Browse by Audience
To investigate the dynamic functional connectivity of thalamo-cortical networks in interictal migraine patients and whether clinical features are associated with abnormal connectivity.
Learn More >Persistent and neuropathic pain affects >15% of the global population. Apart from being an individual burden to the patient, persistent pain causes considerable subsequent costs in global healthcare systems. Despite the efforts of pharmaceutical companies to develop novel analgesics, pharmacological options for the therapy of persistent and/or neuropathic pain are limited. We discuss here novel approaches to persistent pain therapy that are independent of classical target-based drug discovery, focusing on individualized diagnostic technologies, improvement of existing therapies, and expansion of current pharmacological treatments and future techniques that may broaden pharmacological options for the individual treatment of persistent pain in patients.
Learn More >This study was performed to test whether the risk of developing chronic widespread pain (CWP) in those with regional pain was augmented in those with symptoms of neuropathic pain (NP). Persons free of CWP completed the Douleur Neuropathique 4 (scores ≥3 indicating NP); demographics; Hospital Anxiety and Depression scale; Pittsburgh Sleep Quality Index; and pain medications. Participants were classified as having no pain, regional pain with no symptoms of NP (NP-), or regional pain with symptoms of NP (NP). At the 12-month follow-up, participants with CWP were identified. Logistic regression estimated the odds ratio, with 95% confidence intervals, of CWP in the NP- and NP groups compared with no pain, and NP compared with NP-. Partial population attributable risks estimated the proportion of CWP attributable to baseline NP- or NP exposure. One thousand one hundred sixty-two participants completed the baseline DN4 and provided pain data at follow-up: 523 (45.0%) had no baseline pain, 562 (48.4%) NP-, and 77 (6.6%) NP. One hundred fifty-three (13.2%) had CWP at 12 months: 19 (3.6%) no pain, 108 (19.2%) NP-, and 26 (33.8%) NP. NP- (2.9 [1.9-4.3]) and NP (2.1 [1.1-4.0]) predicted CWP after adjusting for demographics, Hospital Anxiety and Depression scale, Pittsburgh Sleep Quality Index, and medications. The partial population attributable risk was 41.3% (25.2-54.0) for NP- and 6.0% (0.1-11.6) for NP. The NP group were not more likely to develop CWP when compared directly with NP- (1.5 [0.8-2.8]). Neuropathic pain was relatively rare and predicted a small number of new-onset CWP cases. Using these estimates, treatments targeting NP would at best prevent 6% of CWP cases.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Learn More >Pain is a frequent and disabling symptom in multiple sclerosis (MS) patients; however, the underlying mechanisms of MS-related pain is not fully understood. Here, we demonstrated that cathepsin E (CatE) in neutrophils contributes to the generation of mechanical allodynia in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We showed that CatE-deficient (CatE) mice were highly resistant to myelin oligodendrocyte glycoprotein (MOG35-55)-induced mechanical allodynia. After MOG35-55 immunization, neutrophils immediately accumulated in the dorsal root ganglion (DRG). Adoptive transfer of MOG35-55-stimulated wild-type neutrophils into the DRG induced mechanical allodynia in the recipient C57BL/6 mice. On the other hand, the pain threshold did not change when MOG35-55-stimulated CatE neutrophils were transferred into the recipient C57BL/6 mice. MOG35-55 stimulation caused CatE-dependent secretion of elastase in neutrophils. Behavioral analyses revealed that sivelestat, a selective neutrophil elastase inhibitor, suppressed mechanical allodynia induced by adoptively transferred MOG35-55-stimulated neutrophils. MOG35-55 directly bound to toll-like receptor 4, which led to increased production of CatE in neutrophils. Our findings suggest that inhibition of CatE-dependent elastase production in neutrophil might be a potential therapeutic target for pain in MS patients.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Learn More >Neuropathic pain is frequently driven by ectopic impulse discharge (ectopia) generated in injured peripheral afferent neurons. Observations in the spinal nerve ligation (SNL) model in rats suggest that cell bodies in the dorsal root ganglion (DRG) contribute three times more to the ectopic barrage than the site of nerve injury (neuroma). The DRG is therefore a prime interventional target for pain control. Since DRG ectopia is selectively suppressed with lidocaine at concentrations too low to block axonal impulse propagation, we asked whether targeted delivery of dilute lidocaine to the L5 DRG can relieve L5 SNL-induced tactile allodynia without blocking normal sensation or motor function. Results showed that intraforaminal injection of 10 µL bolus doses of 0.2% lidocaine suppressed allodynia transiently, while sustained infusion over 2 weeks using osmotic minipumps suppressed it for nearly 2 weeks. Bolus injections of morphine or fentanyl were ineffective. Lidocaine applied to the cut spinal nerve end or the L4 DRG did not affect allodynia suggesting that discharge originating in the neuroma and in neighboring "uninjured" afferents makes at best a minor contribution. Spike electrogenesis in the DRG is apparently the primary driver of tactile allodynia in the SNL model of neuropathic pain and it can be controlled selectively by superfusing the relevant DRG(s) with non-blocking concentrations of lidocaine. This approach has potential clinical application in conditions such as postherpetic neuralgia and phantom limb pain in which one or only a few identifiable ganglia are implicated as pain drivers.
Learn More >To determine the risk of prolonged opioid use in patients receiving tramadol compared with other short acting opioids.
Learn More >Complex regional pain syndrome (CRPS) typically develops after fracture or trauma. Many of the studies so far have analyzed clinical and molecular markers of CRPS in comparison to healthy or pain controls. This approach, however, neglects mechanisms occurring during physiological trauma recovery. Therefore, we compared the clinical phenotype, sensory profiles, patients reported outcomes (PRO) and exosomal immunobarrier microRNAs (miRs) regulating barrier function and immune response between CRPS and fracture controls (FC) not fulfilling the CRPS diagnostic criteria. We included upper extremity FCs, acute CRPS I patients within one year after trauma, a second disease control group (painful diabetic polyneuropathy, pDN) and healthy controls. FCs were not symptoms-free, but reported some pain, disability, anxiety and cold pain hyperalgesia in quantitative sensory testing (QST). CRPS patients had higher scores for pain, disability and all PROs. In QST, ipsi- and contralateral side differed significantly. However, on the affected side CRPS patients were more sensitive in only three parameters (pinprick pain and blunt pressure) when compared to FCs. Two principal components were identified in the cohort: pain and psychological parameters distinguishing FC and CPRS. Furthermore, the immunobarrier-protective hsa-miR-223-5p was increased in plasma exosomes in FCs with normal healing, but not in CRPS and healthy controls. Low hsa-miR-223-5p was particularly observed in subjects with edema pointing towards barrier breakdown. In summary, normal trauma healing includes some CRPS signs and symptoms. It is the combination of different factors which distinguish CRPS and FC. FC as a control group can assist to discover resolution factors after trauma.
Learn More >Musculoskeletal pain is associated with altered motor control that despite short-term benefit, is hypothesised to have long-term consequences, contributing to the development of chronic pain. However, data on how motor control is altered when pain is sustained beyond a transient event are scarce. Here, we investigated motor adaptation, and its relationship to corticomotor excitability, in the transition to sustained muscle pain. Twenty-eight healthy individuals were injected with nerve growth factor (NGF) into the right extensor carpi radialis brevis (ECRB) muscle on Days 0 and 2. Motor adaptation and corticomotor excitability were assessed on Day -2, prior to injection on Days 0 and 2, and again on Days 4 and 14. Motor adaptation was quantified during a radial-ulnar movement as kinematic variability of wrist flexion-extension and pronation-supination, and as electromyographic (EMG) variability of ECRB activity. Pain, muscle soreness, and functional limitation were assessed from Days 0-14. Pain, muscle soreness and functional limitation were evident at Days 2 and 4 (p<0.001). EMG variability reduced at Days 4 and 14 (p<0.04), with no change in kinematic variability (p=0.9). However, data revealed variation in EMG and kinematic variability between individuals: some displayed increased motor variability while others a decrease. Individuals who displayed an increase in EMG variability following four days of pain also displayed an increase in corticomotor excitability (r=0.43, p=0.034). These findings suggest individual adaptation of the motor system in the transition to sustained pain that could have implications for clinical musculoskeletal pain disorders.
