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General anesthesia (GA) can produce analgesia (loss of pain) independent of inducing loss of consciousness, but the underlying mechanisms remain unclear. We hypothesized that GA suppresses pain in part by activating supraspinal analgesic circuits. We discovered a distinct population of GABAergic neurons activated by GA in the mouse central amygdala (CeA neurons). In vivo calcium imaging revealed that different GA drugs activate a shared ensemble of CeA neurons. CeA neurons also possess basal activity that mostly reflects animals' internal state rather than external stimuli. Optogenetic activation of CeA potently suppressed both pain-elicited reflexive and self-recuperating behaviors across sensory modalities and abolished neuropathic pain-induced mechanical (hyper-)sensitivity. Conversely, inhibition of CeA activity exacerbated pain, produced strong aversion and canceled the analgesic effect of low-dose ketamine. CeA neurons have widespread inhibitory projections to many affective pain-processing centers. Our study points to CeA as a potential powerful therapeutic target for alleviating chronic pain.
Learn More >Neuroinflammation is a crucial mechanism in many neurological disorders. Injury to the peripheral sensory nerves leads to a neuroinflammatory response in the somatosensory pathway, from dorsal root ganglia (DRG) to the spinal cord, contributing to neuropathic pain. How the immune reaction is initiated peripherally and propagated to the spinal cord remains less clear. Here, we find that ciliary neurotrophic factor (CNTF), highly expressed in Schwann cells, mediates neuroinflammatory response through the activating signal transducer and activator of transcription 3 (STAT3) and inducing interleukin 6 (IL-6) in sensory neurons. Cntf deficiency attenuates neuroinflammation in DRG and the spinal cord with alleviated pain post-injury. Recombinant CNTF applied to the sensory nerves recapitulates neuroinflammation in the DRG and spinal cord, with consequent pain development. We delineate the CNTF-STAT3-IL-6 axis in mediating the onset and progression of the inflammatory cascade from the periphery to the spinal cord with therapeutic implications for neuropathic pain.
Learn More >Although the medical definition of itch has been in existence for 360 years, only in the last 20 years have we begun to understand the basic mechanisms that underlie this unique sensation. Therapeutics that specifically target chronic itch as a pathologic entity are currently still not available. Recent seminal advances in itch circuitry within the nervous system have intersected with discoveries in immunology in unexpected ways to rapidly inform emerging treatment strategies. The current review aims to introduce these basic concepts in itch biology and highlight how distinct immunologic pathways integrate with recently identified itch-sensory circuits in the nervous system to inform a major new paradigm of neuroimmunology and therapeutic development for chronic itch.
Learn More >Anxiety is common in patients suffering from chronic pain. Here, we report anxiety-like behaviors in mouse models of chronic pain and reveal that nNOS-expressing neurons in ventromedial prefrontal cortex (vmPFC) are essential for pain-induced anxiety but not algesia, using optogenetic and chemogenetic strategies. Additionally, we determined that excitatory projections from the posterior subregion of paraventricular thalamic nucleus (pPVT) provide a neuronal input that drives the activation of vmPFC nNOS-expressing neurons in our chronic pain models. Our results suggest that the pain signal becomes an anxiety signal after activation of vmPFC nNOS-expressing neurons, which causes subsequent release of nitric oxide (NO). Finally, we show that the downstream molecular mechanisms of NO likely involve enhanced glutamate transmission in vmPFC CaMKIIα-expressing neurons through S-nitrosylation-induced AMPAR trafficking. Overall, our data suggest that pPVT excitatory neurons drive chronic pain-induced anxiety through activation of vmPFC nNOS-expressing neurons, resulting in NO-mediated AMPAR trafficking in vmPFC pyramidal neurons.
Learn More >Attentional biases have been posited as one of the key mechanisms underlying the development and maintenance of chronic pain and co-occurring internalizing mental health symptoms. Despite this theoretical prominence, a comprehensive understanding of the nature of biased attentional processing in chronic pain and its relationship to theorized antecedents and clinical outcomes is lacking, particularly in youth. This study used eye-tracking to assess attentional bias for painful facial expressions and its relationship to theorized antecedents of chronic pain and clinical outcomes. Youth with chronic pain (n = 125) and without chronic pain (n = 52) viewed face images of varying levels of pain expressiveness while their eye gaze was tracked and recorded. At baseline, youth completed questionnaires to assess pain characteristics, theorized antecedents (pain catastrophizing, fear of pain, and anxiety sensitivity), and clinical outcomes (pain intensity, interference, anxiety, depression, and posttraumatic stress). For youth with chronic pain, clinical outcomes were reassessed at 3 months to assess for relationships with attentional bias while controlling for baseline symptoms. In both groups, youth exhibited an attentional bias for painful facial expressions. For youth with chronic pain, attentional bias was not significantly associated with theorized antecedents or clinical outcomes at baseline or 3-month follow-up. These findings call into question the posited relationships between attentional bias and clinical outcomes. Additional studies using more comprehensive and contextual paradigms for the assessment of attentional bias are required to clarify the ways in which such biases may manifest and relate to clinical outcomes.
