various adjunctive pain management therapies showed statistically significant reduction in pain severity. Only one randomized control trial on music therapy for acute background pain showed a reduction in opioid use. One cohort study on hypnosis demonstrated reduced opioid use compared with historical controls. We recommend the development of individualized analgesic regimens with the incorporation of adjunctive therapies in order to improve burn pain management in the midst of an abuse crisis and concomitant national opioid shortage.
Learn More >Migraine is a common disorder most typically presenting as headache and often associated with vertigo and motion sickness. It is a genetically complex condition with multiple genes ultimately contributing to the predisposition and development of this episodic neurological disorder. We identified a large American family of 29 individuals of which 17 members suffered from at least one of these disorders, migraine, vertigo, or motion sickness. Many of these individuals suffered from several simultaneously. We hypothesized that vertigo and motion sickness may involve genes that are independent to those directly contributing to migraine susceptibility.
Learn More >By definition, post-traumatic headache (PTH) attributed to mild traumatic brain injury (mTBI) is not associated with brain structural abnormalities that are seen on routine clinical inspection of brain images. However, subtle brain structural abnormalities, as well as functional abnormalities, detected via research imaging techniques yield insights into the pathophysiology of PTH. The objective of this manuscript is to summarize published findings regarding research imaging of the brain in PTH attributed to mTBI. For this narrative review, PubMed was searched using the terms "post-traumatic headache" or "post-concussion headache" and "imaging" or "magnetic resonance imaging" or "research imaging" or "positron emission tomography". Articles were chosen for inclusion based on their relevance to the topic. Ten articles were ultimately included within this review. The studies investigated white matter tract integrity and functional connectivity in acute PTH, structural measures, white matter tract integrity, cerebral blood flow, and functional connectivity in persistent PTH (PPTH), and proton spectroscopy in both acute and persistent PTH. The articles demonstrate that acute and persistent PTH are associated with abnormalities in brain structure, that acute and persistent PTH are also associated with abnormalities in brain function, that it might be possible to predict the persistence of PTH using brain imaging findings, and that there are differences in imaging findings when comparing PTH to healthy controls and when comparing PTH to migraine. Although it is not entirely clear if the imaging findings are directly attributable to PTH as opposed to the underlying TBI or other post-TBI symptoms, correlations between the imaging findings with headache frequency and headache resolution suggest a true relationship between the imaging findings and PTH. PTH attributed to mTBI is associated with abnormalities in brain structure and function that can be detected via research imaging. Additional studies are needed to determine the specificity of the findings for PTH, to differentiate findings attributed to PTH from those attributed to the underlying TBI and coexistent post-TBI symptoms, and to determine the accuracy of imaging findings for predicting the development of PPTH.
Learn More >Bone cancer pain (BCP) is refractory to currently available clinical treatment owing to its complicated underlying mechanisms. Studies found that extracellular matrix molecules can participate in the regulation of chronic pain. Decorin is one of the most abundant extracellular matrix molecules, the present study evaluated the effect of decorin on the development of BCP. We found that decorin was upregulated in the L4-6 spinal dorsal horn of the BCP rats. Spinal microinjection of a decorin-targeting RNAi lentivirus alleviated BCP-induced mechanical allodynia and reduced the expression of pGluR1-Ser831 in the BCP rats. Meanwhile, decorin knockdown impaired the excitatory synaptogenesis in cultured neurons and prevented the clustering and insertion of pGluR1-Ser831 into postsynaptic membranes. Taken together, the results of our study suggested that decorin contributes to the development of BCP possibly by regulating the activity of excitatory synaptic molecules in the spinal cord. Our findings provide a better understanding of the function of decorin as a possible therapeutic target for alleviating BCP.