Learn More >Complex regional pain syndrome (CRPS) is a severely disabling disease characterized by pain, temperature changes, motor dysfunction and edema that most often occurs as an atypical response to a minor surgery or fracture. Inflammation involving activation and recruitment of innate immune cells, including both peripheral and central myeloid cells (i.e. macrophages and microglia, respectively), is a key feature of CRPS. However, the exact role and time-course of these cellular processes relative to the known acute and chronic phases of the disease are not fully understood. Positron emission tomography (PET) of translocator protein-18kDa (TSPO) is a method for non-invasively tracking these activated innate immune cells. Here, we reveal the temporal dynamics of peripheral and central inflammatory responses over 20 weeks in a tibial fracture/casting mouse model of CRPS through longitudinal TSPO-PET using [F]GE-180. PET tracer uptake quantification in the tibia revealed increased peripheral inflammation as early as 2 days post-fracture and lasting 7 weeks. Centralized inflammation was detected in the spinal cord and brain of fractured mice at 7 and 21 days post-injury. Spinal cord tissue immunofluorescent staining revealed TSPO expression in microglia (CD11b+) at 7 days, but was restricted mainly to endothelial cells (PECAM1+) at baseline and 7 weeks. Our data suggest early and persistent peripheral myeloid cell activation, and transient central microglial activation are limited to the acute phase of CRPS. Moreover, we show that TSPO-PET can be used to noninvasively monitor the spatiotemporal dynamics of myeloid cell activation in CRPS progression with potential to inform disease phase-specific therapeutics.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Learn More >The mechanisms underlying the transition from acute to chronic pain remain unclear. Here, we sought to characterize the transcriptome associated with chronic low back pain as well as the transcriptome of the transition from acute to chronic low back pain. For the analysis, we compared the whole blood transcriptome of: (a) patients at the onset of low back pain who no longer had pain within 6 weeks after onset (acute) with patients who developed chronic low back pain at 6 months (chronic T5); and, (b) patients at the onset of low back pain (chronic T1) who developed chronic pain at 6 months with healthy pain-free (normal) controls. The majority of differentially expressed genes were protein coding. We illustrate a unique chronic low back pain transcriptome characterized by significant enrichment for known pain genes, extracellular matrix genes, and genes from the extended major histocompatibility complex (MHC) genomic locus. The transcriptome of the transition from acute to chronic low back pain was characterized by significant upregulation of antigen presentation pathway (MHC class I and II) genes and downregulation of mitochondrial genes associated with oxidative phosphorylation, suggesting a unique genomic signature of vulnerability to low back pain chronicity.
Learn More >Internalizing mental health issues co-occur with pediatric chronic pain at high rates and are linked to worse pain and functioning. Although the field has prioritized anxiety and posttraumatic stress disorder, little is known about co-occurring depression and chronic pain in youth, despite its high prevalence. The purpose of this narrative review was to examine the existing literature on the co-occurrence of pediatric chronic pain and depressive disorders and symptoms and propose a conceptual model of mutual maintenance to guide future research.
Learn More >Recent findings from a phase II clinical trial showed analgesic effects of an angiotensin II type-2 receptor (AT2R) antagonist in postherpetic neuralgia patients. This study aimed to investigate whether AT2R antagonism could provide effective analgesia in voluntary measures of unevoked/ongoing pain-like behaviors in mice with experimental neuropathy. Mice were subjected to spared nerve injury to induce neuropathy and tested in 2 operant behavioral tests to measure ongoing mechanical and cold pain hypersensitivities. Systemic administration of an AT2R antagonist provided effective analgesia in these behavioral measures of mechanical and cold pain in spared nerve injury mice, suggesting its effectiveness in neuropathic pain.
Learn More >mRNA function is meticulously controlled. We provide an overview of the integral role that posttranscriptional controls play in the perception of painful stimuli by sensory neurons. These specialized cells, termed nociceptors, precisely regulate mRNA polarity, translation, and stability. A growing body of evidence has revealed that targeted disruption of mRNAs and RNA-binding proteins robustly diminishes pain-associated behaviors. We propose that the use of multiple independent regulatory paradigms facilitates robust temporal and spatial precision of protein expression in response to a range of pain-promoting stimuli. This article is categorized under: RNA in Disease and Development > RNA in Disease Translation > Translation Regulation RNA Turnover and Surveillance > Regulation of RNA Stability.
Learn More >Peripheral sensory neurons express multiple voltage-gated sodium channels (Na ) critical for the initiation and propagation of action potentials and transmission of sensory input. Three pore-forming sodium channel isoforms are primarily expressed in the peripheral nervous system (PNS): Na 1.7, Na 1.8 and Na 1.9. These sodium channels have been implicated in painful and painless channelopathies and there has been intense interest in them as potential therapeutic targets in human pain. Emerging evidence suggests Na 1.6 channels are an important isoform in pain sensing. This study aimed to assess, using pharmacological approaches, the function of Na 1.6 channels in peripheral sensory neurons. The potent and Na 1.6 selective β-scorpion toxin Cn2 was used to assess the effect of Na 1.6 channel activation in the PNS. The multidisciplinary approach included; Ca imaging, whole-cell patch-clamp recordings, skin- and gut-nerve preparations and in vivo behavioural assessment of pain behaviours. Cn2 facilitates Na 1.6 early channel opening, increased persistent and resurgent currents in large diameter DRG neurons. This promotes enhanced excitatory drive and tonic action potential firing in these neurons. In addition, Na 1.6 channel activation in the skin and gut leads to increased response to mechanical stimuli. Finally, intra-plantar injection of Cn2 causes mechanical but not thermal allodynia. This study confirms selectivity of Cn2 on Na 1.6 channels in sensory neurons. Activation of Na 1.6 channels, in terminals of the skin and viscera, leads to profound changes in neuronal responses to mechanical stimuli. In conclusion, sensory neurons expressing Na 1.6 are important for the transduction of mechanical information in sensory afferents innervating the skin and viscera. This article is protected by copyright. All rights reserved.
Learn More >IV ketamine is widely used to treat patients with chronic pain, yet the long-term impact remains uncertain. We synthesized evidence from randomized control trials to investigate the effectiveness of IV ketamine infusions for pain relief in chronic conditions and to determine whether any pain classifications or treatment regimens are associated with greater benefit.
Learn More >Our preliminary experiment indicated the activation of with-nolysine kinases 1 (WNK1) in bone cancer pain (BCP) rats. This study aimed to investigate the underlying mechanisms via which WNK1 contributed to BCP. A rat model of BCP was induced by Walker-256 tumor cell implantation. WNK1 expression and distribution in the lumbar spinal cord dorsal horn (DH) and dorsal root ganglion (DRG) were examined. SPS1-related proline/alanine-rich kinase (SPAK), oxidative stress-responsive kinase 1 (OSR1), sodium-potassium-chloride cotransporter 1 (NKCC1), and potassium-chloride cotransporter 2 (KCC2) expression were assessed. Pain behaviors including mechanical allodynia and movement-evoked pain were measured. BCP rats exhibited significant mechanical allodynia, with increased WNK1 expression in the DH and DRG neurons, elevated SPAK/OSR1 and NKCC1 expression in the DRG, and decreased KCC2 expression in the DH. WNK1 knock-down by siRNA alleviated mechanical allodynia and movement-evoked pain, inhibited WNK1-SPAK/OSR1-NKCC1 activities, and restored KCC2 expression. In addition, closantel (a WNK1-SPAK/OSR1 inhibitor) improved pain behaviors, down-regulated SPAK/OSR1 and NKCC1 expression, and up-regulated KCC2 expression in BCP rats. Activation of WNK1-SPAK/OSR1 signaling contributed to BCP in rats by modulating NKCC1 and KCC2 expression. Therefore, suppression of WNK1-SPAK/OSR1 may serve as a potential target for BCP therapy. Perspective: Our findings demonstrated that the WNK1-SPAK/OSR1 signaling contributed to BCP in rats via regulating NKCC1 and KCC2. Suppressing this pathway reduced pain behaviors. Based on these findings, the WNK1-SPAK/OSR1 signaling may be a potential target for BCP therapy.