Learn More >Chronic pain is associated with persistent structural and functional changes throughout the neuroaxis, including in the prefrontal cortex (PFC). The PFC is important in the integration of sensory, cognitive and emotional information and in conditioned pain modulation. We previously reported wide-spread epigenetic reprogramming in the PFC many months following nerve injury in rodents. Epigenetic modifications, including DNA methylation, can drive changes in gene expression without modifying DNA sequences. To date, little is known about epigenetic dysregulation at the onset of acute pain or how it progresses as pain transitions from acute to chronic. We hypothesize that acute pain following injury results in rapid and persistent epigenetic remodelling in the PFC that evolves as pain becomes chronic. We further propose that understanding epigenetic remodelling will provide insights into the mechanisms driving pain-related changes in the brain. Epigenome-wide analysis was performed in the mouse PFC 1 day, 2 weeks, 6 months, and 1 year following peripheral injury using the spared nerve injury (SNI) in mice. SNI resulted in rapid and persistent changes in DNA methylation, with robust differential methylation observed between SNI and sham-operated control mice at all time points. Hundreds of differentially methylated genes were identified, including many with known function in pain. Pathway analysis revealed enrichment in genes related to stimulus response at early time points, immune function at later time points and actin and cytoskeletal regulation throughout the time course. These results emphasize the importance of considering pain chronicity in both pain research and in treatment optimization.
Learn More >Attentional biases are posited to play a key role in the development and maintenance of chronic pain in adults and youth. However, research to date has yielded mixed findings and few studies have examined attentional biases in pediatric samples. The present study used eye-gaze tracking to examine attentional biases to pain-related stimuli in a clinical sample of youth with chronic pain and pain-free controls. The moderating role of attentional control was also examined. Youth with chronic pain (n = 102) and pain-free controls (n = 53) viewed images of children depicting varying levels of pain expressiveness paired with neutral faces while their eye gaze was recorded. Attentional control was assessed using both a questionnaire and a behavioural task. Both groups were more likely to first fixate on high pain faces but showed no such orienting bias for moderate or low pain faces. Youth with chronic pain fixated longer on all pain faces than neutral faces, whereas youth in the control group exhibited a total fixation bias only for high and moderate pain faces. Attentional control did not moderate attentional biases between or within groups. The results lend support to theoretical models positing the presence of attentional biases in youth with chronic pain. Further research is required to clarify the nature of attentional biases and their relationship to clinical outcomes.
Learn More >The opioid epidemic has plagued the United States with high levels of abuse and poor quality of life for chronic pain patients requiring continuous use of opioids. New drug discovery efforts have been implemented to mitigate this epidemic, however, new medications are still limited by low efficacy and/or high side effect and abuse potential. Intermittent fasting (IF) has recently been shown to improve a variety of pathological states, including stroke and neuroinflammation. Numerous animal and human studies have shown the benefits of IF in these disease states, but not in pain and opioid treatment. We thus subjected male and female CD-1 mice to 18-hour fasting intervals followed by 6-hour feed periods with standard chow for 1 week. Mice which underwent this diet displayed an enhanced anti-nociceptive response to morphine both in efficacy and duration using thermal tail flick and post-operative paw incision pain models. While showing enhanced anti-nociception, IF mice also demonstrated no morphine reward and reduced tolerance and constipation. Seeking a mechanism for these improvements, we found that the mu opioid receptor (MOR) showed enhanced efficacy and reduced tolerance in the spinal cord and periaqueductal grey (PAG) respectively from IF mice using a S-GTPγS coupling assay. These improvements in receptor function were not due to changes in MOR protein expression. These data suggest that a daily IF diet may improve the therapeutic index of acute and chronic opioid therapies for pain patients in the clinic, providing a novel tool to improve patient therapy and reduce potential abuse.