Learn More >Background and aims Chronic low back pain (CLBP) is a complex disorder where central and peripheral nociceptive processes are influenced by factors from multiple dimensions associated with CLBP (e.g. movement, pain sensitivity, psychological). To date, outcomes for treatments matched to unidimensional subgroups (e.g. psychologically-based) have been poor. Therefore, unidimensional subgrouping may not reflect the complexity of CLBP presentations at an individual level. The aim of this study was therefore to explore patterns of classification at an individual level across the three previously-published, data-driven, within-dimension subgrouping studies. Methods Cross-sectional, multidimensional data was collected in 294 people with CLBP. Statistical derivation of subgroups within each of three clinically-important dimensions (pain sensitivity, psychological profile, pain responses following repeated spinal bending) was briefly reviewed. Patterns of classification membership were subsequently tabulated across the three dimensions. Results Of 27 possible patterns across these dimensions, 26 were represented across the cohort. Conclusions This result highlights that while unidimensional subgrouping has been thought useful to guide treatment, it is unlikely to capture the full complexity of CLBP. The amount of complexity important for best patient outcomes is currently untested. Implications For clinicians this study highlights the high variability of presentations of people with CLBP at the level of the individual. For example, clinician's should not assume that those with high levels of pain sensitivity will also have high psychological distress and have pain summation following repeated spinal bending. A more flexible, multidimensional, clinically-reasoned approach to profile patient complexity may be required to inform individualised, patient-centred care. Such individualised care might improve treatment efficacy. This study also has implications for researchers; highlighting the inadequacy of unidimensional subgrouping processes and methodological difficulties in deriving subgroups across multidimensional data.
Learn More >Advanced glycation end-products (AGEs) are proteins/lipids that are glycated upon sugar exposure and are often increased during inflammatory diseases such as osteoarthritis and neurodegenerative disorders. Here, we developed an extracellular matrix (ECM) using glycated type I collagen (ECM-GC), which produced similar levels of AGEs to those detected in the sera of arthritic mice. In order to determine whether AGEs were sufficient to stimulate sensory neurons, dorsal root ganglia (DRGs) cells were cultured on ECM-GC or ECM-NC-coated plates. ECM-GC or ECM-NC were favorable for DRG cells expansion. However, ECM-GC cultivated neurons displayed thinner F-actin filaments, rounded morphology, and reduced neuron interconnection compared to ECM-NC. In addition, ECM-GC did not affect RAGE expression levels in the neurons, although induced rapid p38, MAPK and ERK activation. Finally, ECM-GC stimulated the secretion of nitrite and TNF-α by DRG cells. Taken together, our in vitro glycated ECM model suitably mimics the in vivo microenvironment of inflammatory disorders and provides new insights into the role of ECM impairment as a nociceptive stimulus.
Learn More >Opioids are commonly prescribed to patients with painful and symptomatic degenerative joint disease preoperatively as a nonoperative intervention to reduce patients' symptoms and pain. The goal of total joint arthroplasty (TJA) is to reduce or eliminate the painful symptoms of degenerative joint disease. Due to the addictive property of opioid medications, some patients may develop a pattern of chronic opioid use after TJA.
Learn More >Small-surface-area electrodes have successfully been used to preferentially activate cutaneous nociceptors, unlike conventional large area-electrodes, which preferentially activate large non-nociceptor fibers. Assessments of the strength-duration relationship, threshold electrotonus, and slowly increasing pulse forms have displayed different perception thresholds between large and small surface electrodes, which may indicate different excitability properties of the activated cutaneous nerves. In this study, the origin of the differences in perception thresholds between the two electrodes was investigated. It was hypothesized that different perception thresholds could be explained by the varying distributions of voltage-gated ion channels and by morphological differences between peripheral nerve endings of small and large fibers. A two-part computational model was developed to study activation of peripheral nerve fibers by different cutaneous electrodes. The first part of the model was a finite-element model, which calculated the extracellular field delivered by the cutaneous electrodes. The second part of the model was a detailed multicompartment model of an Aδ-axon as well as an Aβ-axon. The axon models included a wide range of voltage-gated ion channels: Na, Na, Na, K, K, K, and HCN channel. The computational model reproduced the experimentally assessed perception thresholds for the three protocols, the strength-duration relationship, the threshold electrotonus, and the slowly increasing pulse forms. The results support the hypothesis that voltage-gated ion channel distributions and morphology differences between small and large fibers were sufficient to explain the difference in perception thresholds between the two electrodes. In conclusion, assessments of perception thresholds using the three protocols may be an indirect measurement of the membrane excitability, and computational models may have the possibility to link voltage-gated ion channel activation to perception threshold measurements.