Learn More >Increased mRNA translation in sensory neurons following peripheral nerve injury contributes to the induction and maintenance of chronic neuropathic pain. Metformin, a common anti-diabetic drug and an activator of AMP-activated protein kinase (AMPK), inhibits cap-dependent mRNA translation and reverses mechanical hypersensitivity caused by a neuropathic injury in both mice and rats. P-bodies are RNA granules that comprise sites for metabolizing mRNA through the process of de-capping followed by RNA decay. These RNA granules may also sequester mRNAs for storage. We have previously demonstrated that induction of cap-dependent translation in cultured trigeminal ganglion (TG) neurons decreases P-body formation and AMPK activators increase P-body formation. Here we examined the impact of AMPK activation on protein synthesis and P-body formation and on mouse dorsal root ganglion (DRG) neurons. We demonstrate that AMPK activators inhibit nascent protein synthesis and increase P-body formation in DRG neurons. We also demonstrate that mice with a spared-nerve injury (SNI) show decreased P-bodies in the DRG, consistent with increased mRNA translation resulting from injury. Metformin treatment normalizes this effect in SNI mice and increases P-body formation in sham animals. These findings indicate that P-bodies are dynamically regulated by nerve injury and this effect can be regulated via AMPK activation.
Learn More >We explored the ongoing question of whether placebo analgesia alters afferent nociceptive processing in a novel paradigm designed to minimize the role of response bias in placebo measurement. First, healthy adult participants received a standard heat placebo induction and conditioning procedure using a topical "analgesic" cream applied to one arm. During a subsequent placebo testing procedure, participants rated stimuli on the placebo-treated arm and untreated arm, using a task that minimized subjects' ability to guess the expected response, thus reducing experimenter demand. Retrospectively participants reported moderate analgesia effectiveness (mean=5.3/10), but for individual temperature ratings, only 2 subjects exhibited a perceptual placebo response >5 points. Next, these subjects completed a novel, exploratory task designed to measure changes in inter-arm in discriminative accuracy that would be expected from changes in afferent nociception. Both placebo responders (but no non-responders) showed reduced discriminative ability when the hotter stimulus occurred on the placebo arm, an effect consistent with alterations in nociceptive afferent flow and unlikely to be caused by response bias.
Learn More >Neuropathic pain results from nerve injuries that cause ectopic firing and increased nociceptive signal transmission due to activation of key membrane receptors and channels. The dysregulation of trafficking of voltage-gated ion channels is an emerging mechanism in the etiology of neuropathic pain. We identify increased phosphorylation of collapsin response mediator protein 2 (CRMP2), a protein reported to regulate presynaptic voltage-gated calcium and sodium channels. A spared nerve injury (SNI) increased expression of a cyclin dependent kinase 5 (Cdk5)-phosphorylated form of CRMP2 in the dorsal horn of the spinal cord and the dorsal root ganglia (DRG) in the ipsilateral (injured) versus the contralateral (non-injured) sites. Biochemical fractionation of spinal cord from SNI rats revealed the increase in Cdk5-mediated CRMP2 phosphorylation to be enriched to pre-synaptic sites. CRMP2 has emerged as a central node in assembling nociceptive signaling complexes. Knockdown of CRMP2 using a small interfering RNA (siRNA) reversed SNI-induced mechanical allodynia implicating CRMP2 expression as necessary for neuropathic pain. Intrathecal expression of a CRMP2 resistant to phosphorylation by Cdk5 normalized SNI-induced mechanical allodynia, whereas mimicking constitutive phosphorylation of CRMP2 resulted in induction of mechanical allodynia in naïve rats. Collectively, these results demonstrate that Cdk5-mediated CRMP2 phosphorylation is both necessary and sufficient for peripheral neuropathic pain.
Learn More >Musculoskeletal pain reduces corticomotor excitability (CE) and methods modulating such CE reduction remain elusive. This study aimed to modulate pain-induced CE reduction by performing action observation and motor imagery (AOMI) during experimental muscle pain. Twelve healthy subjects participated in three cross-over and randomized sessions separated by one week. During the AOMI session subjects performed an AOMI task for 10 mins. In the AOMI+PAIN session, hypertonic saline was injected in the first dorsal interosseous (FDI) muscle prior to performing the AOMI task. In the PAIN session, subjects remained at rest for 10 min or until pain-resolve after the hypertonic saline injection. CE was assessed using transcranial magnetic stimulation motor-evoked potentials (TMS-MEPs) of the FDI muscle at baseline, during, immediately after, and 10 min after AOMI and/or PAIN. Facilitated TMS-MEPs were found after two and four mins of AOMI performance (P<0.017) whereas a reduction in TMS-MEPs appeared at four mins (P<0.017) during the PAIN session. Performing the AOMI task during pain counteracted the reduction in CE, as evident by no change in TMS-MEPs during the AOMI+PAIN session (P>0.017). Pain intensity was similar between the AOMI+PAIN and PAIN sessions (P=0.71). This study, that may be considered a pilot, demonstrated the counteracting effects of AOMI on pain-induced reduction in CE and warrants further studies in a larger population. PERSPECTIVE: This is the first study to demonstrate a method counteracting the reduction in corticomotor excitability associated with acute pain and advances therapeutic possibilities for individuals with chronic musculoskeletal pain.
Learn More >Pain has well established effects on attention. At present parallel literatures exist which have examined the effects of experimentally induced pain and consider cognitive performance in patients with chronic pain states. However, no study to date as attempted to examine the combined or differing effects of these two manifestations of pain in a single study. 24 participants with fibromyalgia (age 43.00, SD 28.28) and 26 healthy controls (age=36.07 SD=11.93) completed an n-back task, an attentional switching task, and a divided attention task, once during induced, moderately-intense pressure pain, and once without induced pain. Pain induction had selective effects on the n-back task, and an overall reduction in accuracy on the attentional switching task. Conversely, patients with fibromyalgia were selectively impaired in performance on the divided attention task. These data therefore suggest that the effects of pain are not summative and rather that the mechanisms that underlie the negative effects of pain on performance in acute and chronic states may differ. More research is needed to examine these mechanisms and how these negative effects can be ameliorated to treat cognitive symptoms in pain. Perspective: This article presents a study to examine the effects of an acute, induced pain model on cognitive performance in both fibromyalgia and healthy control populations. We established that the effects of acute and chronic pain on attention are different, suggesting different models need to be developed to understand these phenomena.
Learn More >Endogenous neuropeptide Y (NPY) exerts long-lasting spinal inhibitory control of neuropathic pain, but its mechanism of action is complicated by the expression of its receptors at multiple sites in the dorsal horn: NPY Y1 receptors (Y1Rs) on post-synaptic neurons and both Y1Rs and Y2Rs at the central terminals of primary afferents. We found that Y1R-expressing spinal neurons contain multiple markers of excitatory but not inhibitory interneurons in the rat superficial dorsal horn. To test the relevance of this spinal population to the development and/or maintenance of acute and neuropathic pain, we selectively ablated Y1R-expressing interneurons with intrathecal administration of an NPY-conjugated saporin ribosomal neurotoxin that spares the central terminals of primary afferents. NPY-saporin decreased spinal Y1R immunoreactivity but did not change the primary afferent terminal markers isolectin B4 or calcitonin-gene-related peptide immunoreactivity. In the spared nerve injury (SNI) model of neuropathic pain, NPY-saporin decreased mechanical and cold hypersensitivity, but disrupted neither normal mechanical or thermal thresholds, motor coordination, nor locomotor activity. We conclude that Y1R-expressing excitatory dorsal horn interneurons facilitate neuropathic pain hypersensitivity. Furthermore, this neuronal population remains sensitive to intrathecal NPY after nerve injury. This neuroanatomical and behavioral characterization of Y1R-expressing excitatory interneurons provides compelling evidence for the development of spinally-directed Y1R agonists to reduce chronic neuropathic pain.
Learn More >Wnt signaling pathway has been investigated extensively for its diverse metabolic and pain modulating mechanisms and recently its involvement has been postulated in the development of neuropathic pain. However, there are no reports as yet on involvement of Wnt signaling pathway in one of the most debilitating neurovascular complication of diabetes, i.e, diabetic peripheral neuropathy (DPN). Thus, in the present study, involvement of Wnt signaling was investigated in DPN using Wnt signaling inhibitors namely LGK974 (Porcupine inhibitor), NSC668036 (Disheveled inhibitor) and PNU74654 (β-catenin inhibitor). Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg) to male Sprague Dawley rats. Diabetic rats after six weeks of diabetes induction showed increased expression of Wnt signaling proteins in the spinal cord (L4-L6 lumbar segment), dorsal root ganglions (DRGs) and sciatic nerves. Subsequent increase in inflammation, endoplasmic reticulum (ER) stress and loss of intraepidermal nerve fiber density (IENFD) was also observed, leading to neurobehavioral and nerve functional deficits in diabetic rats. Intrathecal administration of Wnt signaling inhibitors (each at doses of 10 and 30 µM) in diabetic rats showed improvement in pain-associated behaviors (heat, cold & mechanical hyperalgesia) and nerve functions (motor, sensory nerve conduction velocities and nerve blood flow) by decreasing the expression of Wnt pathway proteins, inflammatory marker, matrix metalloproteinase 2 (MMP2), ER stress marker, glucose-regulated protein 78 (GRP78) and improving IENFD. All these results signify the neuroprotective potential of Wnt signaling inhibitors in DPN. Perspective: This study emphasizes the involvement of Wnt signaling pathway in diabetic peripheral neuropathy (DPN). Blockade of this pathway using Wnt inhibitors provided neuroprotection in experimental DPN in rats. This study may provide a basis for exploring the therapeutic potential of Wnt inhibitors in DPN patients.