Learn More >Recently, the adenosine triphosphate (ATP) sensitive potassium channel opener levcromakalim was shown to induce migraine attacks with a far higher incidence than any previous provoking agent such as calcitonin gene-related peptide. Here, we show efficacy of ATP sensitive potassium channel inhibitors in two validated rodent models of migraine.
Learn More >Previous studies regarding the quantitative sensory testing are inconsistent in migraine. We hypothesized that the quantitative sensory testing results were influenced by headache frequency or migraine phase.
Learn More >Ethnic differences in placebo and nocebo responses are an important, yet underresearched, patient factor that might contribute to treatment disparities.
Learn More >Research indicates pain-related disparities in the impact of knee osteoarthritis (OA) across both sex and ethnicity/race. While several factors likely contribute to these disparities, experiences of discrimination are associated with poor OA-related pain, disability, and functional performance. However, the mechanisms that mediate experiences of discrimination and OA-related outcomes are unclear. The current cross-sectional study examined the associations between everyday experiences of discrimination and clinical pain, disability and functional performance among non-Hispanic Black (NHB) and non-Hispanic White (NHW) persons with or at risk of knee OA and assessed the serial mediated model of perceived stress and pain catastrophizing on these relationships in women only.
Learn More >The opioid epidemic has led to a serious examination of the use of opioids for the treatment of pain. Opioid drugs are effective due to the expression of opioid receptors throughout the body. These receptors respond to endogenous opioid peptides that are expressed as polypeptide hormones that are processed by proteolytic cleavage. Endogenous opioids are expressed throughout the peripheral and central nervous system and regulate many different neuronal circuits and functions. One of the key functions of endogenous opioid peptides are to modulate our responses to pain. This review will focus on the descending pain modulatory circuit which consists of the ventrolateral periaqueductal gray (PAG) projections to the rostral ventromedial medulla (RVM). RVM projections modulate incoming nociceptive afferents at the level of the spinal cord. Stimulation within either the PAG or RVM results in analgesia and this circuit has been studied in detail in terms of the actions of exogenous opioids, such as morphine and fentanyl. Further emphasis on understanding the complex regulation of endogenous opioids will help to make rational decisions with regard to the use of opioids for pain. We also include a discussion of the actions of endogenous opioids in the amygdala, an upstream brain structure that has reciprocal connections to the PAG that contribute to the brain's response to pain.
Learn More >Human fear conditioning research since Watson's case study on "Little Albert" has vastly evolved and its impact today is reaching far beyond phobic anxiety. This review focuses on how fear conditioning research, mainly using exteroceptive conditioned stimuli (CSs) and aversive, non-noxious stimuli as unconditioned stimuli (USs), has been extended and translated to chronic pain research. We describe the different pain-related fear conditioning paradigms using proprioceptive and interoceptive CSs and painful stimuli as USs that have been developed to study specific forms of pain-related fear (i.e. fear of movement, fear of touch, fear of visceral sensations, and fear of penetration) that are relevant for different chronic pain conditions (i.e. musculoskeletal pain, neuropathic pain, visceral pain, and genital pain). We present evidence that patients with chronic pain demonstrate impaired safety learning and excessive fear generalization; learning anomalies that have also been observed in anxiety disorders. Extinction-based protocols (exposure in vivo) have been developed to reduce pain-related fear and increase daily functioning in various chronic pain disorders. Finally, we outline some challenges and future directions to further our understanding of learning mechanisms underlying the development, persistence, and treatment of chronic pain disability.
Learn More >Voltage-gated calcium channels (VGCCs) are multi-subunit complexes that play a crucial role in neuronal signaling. Auxiliary α2δ subunits of VGCCs modulate trafficking and biophysical properties of the pore-forming α1 subunit and trigger excitatory synaptogenesis. Alterations in the expression level of α2δ subunits were implicated in several syndromes and diseases, including chronic neuropathic pain, autism and epilepsy. However, the contribution of distinct α2δ subunits to excitatory/inhibitory imbalance and aberrant network connectivity characteristic for these pathological conditions remains unclear. Here, we show that α2δ1 overexpression enhances spontaneous neuronal network activity in developing and mature cultures of hippocampal neurons. In contrast, overexpression, but not downregulation, of α2δ3 enhances neuronal firing in immature cultures, whereas later in development it suppresses neuronal activity. We found that α2δ1 overexpression increases excitatory synaptic density and selectively enhances presynaptic glutamate release, which is impaired upon α2δ1 knock-down. Overexpression of α2δ3 increases the excitatory synaptic density as well, but also facilitates spontaneous GABA release and triggers an increase in the density of inhibitory synapses, which is accompanied by enhanced axonal outgrowth in immature interneurons. Together, our findings demonstrate that α2δ1 and α2δ3 subunits play distinct but complementary roles in driving formation of structural and functional network connectivity during early development. An alteration in α2δ surface expression during critical developmental windows can therefore play a causal role and have a profound impact on the excitatory-to-inhibitory balance and network connectivity.The computational capacity of neuronal networks is determined by their connectivity. Chemical synapses are the main interface for transfer of information between individual neurons. The initial formation of network connectivity requires spontaneous electrical activity and the calcium channel-mediated signaling. We found that in early development auxiliary α2δ3 subunits of calcium channels foster presynaptic release of GABA, trigger formation of inhibitory synapses and promote axonal outgrowth in inhibitory interneurons. In contrast, later in development α2δ1 subunits promote the glutamatergic neurotransmission and synaptogenesis, as well as strongly enhance neuronal network activity. We propose that formation of connectivity in neuronal networks is associated with a concerted interplay of α2δ1 and α2δ3 subunits of calcium channels.