Learn More >Fibromyalgia is a disease characterised as generalised chronic primary pain that causes functional disability and a reduction in patients' quality of life, without specific pathophysiology or appropriate treatment. Previous studies have shown that kinins and their B and B receptors contribute to chronic painful conditions. Thus, we investigated the involvement of kinins and their B and B receptors in a fibromyalgia-like pain model induced by reserpine in mice. Nociceptive parameters (mechanical allodynia, cold sensitivity and overt nociception) and behaviours of burrowing, thigmotaxis, and forced swimming were evaluated after reserpine administration in mice. The role of kinin B and B receptors was investigated using knockout mice or pharmacological antagonism. The protein expression of kinin B and B receptors and the levels of bradykinin and monoamines were measured in the sciatic nerve, spinal cord and cerebral cortex of the animals. Knockout mice for the kinin B and B receptor reduced reserpine-induced mechanical allodynia. Antagonism of B and B receptors also reduced mechanical allodynia, cold sensitivity and overt nociception reserpine-induced. Reserpine altered thigmotaxis, forced swimming and burrowing behaviour in the animals; with the latter being reversed by antagonism of kinin B receptor. Moreover, reserpine increased the protein expression of kinin B and B receptors and levels of kinin, as well as reduced the levels of monoamines in peripheral and central structures. Kinins and its B and B receptors are involved in fibromyalgia-like pain symptoms. B or B receptors might represent a potential target for the relief of fibromyalgia-like pain symptoms.
Learn More >Exercise therapy such as motor control training (MCT) has been shown to reduce pain and disability in people with low back pain (LBP). It is unknown which patients are most likely to benefit. This longitudinal cohort study aimed to: (1) retrospectively examine records from a large cohort of patients who received MCT treatment, (2) identify potentially important predictors of response to MCT and (3) test the predictors on an independent (split) sample derived from the original cohort of patients, using one group to identify the predictors and the other to test them.
Learn More >Vestibular migraine (VM) has been recognized as a diagnostic entity over the past three decades. It affects up to 1% of the general population and 7% of patients seen in dizziness clinics. It is still underdiagnosed; consequently, it is important to conduct clinical studies that address diagnostic indicators of VM. The aim of this study was to assess auditory brainstem function in women with vestibular migraine using electrophysiological testing, contralateral acoustic reflex and loudness discomfort level.
Learn More >Chronic widespread pain (CWP) is one of the most difficult pain conditions to treat due to an unknown etiology and a lack of innovative treatment design and effectiveness. Based upon preliminary findings within the fields of motivational psychology, integrative neuroscience, diaphragmatic breathing, and vagal nerve stimulation, we propose a new treatment intervention, motivational non-directive (ND) resonance breathing, as a means of reducing pain and suffering in patients with CWP. Motivational ND resonance breathing provides patients with a noninvasive means of potentially modulating five psychophysiological mechanisms imperative for endogenously treating pain and increasing overall quality of life.
Learn More >Genome-wide-association studies in chronic low back pain patients identified sepiapterin reductase as a high interest target for developing new analgesics. Here we used F NMR fragment screening for the discovery of novel, ligand-efficient SPR inhibitors. We report the crystal structures of six chemically diverse inhibitors complexed with SPR, identifying relevant interactions and binding modes in the sepiapterin pocket. Exploration of our initial fragment screening hit led to double-digit nanomolar inhibitors of SPR with excellent ligand efficiency.
Learn More >: To study chronic widespread pain (CWP) over time in patients with spondyloarthritis (SpA), and to identify risk factors for development and persistence of CWP. : In this cohort study with baseline and 2.5 year follow-up postal surveys, patients with ankylosing spondylitis (AS) and undifferentiated spondyloarthritis (USpA) (47% women) answered questions regarding pain, and were categorized as no chronic pain (NCP), chronic regional pain (CRP), or CWP. For each risk factor candidate (disease duration, body mass index, smoking, and patient-reported outcome measures), logistic regression analyses with CWP as the main outcome were performed separately, together with a basic model including age, gender, and SpA subgroup. : Altogether, 644 patients could be categorized at both time-points, yielding similar prevalence estimates at baseline and follow-up, although 38% transitioned between pain groups. Risk factors (odds ratio; 95% confidence interval) for development of CWP included more pain regions (1.36; 1.20‒1.53), higher pain intensity (1.35; 1.20‒1.52), worse fatigue (1.25; 1.13‒1.38), and worse global health (1.35; 1.19‒1.54). Persistent CWP was reported by 72%. In addition to factors predicting development of CWP, higher age (1.02; 1.00‒1.04), female gender (1.82; 1.06‒3.10), and anxiety (1.07; 1.00-1.14) also predicted persistence. : The prevalence of CWP remained high over time, but with individual transitions between the pain groups. The development and persistence of CWP were predicted by more pain and worse health, with the addition of female gender and higher age for persistent CWP. Special attention and treatment alternatives for patients with SpA and concomitant CWP are essential in the clinic.
Learn More >