Learn More >Chronic low back pain (CLBP) is a common health issue worldwide. Tai Chi, Qigong, and Yoga, as the most widely practiced mindful exercises, have promising effects for CLBP-specific symptoms.
Learn More >Few investigators have developed and tested nonpharmacological interventions for helping persons with sickle cell disease (SCD) manage persistent pain.
Learn More >Neuropathic pain, which presents abnormal pain manifestations including allodynia and hyperalgesia, is associated with central sensitization involving N-methyl-D-aspartate receptorsIn the freeze-injury hyperalgesia model, a cold burn leads to development of both primary hyperalgesia and secondary hyperalgesia, which develops away from the site of injury without apparent tissue modification, and is associated with central sensitization and activation of N-methyl-D-aspartate receptors in the spinal cordDextromethorphan, which is an N-methyl-D-aspartate receptor antagonist, is antihyperalgesic in preclinical pain models WHAT THIS ARTICLE TELLS US THAT IS NEW: Using the freeze-injury pain model in a randomized, double-blind, placebo-controlled crossover trial of 30-mg doses of oral dextromethorphan in 20 male volunteers, dextromethorphan was antihyperalgesic and reversed peripheral and central neuronal sensitizationBecause dextromethorphan had no intrinsic antinociceptive effect in acute pain on healthy skin, N-methyl-D-aspartate receptors may need to be sensitized by pain for dextromethorphan to be effective BACKGROUND:: Central pain sensitization is often refractory to drug treatment. Dextromethorphan, an N-methyl-D-aspartate receptor antagonist, is antihyperalgesic in preclinical pain models. The hypothesis is that dextromethorphan is also antihyperalgesic in humans.
Learn More >Altered Toll-like receptor (TLR) 4 activation has been identified in several chronic pain conditions but has not been well studied in interstitial cystitis/bladder pain syndrome (IC/BPS). Our published human studies indicated that IC/BPS patients present altered systemic TLR4-mediated inflammatory responses, which were significantly correlated with reported pain severity. In this study, we sought to determine whether altered TLR4 activation plays a role in pelvic/bladder pain seen in IC/BPS patients using our validated IC/BPS-like transgenic autoimmune cystitis model (URO-OVA). URO-OVA mice developed responses consistent with pelvic and bladder pain after cystitis induction, which was associated with increased splenocyte production of TLR4-mediated proinflammatory cytokines interleukin (IL)-1b, IL-6 and tumor necrosis factor (TNF)-a. Increased spinal expression of mRNAs for proinflammatory cytokines IL-6 and TNF-a, glial activation markers CD11b and glial fibrillary acidic protein (GFAP), and endogenous TLR4 ligand high mobility group box 1 (HMGB1) was also observed after cystitis induction. Compared to URO-OVA mice, URO-OVA (TLR4-deficient URO-OVA) mice developed significantly reduced nociceptive responses, although similar bladder inflammation and voiding dysfunction, after cystitis induction. Intravenous administration of TAK-242 (a TLR4 selective antagonist) significantly attenuated nociceptive responses in cystitis-induced URO-OVA mice, which was associated with reduced splenocyte production of TLR4-mediated IL-1b, IL-6 and TNF-a as well as reduced spinal expression of mRNAs for IL-6, TNF-a, CD11b, GFAP, and HMGB1. Our results indicate that altered TLR4 activation plays a critical role in bladder nociception independent of inflammation and voiding dysfunction in the URO-OVA model, providing a potential mechanistic insight and a therapeutic target for IC/BPS pain.
Learn More >In this 12-week, randomized, double-blind, placebo controlled, multicenter, 3-arm, parallel group, phase 3 trial we assessed the effects of a novel SHIP1 activator on bladder pain and urinary symptoms in patients with interstitial cystitis/bladder pain syndrome.
Learn More >To assess the efficacy and safety of a remote electrical neuromodulation (REN) device for the acute treatment of migraine.
Learn More >Previous literature suggests that ketamine may be an effective drug in the palliative care population as this drug has been shown to treat multiple conditions that are common in these patients. This review examines the efficacy of ketamine for the treatment of depression and physical pain in palliative care patients. Eleven studies were included on the topic of ketamine as an antidepressant in the palliative care population. Additionally, 5 RCT studies were included on the topic of physical pain in this population. All 11 studies, including one RCT, found antidepressant effects of ketamine in this patient population. Ketamine's effect on treating physical pain was mixed with the largest and most recent RCTs suggesting no significant analgesic effect. This review suggests that starting qualified patients on intravenous (IV) ketamine and switching to oral or intranasal administration may be the most effective and convenient for treating depression, especially for patients who wish to receive treatment at home. Significant analgesia was found in patients who received epidural or intrathecal ketamine as well as in one study using intravenous administration. More research is necessary to determine which palliative care patients may benefit from ketamine treatment.
Learn More >Interleukin-33 (IL-33) and its receptor ST2 contribute to spinal glial activation and chronic pain. A recent study showed that peripheral IL-33 plays a pivotal role in the pathogenesis of chronic itch induced by poison ivy. However, how IL-33/ST2 signaling in the spinal cord potentially mediates chronic itch remains elusive. Here, we determined that St2 substantially reduced scratching behaviors in 2,4-dinitrofluorobenzene (DNFB)-induced allergic contact dermatitis (ACD) as well as acetone and diethylether followed by water-induced dry skin in mice. Intrathecal administration of the neutralizing anti-ST2 or anti-IL-33 antibody remarkably decreased the scratching response in DNFB-induced ACD mice. Expression of spinal IL-33 and ST2 significantly increased in ACD mice, as evidenced by increased mRNA and protein levels. Immunofluorescence and in situ hybridization demonstrated that increased expression of spinal IL-33 was predominant in oligodendrocytes and astrocytes, whereas ST2 was mainly expressed in astrocytes. Further studies showed that in ACD mice, the activation of astrocytes and increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) were markedly attenuated by St2 . Intrathecal injection of Janus Kinase 2 Inhibitor AG490 significantly alleviated scratching behaviors in ACD mice. rIL-33 pretreatment exacerbated gastrin-releasing peptide (GRP)-evoked scratching behaviors. This increased gastrin-releasing peptide receptor (GRPR) expression was abolished by St2 . Tnf-α upregulation was suppressed by St2 . Our results indicate that the spinal IL-33/ST2 signaling pathway contributes to chronic itch via astrocytic JAK2-STAT3 cascade activation, promoting TNF-α release to regulate the GRP/GRPR signaling-related itch response. Thus, these findings provide a potential therapeutic option for treating chronic pruritus.
Learn More >Neuropathic pain spreads spatially beyond the injured sites, and the mechanism underlying the spread has been attributed to inflammation occurring in the spinal cord. However, the spatial spread of spinal/cortical potentiation induced by conduction block of the peripheral nerves can be observed prior to inflammation. In the present study, we found that spreading potentiation and hypersensitivity acutely induced by unilateral hindpaw ischemia are NO-dependent and that NO is produced by ischemia and quickly diffuses within the spinal cord. We also found that NO production induced by ischemia is not observed in the presence of an antagonist for group II metabotropic glutamate receptors (mGluRs) and that neuronal NO synthase-positive dorsal horn neurons express group II mGluRs. These results strongly suggest that NO-mediated spreading potentiation in the spinal cord is one of the trigger mechanisms for neuropathic pain.
Learn More >Nonclinical safety evaluation of erenumab, a CGRP receptor inhibitor for the prevention of migraine.