Learn More >Opioid analgesics represent a critical treatment for chronic pain in the analgesic ladder of the World Health Organization. However, their use can result in a number of unwanted side-effects including incomplete efficacy, constipation, physical dependence, and overdose liability. Cannabinoids enhance the pain-relieving effects of opioids in preclinical studies and dampen unwanted side-effects resulting from excessive opioid intake. We recently reported that a CB positive allosteric modulator (PAM) exhibits antinociceptive efficacy in models of pathological pain and lacks the adverse side effects of direct CB receptor activation. In the present study, we evaluated whether a CB PAM would enhance morphine's therapeutic efficacy in an animal model of chemotherapy-induced neuropathic pain and characterized its impact on unwanted side-effects associated with chronic opioid administration. In paclitaxel-treated mice, both the CB PAM GAT211 and the opioid analgesic morphine reduced paclitaxel-induced behavioral hypersensitivities to mechanical and cold stimulation in a dose-dependent manner. Isobolographic analysis revealed that combinations of GAT211 and morphine resulted in anti-allodynic synergism. In paclitaxel-treated mice, a sub-threshold dose of GAT211 prevented the development of tolerance to the anti-allodynic effects of morphine over 20 days of once daily dosing. However, GAT211 did not reliably alter somatic withdrawal signs (i.e., jumps, paw tremors) in morphine-dependent neuropathic mice challenged with naloxone. In otherwise naïve mice, GAT211 also prolonged antinociceptive efficacy of morphine in the tail-flick test and reduced the overall right-ward shift in the ED for morphine to produce antinociception in the tail-flick test, consistent with attenuation of morphine tolerance. Pretreatment with GAT211 did not alter somatic signs of μ opioid receptor dependence in mice rendered dependent upon morphine via subcutaneous implantation of a morphine pellet. Moreover, GAT211 did not reliably alter μ-opioid receptor-mediated reward as measured by conditioned place preference to morphine. Our results suggest that a CB PAM may be beneficial in enhancing and prolonging the therapeutic properties of opioids while potentially sparing unwanted side-effects (e.g., tolerance) that occur with repeated opioid treatment.
Learn More >To narratively review the pathophysiological rationale of dual therapy with anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A in treatment-resistant chronic migraine prevention.
Learn More >The treatment of chronic low back pain (cLBP) often involves multimodal pharmacologic and non-pharmacologic strategies. There remain shortcomings with these tools with regards to both effect size and side effects.
Learn More >Prospective trials of enhanced recovery after spine surgery are lacking. We tested the hypothesis that an enhanced recovery pathway improves quality of recovery after one- to two-level lumbar fusion.
Learn More >Cathepsin S (CatS) is a cysteine protease found in lysosomes of hematopoietic and microglial cells and in secreted form in the extracellular space. While CatS has been shown to contribute significantly to neuropathic pain, the precise mechanisms remain unclear. In this report, we describe JNJ-39641160, a novel non-covalent, potent, selective and orally-available CatS inhibitor that is peripherally-restricted (non-CNS penetrant) and may represent an innovative class of immunosuppressive and analgesic compounds and tools useful toward investigating peripheral mechanisms of CatS in neuropathic pain. In C57BL/6 mice, JNJ-39641160 dose-dependently blocked the proteolysis of the invariant chain; and inhibited both T-cell activation and antibody production to a vaccine antigen. In the spared nerve injury (SNI) model of chronic neuropathic pain, in which T-cell activation has previously been demonstrated to be a prerequisite for the development of pain hypersensitivity, JNJ-39641160 fully reversed tactile allodynia in wild type mice but was completely ineffective in the same model in CatS knockout mice (which exhibited a delayed onset in allodynia). By contrast, in the acute mild thermal injury (MTI) model, JNJ-39641160 only weakly attenuated allodynia at the highest dose tested. These findings support the hypothesis that blockade of peripheral CatS alone is sufficient to fully reverse allodynia following peripheral nerve injury and suggest that the mechanism of action likely involves interruption of T-cell activation and peripheral cytokine release. In addition, they provide important insights toward the development of selective CatS inhibitors for the treatment of neuropathic pain in humans.