Calcitonin gene-related peptide (CGRP) and its receptor have been implicated as a key mediator in the pathophysiology of migraine. Thus, erenumab, a monoclonal antibody antagonist of the CGRP receptor, administered as a once monthly dose of 70 or 140 mg has been approved for the preventive treatment of migraine in adults. Due to the species specificity of erenumab, the cynomolgus monkey was used in the pharmacology, pharmacokinetics, and toxicology studies to support the clinical program. There were no effects of erenumab on platelets in vitro (by binding, activation or phagocytosis assays). Specific staining of human tissues with erenumab did not indicated any off-target binding. There were no erenumab-related findings in a cardiovascular safety pharmacology study in cynomolgus monkeys or in vitro in human isolated coronary arteries. Repeat-dose toxicology studies conducted in cynomolgus monkeys at dose levels up to 225 mg/kg (1 month) or up to 150 mg/kg (up to 6 months) with twice weekly subcutaneous (SC) doses showed no evidence of erenumab-mediated adverse toxicity. There were no effects on pregnancy, embryo-fetal or postnatal growth and development in an enhanced pre-postnatal development study in the cynomolgus monkey. There was evidence of placental transfer of erenumab based on measurable serum concentrations in the infants up to 3 months post birth. The maternal and developmental no-observed-effect level (NOEL) was the highest dose tested (50 mg/kg SC Q2W). These nonclinical data in total indicate no safety signal of concern to date and provide adequate margins of exposure between the observed safe doses in animals and clinical dose levels.
Learn More >The conceptualization of placebo has changed from inactive pills to a detailed understanding of how patients' perception of receiving a treatment influences pain processing and overall treatment outcome. Large placebo effects were recently demonstrated in chronic neuropathic pain, thereby opening the question of whether placebo effects also apply to orofacial neuropathic pain. In this article, we review the new definitions, magnitude, and social, psychological, neurobiologic, and genetic mechanisms of placebo effects in pain, especially neuropathic pain, to illustrate that placebo effects are not simply response bias but psychoneurobiological phenomena that can be measured at many levels of the neuroaxis. We use this knowledge to carefully illustrate how patients' perceptions of the treatment, the relationship with the health care provider, and the expectations and emotions toward a treatment can influence test and treatment outcome and potentially skew the results if they are not taken into consideration. Orofacial neuropathic pain is a new research area, and we review the status on definition, diagnosis, mechanisms, and pharmacologic treatment of neuropathic pain after trigeminal nerve injury, as this condition may be especially influenced by placebo factors. Finally, we have a detailed discussion of how knowledge of placebo mechanisms may help improve the understanding, diagnosis, and treatment of orofacial neuropathic pain, and we illustrate pitfalls and opportunities of applying this knowledge to the test of dental treatments.
Learn More >Surgical care episodes place opioid-naive patients at risk for transitioning to new persistent postoperative opioid use. With one of the central principles being the application of multimodal pain interventions to reduce the reliance on opioid-based medications, enhanced recovery pathways provide a framework that decreases perioperative opioid use. The fourth Perioperative Quality Initiative brought together a group of international experts representing anesthesiology, surgery, and nursing with the objective of providing consensus recommendations on this important topic. Fourth Perioperative Quality Initiative was a consensus-building conference designed around a modified Delphi process in which the group alternately convened for plenary discussion sessions in between small group discussions. The process included several iterative steps including a literature review of the topics, building consensus around the important questions related to the topic, and sequential steps of content building and refinement until agreement was achieved and a consensus document was produced. During the fourth Perioperative Quality Initiative conference and thereafter as a writing group, reference applicability to the topic was discussed in any area where there was disagreement. For this manuscript, the questions answered included (1) What are the potential strategies for preventing persistent postoperative opioid use? (2) Is opioid-free anesthesia and analgesia feasible and appropriate for routine operations? and (3) Is opioid-free (intraoperative) anesthesia associated with equivalent or superior outcomes compared to an opioid minimization in the perioperative period? We will discuss the relevant literature for each questions, emphasize what we do not know, and prioritize the areas for future research.
Learn More >Pain impacts the lives of millions of community-dwelling older adults. An important characteristic of pain is "pain interference" which describes the influence of pain on function. A description of pain interference is limited in rural settings where the number of older adults is expected to increase, and health disparities exist.
Learn More >Chronic pain is a common, complex, and distressing problem that has a profound impact on individuals and society. It frequently presents as a result of a disease or an injury; however, it is not merely an accompanying symptom, but rather a separate condition in its own right, with its own medical definition and taxonomy. Studying the distribution and determinants of chronic pain allows us to understand and manage the problem at the individual and population levels. Targeted and appropriate prevention and management strategies need to take into account the biological, psychological, socio-demographic, and lifestyle determinants and outcomes of pain. We present a narrative review of the current understanding of these factors.
Learn More >Excitation of dorsal root ganglion (DRG) neurons by interleukin 1β (IL-1β) is implicated in the onset of neuropathic pain. To understand its mechanism of action, isolectin B4 positive (IB) DRG neurons were exposed to 100pM IL-1β for 5-6d. A reversible increase in action potential (AP) amplitude reflected increased TTX-sensitive sodium current (TTX-S I). An irreversible increase in AP duration reflected decreased Ca- sensitive K conductance (BK(Ca) channels). Different processes thus underlie regulation of the two channel types. Since changes in AP shape facilitated Ca influx, this explains how IL-1β facilitates synaptic transmission in the dorsal horn; thereby provoking pain.
Learn More >Motor imagery (M.I.) training has been widely used to enhance motor behavior. To characterize the neural foundations of its rehabilitative effects in a pathological population we studied twenty-two patients with rhizarthrosis, a chronic degenerative articular disease in which thumb-to-fingers opposition becomes difficult due to increasing pain while the brain is typically intact. Before and after surgery, patients underwent behavioral tests to measure pain and motor performance and fMRI measurements of brain motor activity. After surgery, the affected hand was immobilized, and patients were enrolled in a M.I. training. The sample was split in those who had a high compliance with the program of scheduled exercises (T+, average compliance: 84%) and those with low compliance (T-, average compliance: 20%; cut-off point: 55%). We found that more intense M.I. training counteracts the adverse effects of immobilization reducing pain and expediting motor recovery. fMRI data from the post-surgery session showed that T+ patients had decreased brain activation in the premotor cortex and the supplementary motor area (SMA); meanwhile, for the same movements, the T- patients exhibited a reversed pattern. Furthermore, in the post-surgery fMRI session, pain intensity was correlated with activity in the ipsilateral precentral gyrus and, notably, in the insular cortex, a node of the pain matrix. These findings indicate that the motor simulations of M.I. have a facilitative effect on recovery by cortical plasticity mechanisms and optimization of motor control, thereby establishing the rationale for incorporating the systematic use of M.I. into standard rehabilitation for the management of post-immobilization syndromes characteristic of hand surgery.
Learn More >Recently, a relationship was found between periodontitis and chronic migraine. Calcitonin gene-related peptide (CGRP) is a key element in migraine pathophysiology. However, no information exists of the potential association between periodontal inflammation and CGRP in chronic migraine. The aim of the study was, therefore, to investigate whether there is a link between periodontitis and peripheral levels of CGRP in a cohort of patients with chronic migraine.
Learn More >A secondary consequence of spinal cord injury (SCI) is debilitating chronic neuropathic pain, which is commonly morphine resistant and inadequately managed by current treatment options. Consequently, new pain management therapies are desperately needed. We previously reported that dopamine D3 receptor (D3R) dysfunction was associated with opioid resistance and increases in D1 receptor (D1R) protein expression in the spinal cord. Here, we demonstrate that in a model of SCI neuropathic pain, adjuvant therapy with a D3R agonist (pramipexole) or D1R antagonist (SCH 39166) can restore the analgesic effects of morphine and reduce reward potential. Prior to surgery thermal and mechanical thresholds were tested in three groups of female rats (naïve, sham, SCI). After surgery, testing was repeated under the following drug conditions: 1) saline, 2) morphine, 3) pramipexole, 4) SCH 39166, 5) morphine + pramipexole, and 6) morphine + SCH 39166. Reward potential of morphine and both combinations was assessed using conditioned place preference. Following SCI, morphine + pramipexole and morphine + SCH 39166 significantly increased both thermal and mechanical thresholds. Morphine alone induced conditioned place preference, but when combined with either the D3R agonist or D1R antagonist preference was not induced. The data suggest that adjunct therapy with receptor-specific dopamine modulators can restore morphine analgesia and decrease reward potential and thus, represents a new target for pain management therapy after SCI.
Learn More >Postoperative pain is common and promotes opioid use. Surgical wounds are hypoxic because normal perfusion is impaired. Local wound ischemia and acidosis promote incisional pain. Some evidence suggests that improving oxygen supply to surgical wounds might reduce pain. We therefore tested the hypothesis that supplemental (80% inspired) intraoperative oxygen reduces postoperative pain and opioid consumption.
Learn More >The purpose of this review is to explore the effects of the opioid crisis on pediatric patients in the postoperative setting and provide recommendations for well-tolerated opioid prescribing practices.
Learn More >Vasculitic peripheral neuropathy (VPN) arises from an inflammatory obstruction in the blood vessels supplying peripheral nerves and subsequent ischemic insults, which exhibits the clinical features of neuropathic pain and impaired peripheral nerve function. VPN induced by ischemia-reperfusion (IR) has been reported to involve nuclear factor-κB (NF-κB)-mediated neuroinflammation. Recent studies have suggested that endoplasmic reticulum (ER) stress has been implicated in the development of peripheral neuropathies. Resveratrol possesses a potent anti-inflammatory capacity. We hypothesized that resveratrol may exert a protective effect against VPN through modulating the interrelated ER stress and NF-κB pathways. Male Sprague-Dawley rats were allocated into 5 groups: sham, sham + resveratrol 40 mg/kg (R40), IR, IR + R20 and IR + R40. VPN was induced by occluding the right femoral artery for 4 hours followed by reperfusion. Our data has shown that VPN induced by IR led to hind paw mechanical allodynia, heat hyperalgesia, and impaired motor nerve conduction velocity (MNCV). With resveratrol intervention, the behavioral parameters were improved in a dose-dependent manner and the MNCV levels were increased as well. The molecular data revealed that VPN induced by IR significantly increased the expression of NF-κB as well as the ER stress sensor proteins, protein kinase RNA-like endoplasmic reticulum kinase, inositol-requiring enzyme 1 and activating transcription factor 6 in the sciatic nerves. More importantly, resveratrol significantly attenuated the expression of NF-κB and the ER stress sensor proteins after IR. In conclusion, resveratrol alleviates VPN induced by IR. The mechanisms may involve modulating NF-κB-mediated neuroinflammation via suppressing ER stress. This article is protected by copyright. All rights reserved.
Learn More >Cannabidiol (CBD), the non-psychoactive component of Cannabis sativa, acts on a diverse selection of membrane proteins with promising therapeutic potential in epilepsy and chronic pain. One such protein is the voltage-gated sodium channel (Na). CBD shows a lack of specificity for sodium channels; however, the method of interaction is still unknown. In this review, we will outline the studies that report reproducible results of CBD and other cannabinoids changing membrane channel function, with particular interest on Na. Na are implicated in fatal forms of epilepsy and are also associated with chronic pain. This makes Na potential targets for CBD interaction since it has been reported to reduce pain and seizures. One potential method of interaction that is of interest in this review is whether CBD affects channel function by altering lipid bilayer properties, independent of any possible direct interaction with membrane channels. CBD's ability to interact with its targets is a novel and important discovery. This discovery will not only prompt further research towards CBD's characterization, but also promotes the application of cannabinoids as potentially therapeutic compounds for diseases like epilepsy and pain.
Learn More >Neuroimaging studies revealed that trigeminal neuralgia was related to alternations in brain anatomical function and regional function. However, the functional characteristics of network organization in the whole brain is unknown.
Learn More >Galanin and galanin receptors (GalRs) play important roles in the transmission and modulation of nociceptive information. Our previous research has shown that the expression of GalR1 is upregulated and that GalR1 activation in the nucleus accumbens (NAc) of rats with neuropathic pain has an antinociceptive effect. However, the antinociceptive role of NAc galanin in neuralgia remains unclear. The present study aimed to explore the antinociceptive effect induced by galanin in rats with neuropathic pain and the underlying mechanism. The results showed that the intra-NAc injection of galanin induced a dose-dependent increase in hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation in mononeuropathic rats and that this effect was stronger than that in intact rats. The intra-NAc injection of the non-selective GalR antagonist galantide reduced HWL in the rats with neuropathic pain, but there was no influence of galantide on HWL in intact rats. Moreover, galanin expression in the NAc was upregulated after sciatic nerve ligation. All of these results demonstrate that galanin plays a role in antinociception via binding to GalRs in the NAc of rats and that endogenous galanin is involved in the antinociception after peripheral nerve injury.
Learn More >Current guidelines recommend opioid therapy to chronic non-malignant pain (CNP) patients when the benefits for pain and function outweigh risks. This systematic review examined the effects of opioid therapy on sleep – a valued functional outcome- in CNP. Electronic and hand searches of relevant studies up through July 2017 identified 18 eligible studies providing data from 3,746 CNP patients for analysis. Twelve of these studies were randomised controlled trials of up to 12-month in duration. Morphine sulfate, oxycodone and transdermal fentanyl were the most tested therapies (n = 4 each). Only two studies used objective sleep measures in addition to self-report ratings, questionnaires or sleep diaries. Whilst calmer sleep with less body/leg movements and fewer awakenings could be achieved following opioid therapy, these might occur with increased sleep-disordered breathing and a much-shortened rapid eye movement (REM) sleep latency. Both the narrative synthesis and exploratory meta-analysis suggest that opioid therapy in CNP is associated with improved self-reported sleep quality. However, the effect is inconsistent, small (Standardised Mean Difference = 0.36), and may be accompanied by excessive daytime sleepiness. As a Cochrane-recommended assessment revealed "unclear" or "high" overall risk of bias for all studies, future opioid trials of stronger methodology and better reporting are needed to confirm and elucidate the effect.
Learn More >Multiple cranial nerve blocks of the greater and lesser occipital, supraorbital, supratrochlear and auriculotemporal nerves are widely used in the treatment of primary headaches. We present efficacy and safety data for these procedures.
Learn More >Migraine is the most common of all neurological disorders. A breakthrough in migraine treatment emerged in the early nineties with the introduction of 5-HT1B/D receptor agonists called triptans. Triptans are used as the standard of care for acute migraine; however, they have significant limitations such as incomplete and inconsistent pain relief, high rates of headache recurrence, class- specific side effects and cardiovascular contraindications. First- and second-generation calcitonin gene-related peptide (CGRP) receptor antagonists, namely gepants, is a class of drugs primarily developed for the acute treatment of migraine. CGRP is the most evaluated target for migraine treatments that are in development. Areas covered: This article reviews the available data for first- and second-generation CGRP receptor antagonists, the role of CGRPs in human physiology and migraine pathophysiology and the possible mechanism of action and safety of CGRP targeted drugs. Expert opinion: Available data suggest that second generation of gepants has clinical efficacy similar to triptans and lasmiditan (5-HT1F receptor agonist) and has improved tolerability. Future studies will assess their safety, especially in specific populations such as patients with cardiovascular disease and pregnant women.
Learn More >Spinal cord injury (SCI) is a tragic event causing irreversible losses of sensory, motor, and autonomic functions, that may also be associated with chronic neuropathic pain. Serotonin (5-HT) neurotransmission in the spinal cord is critical for modulating sensory, motor, and autonomic functions. Following SCI, 5-HT axons caudal to the lesion site degenerate, and the degree of axonal degeneration positively correlates with lesion severity. Rostral to the lesion, 5-HT axons sprout, irrespective of the severity of the injury. Unlike callosal fibers and cholinergic projections, 5-HT axons are more resistant to an inhibitory milieu and undergo active sprouting and regeneration after central nervous system (CNS) traumatism. Numerous studies suggest that a chronic increase in serotonergic neurotransmission promotes 5-HT axon sprouting in the intact CNS. Moreover, recent studies in invertebrates suggest that 5-HT has a pro-regenerative role in injured axons. Here we present a brief description of 5-HT discovery, 5-HT innervation of the CNS, and physiological functions of 5-HT in the spinal cord, including its role in controlling bladder function. We then present a comprehensive overview of changes in serotonergic axons after CNS damage, and discuss their plasticity upon altered 5-HT neurotransmitter levels. Subsequently, we provide an in-depth review of therapeutic approaches targeting 5-HT neurotransmission, as well as other pre-clinical strategies to promote an increase in re-growth of 5-HT axons, and their functional consequences in SCI animal models. Finally, we highlight recent findings signifying the direct role of 5-HT in axon regeneration and suggest strategies to further promote robust long-distance re-growth of 5-HT axons across the lesion site and eventually achieve functional recovery following SCI.
Learn More >Chronic postsurgical pain is pain that develops and persists for at least 3 months after a surgical procedure. The purpose of this review was to discover what evidence exists regarding the influence of race and ethnicity on postoperative pain intensity and what evidence exists regarding the influence of genetic polymorphisms on postoperative pain intensity.
Learn More >Metacognitions, which are beliefs about our own thinking processes, can modulate worry and rumination and thereby influence emotional distress. This study aimed to develop a self-report measure of unhelpful pain-related metacognitions which might serve as a clinical and research tool to better understand pain catastrophizing, a significant risk factor for adverse pain outcomes. Two phases of validation are presented. Phase 1 reports on how the Pain Metacognitions Questionnaire (PMQ) was empirically developed through a qualitative study of 20 people with chronic back ( = 15) or knee ( = 5) pain in secondary or tertiary care and then validated in a large internet sample of people experiencing pain ( = 864). Rasch analysis yielded a 21-item scale with two dimensions (positive and negative metacognition) assessing how useful and problematic people believe rumination about pain to be, respectively. In Phase 2, further validation using a new sample ( = 510) replicated initial findings. Both PMQ subscales have good retest reliability ( = 0.76, = 0.72) and internal consistency (0.86, 0.87). They correlate negatively with mindfulness and positively with pain intensity, disability, anxiety, depression, catastrophizing, rumination, and metacognition. The PMQ also predicts unique variance in catastrophizing when other variables are controlled and predicts 'patient' status for pain catastrophizing. Sensitivity analysis yielded preliminary suggestions for clinically meaningful cut-offs. Unhelpful pain metacognitions can be validly and reliably measured using a self-report instrument. Future studies using the PMQ might shed new light on pain-related thinking processes to develop better interventions for people prone to worry and rumination about their pain.
Learn More >Disability in inflammatory bowel disease (IBD) is under-investigated. Models theorize that disability is the result of a disease and its related impairments, limitations, and restrictions. This disablement process can be affected by psychosocial factors. Pain, depression, catastrophizing, and social support are associated with IBD-disability outcomes, but no studies have examined these factors concurrently. This study examined the role of psychosocial factors in the process of IBD disablement within the context of pain. Depressive symptoms, pain catastrophizing, and perceived social support were proposed as mediators in the relationship between pain and pain-related disability in cross-sectional and longitudinal models. Cross-sectionally, the mediation effects of depressive symptoms and pain catastrophizing, but not perceived social support, were significant. Longitudinally, depression was a significant mediator. Depressive symptoms and pain catastrophizing have mechanistic roles in the relationship between IBD patients' pain and pain-related disability and should be targets for intervention.
Learn More >Migraine is a common disabling disorder that affects 36 million Americans. The clinical features of migraine are less typical in the people above age 60, making the diagnosis and treatment difficult in this group. In this review, we will discuss migraine-specific drugs and their use in populations about age 60 who suffer from migraine. This discussion will include an overview of traditional treatments for the acute and preventive treatment of migraine, and considerations for their use in patient populations above age 60. In addition, we will discuss newer agents that show a more promising safety profile.
Learn More >Telephone cognitive behavioural therapy (tCBT) is an acceptable and effective treatment for patients with chronic widespread pain (CWP). Preventing the onset of CWP offers considerable benefits to the individual and society and the MAmMOTH study is the first aimed at CWP prevention. The study is a two-arm randomised trial testing a course of tCBT against usual care for prevention of CWP. This nested qualitative study explores patients' treatment experiences, with a view to understanding their potential influences on acceptability of the intervention.
Learn More >Treatment with cannabidiol (CBD) or KLS-13019 (novel CBD analog), has previously been shown to prevent paclitaxel-induced mechanical allodynia in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). The mechanism of action for CBD- and KLS-13019-mediated protection now has been explored with dissociated dorsal root ganglion (DRG) cultures using small interfering RNA (siRNA) to the mitochondrial Na Ca exchanger-1 (mNCX-1). Treatment with this siRNA produced a 50-55% decrease in the immunoreactive (IR) area for mNCX-1 in neuronal cell bodies and a 72-80% decrease in neuritic IR area as determined with high-content image analysis. After treatment with 100 nM KLS-13019 and siRNA, DRG cultures exhibited a 75 ± 5% decrease in protection from paclitaxel-induced toxicity; whereas siRNA studies with 10 μM CBD produced a 74 ± 3% decrease in protection. Treatment with mNCX-1 siRNA alone did not produce toxicity. The protective action of cannabidiol and KLS-13019 against paclitaxel-induced toxicity during a 5-h test period was significantly attenuated after a 4-day knockdown of mNCX-1 that was not attributable to toxicity. These data indicate that decreases in neuritic mNCX-1 corresponded closely with decreased protection after siRNA treatment. Pharmacological blockade of mNCX-1 with CGP-37157 produced complete inhibition of cannabinoid-mediated protection from paclitaxel in DRG cultures, supporting the observed siRNA effects on mechanism.
Learn More >Multimorbidity refers to the presence of two or more chronic health conditions within one person, where no one condition is primary. Research suggests that multimorbidity is highly correlated with chronic pain, which is pain lasting longer than 3 months. Psychotherapeutic interventions for people living with chronic illness have resulted in reduced symptom reporting and improved psychological well-being. There is a dearth of research, however, using online psychotherapy for people living with multimorbidity where chronic pain is a central condition. This study will compare the effectiveness of an online acceptance and commitment therapy (ACT) intervention with a waiting list control condition in terms of improving health-related quality of life (HRQoL) and reducing levels of pain interference in people with chronic pain and at least one other condition.
Learn More >Sleep problems are common for individuals living with physical disabilities and chronic pain. However, the factors that influence the relationship between pain and sleep problems in these populations remain unknown.
Learn More >We evaluated the frequency of six commonly reported adult migraine premonitory symptoms in children and adolescents with episodic and chronic migraine and elicited psychological or behavioral comorbidities that may be associated with these symptoms.
Learn More >Emerging evidence implicates the upregulation of matrix metalloproteinase (MMP)-9/2 in the dorsal root ganglion (DRG) and spinal cord as a contributor to the pathogenesis of chronic pain. In the current study, the expression of MMP-9/2 in wounded tissue, ipsilateral DRG, and the spinal dorsal horn as well as its role in the development of postoperative pain were examined following plantar incision in rats. Our results showed that plantar incision resulted in increased expression of MMP-9/2 in wounded tissue and ipsilateral L4/5 DRGs. Although gelatin zymography detected an increased activity of MMP-9, only MMP-2 protein was increased in the spinal cord. Results of double immunofluorescence staining showed MMP-2 expression in DRG neurons and satellite glial cells, but MMP-9 was found only in neurons. In the spinal cord, MMP-2 was expressed in neurons and astrocytes, and MMP-9 was expressed in neurons and somewhat in microglial cells. Planter incision also elicited increased expression of p-Erk, p-p38, and IL-1β in wounded tissue, ipsilateral L4/5 DRGs, and dorsal horn. Prior intraplantar or intrathecal injection of MMP-9- and MMP-2-specific inhibitors partially prevented reductions of paw withdrawal threshold and paw withdrawal latency following plantar incision. The maturation of IL-1β was also inhibited by the treatment. Moreover, MMP-9 inhibition suppressed p38, and MMP-2 inhibitor reduced the Erk phosphorylation in wounded tissue, DRGs, and dorsal horn. Immunofluorescence staining detected colocalization of MMP-9 with p38 and MMP-2 with Erk in DRG and spinal cord. Together, the above results reveal that upregulated MMP-9 via p38/IL-1β and MMP-2 via Erk/IL-1β signaling in the wounded tissue, ipsilateral DRG, and dorsal horn contribute to the development of postoperative pain.
Learn More >To compare the effectiveness of a biobehavioral approach with and without orthopedic manual physical therapy on the intensity and frequency of pain in patients diagnosed with nonspecific chronic low back pain.
Learn More >Migraine is a highly prevalent and disabling neurological disorder which is commonly linked with a broad range of psychiatric comorbidities, especially among subjects with migraine with aura or chronic migraine. Defining the exact nature of the association between migraine and psychiatric disorders and bringing out the pathophysiological mechanisms underlying the comorbidity with psychiatric conditions are relevant issues in the clinical practice.
Learn More >Representations of the body and peripersonal space can be distorted for people with some chronic pain conditions. Experimental pain induction can give rise to similar, but transient distortions in healthy individuals. However, spatial and bodily representations are dynamic, and constantly update as we interact with objects in our environment. It is unclear whether induced pain disrupts the mechanisms involved in updating these representations. In the present study, we sought to investigate the effect of induced pain on the updating of peripersonal space and body representations during and following tool-use. We compared performance under three conditions (pain, active placebo, neutral) on a visuotactile crossmodal congruency task and a tactile distance judgement task to measure updating of peripersonal space and body representations, respectively. Consistent with previous findings, the difference in crossmodal interference from visual distractors in the same compared to opposite visual field to the tactile target was less when tools were crossed than uncrossed. This suggests an extension of peripersonal space to incorporate the tips of the tools. Also consistent with previous findings, estimates of the felt tactile distance judgements decreased after active tool-use. In contrast to our predictions, however, we found no evidence that pain interfered with performance on either task when compared to the control conditions. Our findings suggest that the updating of peripersonal space and body representations is not disrupted by induced pain. That is, experiencing acute pain does not give rise to distorted representations of the body and peripersonal space that can be present in people with chronic pain conditions.
Learn More >We aimed to investigate migraine diagnoses in a hospital setting, use of prescription migraine medicine and levels of serotonin in patients with atrial septal defect. Using Danish national registries to identify all patients born before 1994 diagnosed with atrial septal defect between 1959 and 2013, thus including 2277 patients and a gender and age matched comparison cohort of 22756. Plasma serotonin was measured in 136 patients with a small, unclosed, atrial septal defects and 18 controls. Patients with atrial septal defect had an increased risk of receiving a migraine diagnosis (HR 3.4 (95% CI: 2.6-4.6)) and receiving migraine medicine (HR 1.8 (95% CI: 1.2-2.5)). Ten years after closure, 93% of those using migraine medicine pre-closure, were still receiving this. The risk of having very high plasma serotonin levels was increased in patients with atrial septal defect compared with the control group, but there was no difference in the median values between the two groups. Migraine and use of migraine medicine were increased in atrial septal defect patients. The use of medicine was not diminished by closure of the defect. Plasma serotonin was severely elevated in 18% of the patients with atrial septal defect.
Learn More >rheumatic diseases are the most frequent cause of non-malignant chronic pain. In recent years, pain and its management have become more important in rheumatology.
Learn More >The accurate diagnosis and treatment of pain is dependent upon the knowledge of variables that might alter this response. Some of these variables are the locality of the noxious stimulus, the sex of the individual, and the presence of chronic diseases. Among these chronic diseases, hypertension is considered a serious and silent disease that has been associated with hypoalgesia. The main goal of this study was to evaluate the potential nociceptive differences in spontaneously hypertensive rats (SHR) regarding the locality of the stimulus, the temporomandibular joint or paw, the sex, and the role of ovarian hormones in a model of mechanical nociception (Von Frey test) or formalin-induced inflammatory nociception. Our results indicate that SHR has lower orofacial mechanical nociception beyond the lower mechanical nociception in the paw compared to WKY rats. In a model of formalin-induced inflammatory nociception, SHR also has a decreased nociception compared to normotensive rats. We also sought to evaluate the influence of sex and ovarian hormones on orofacial mechanical nociception in SHR. We observed that female SHR has higher mechanical nociception than male SHR only in the paw, but it has higher formalin-induced orofacial nociception than male SHR. Moreover, the absence of ovarian hormones caused an increase in mean arterial pressure and a decrease in paw nociception in female SHR.
Learn More >We aimed to assess the safety of opioids in the management of osteoarthritis (OA) in a systematic review and meta-analysis of randomized, placebo-controlled trials.
Learn More >Pain following herpes zoster (HZ) can persist for months and negatively impact quality of life. To evaluate the effect of zoster vaccine live (ZVL) on progression of pain following HZ, we conducted a prospective cohort study of HZ cases at Kaiser Permanente Southern California.
Learn More >Conditioned pain modulation (CPM) is impaired in people with chronic pain such as knee osteoarthritis (KOA). The purpose of this randomized, controlled clinical trial was to investigate whether strong electroacupuncture (EA) was more effective on chronic pain by strengthening the CPM function than weak EA or sham EA in patients with KOA.
Learn More >Endometriosis impacts the physical, psychological and quality of life domains of women. Despite the medical and/or surgical management of endometriosis, the presence of persistent pelvic pain and psychological distress often continues, suggesting a role for psychological interventions in treatment planning. The present study aimed to conduct the first systematic review, with narrative data synthesis, on psychological interventions for endometriosis-related symptoms. The study also aimed to determine the effectiveness of current interventions in resolving psychological and pain-related loss of function associated with endometriosis and to identify gaps in the literature requiring further research. A total of 15,816 studies were retrieved through database searching and handsearching, with two researchers identifying 11 full-text studies that met inclusion criteria. Three studies of 'moderate' quality were identified, although the overall quality of studies was found to be 'weak', with a 'high' risk of bias. The findings regarding the effectiveness of psychological interventions for endometriosis-related symptoms remain inconclusive. Further research into psychological interventions for women with endometriosis that employ evidence-based protocols with high intervention integrity is recommended.
Learn More >Tarlov cysts (TCs) are dilations of nerve roots arising from pathologically increased hydrostatic pressure (HP) in the spinal canal. There is much controversy regarding whether these cysts are a rare source of pain or often produce symptoms. The aim of this review was to identify the reasons that symptomatic TCs (STCs) are easily overlooked.
Learn More >Chronic pain patients managed with opioids are at an increased risk of opioid misuse or opioid use disorder (OUD). In recent years, there has seen a stark increase in abuse, misuse, and diversion of prescription opioid medications. The aim of this study is to investigate trends in changing rates of opioid use disorder amongst chronic pain patients.
Learn More >There is increasing interest in the role of pro-inflammatory cytokines in the pathogenesis of sciatica and whether these could be potential targets for treatment. We sought to investigate serum biomarker levels in patients with low back-related leg pain, including sciatica.
Learn More >Features of the pain in hypermobile Ehlers-Danlos syndrome (hEDS) are complex and insufficiently known by clinicians. We enrolled 37 hEDS patients. Disease status was ascertained using revised 2017 International Classification criteria, in the EDS French National Reference Center. Patients were evaluated with a clinical examination, quantitative sensory testing, and validated questionnaires. Thirty-seven patients were evaluated. Pain had appeared at 10 ± 5 years old and became chronic at 20 ± 9 years old. hEDS was diagnosed at only 24 ± 10 years old. Ninety-seven percent of them had severe chronic pain, which gradually increased over time in 75% of them. The main location of pain was in joints and predominated in lower limbs. Patients with a generalized presentation of pain had older chronic pain and a higher impact on the affective component. Neuropathic pain was frequent in the most painful joint and associated with heat hypoesthesia. An asymmetric proprioception was found in one third of the patients. A very high rate of attempted suicide was observed. To conclude, pain in hEDS is severe, chronic, and disabling. Sensorial and proprioceptive sensibilities are also affected. Peripheral neuropathic pain is frequent and central sensitization appears to be a key step in the evolution of disease.
Learn More >Among the different types of pain observed in Parkinson's disease, parkinsonian central pain (PCP) has the highest severity, and is poorly characterized and difficult to describe not only by patients but also by neurologists. Thus PCP remains not strictly defined and is difficult to distinguish from other types of pain on the basis of clinical description. Yet, standardizing PCP diagnosis is critical to improve the treatment of this debilitating pain subtype, but also to homogenize further studies investigating the pathophysiological mechanisms underlying this condition. Accounting for the lack of reliable validated positive clinical criteria for PCP, and as the clinical features of PCP are difficult to specify, we suggest to consider so far the gold standard diagnosis of PCP mainly based on exclusion criteria. We propose a new algorithm aiming to disentangle PCP from other chronic pain subtypes in Parkinson's disease, by sequentially ruling out what PCP is not.
Learn More >To investigate the effect of phase polarity and charge balance of spinal cord stimulation (SCS) waveforms on pain behavior and gene expression in a neuropathic pain rodent model. We hypothesized that differing waveforms will result in diverse behavioral and transcriptomics expression due to unique mechanisms of action.
Learn More >