Learn More >Migraine is a complex disorder, involving peripheral and central brain structures, where mechanisms and site of attack initiation are an unresolved puzzle. While abnormal pontine neuronal activation during migraine attacks has been reported, exact implication of this finding is unknown. Evidence suggests an important role of glutamate in migraine, implying a possible association of pontine hyperactivity to increased glutamate levels. Migraine without aura patients were scanned during attacks after calcitonin gene-related peptide and sildenafil in a double-blind, randomized, double-dummy, cross-over design, on two separate study days, by proton magnetic resonance spectroscopy and pseudo-continuous arterial spin labeling at 3T. Headache characteristics were recorded until 24 h after drug administrations. Twenty-six patients were scanned during migraine, yielding a total of 41 attacks. Cerebral blood flow increased in dorsolateral pons, ipsilateral to pain side during attacks, compared to outside attacks (13.6%, p = 0.009). Glutamate levels in the same area remained unchanged during attacks (p = 0.873), while total creatine levels increased (3.5%, p = 0.041). In conclusion, dorsolateral pontine activation during migraine was not associated with higher glutamate levels. However, the concurrently increased total creatine levels may suggest an altered energy metabolism, which should be investigated in future studies to elucidate the role of pons in acute migraine.
Learn More >Interplay between body schema, visuospatial perception and pain in patients with spinal cord injury.
Changes in body representations (body image and/or body schema) have been reported in several chronic musculoskeletal pain syndromes, but rarely in patients with neuropathic pain and never in patients with spinal cord injury (SCI)-related pain.
Learn More >Exercise induced hypoalgesia (EIH) can be impaired in patients with chronic pain and may be dependent on exercise type. Factors predictive of EIH are not known. This study aimed to: (1) compare EIH in participants with chronic WAD to asymptomatic controls, (2) determine if EIH differs between aerobic and isometric exercise, (3) determine predictors of EIH.
Learn More >Nowadays, pain represents one of the most important societal burdens. Current treatments are, however, too often ineffective and/or accompanied by debilitating unwanted effects for patients dealing with chronic pain. Indeed, the prototypical opioid morphine, as many other strong analgesics, shows harmful unwanted effects including respiratory depression and constipation, and also produces tolerance, physical dependence, and addiction. The urgency to develop novel treatments against pain while minimizing adverse effects is therefore crucial. Over the years, the delta-opioid receptor (DOP) has emerged as a promising target for the development of new pain therapies. Indeed, targeting DOP to treat chronic pain represents a timely alternative to existing drugs, given the weak unwanted effects spectrum of DOP agonists. Here, we review the current knowledge supporting a role for DOP and its agonists for the treatment of pain. More specifically, we will focus on the cellular and subcellular localization of DOP in the nervous system. We will also discuss in further detail the molecular and cellular mechanisms involved in controlling the cellular trafficking of DOP, known to differ significantly from most G protein-coupled receptors. This review article will allow a better understanding of how DOP represents a promising target to develop new treatments for pain management as well as where we stand as of our ability to control its cellular trafficking and cell surface expression.
Learn More >Dexmedetomidin is a new-generation, highly selective α2 adrenergic receptor agonist with a large number of advantages, including its sedative and analgesic properties, its ability to inhibit sympathetic nerves, its reduced anesthetic dosage, its hemodynamic stability, its mild respiratory depression abilities, and its ability to improve postoperative recognition. Its safety and effectiveness, as well as its ability to provide a certain degree of comfort to patients, make it a useful anesthetic adjuvant for a wide range of clinical applications. For example, dexmedetomidine is commonly used in patients undergoing general anesthesia, and it also exerts sedative effects during tracheal intubation or mechanical ventilation in intensive care unit patients. In recent years, with the deepening of clinical research on dexmedetomidine, the drug is still applied in the treatment of spastic pain, myofascial pain, neuropathic pain, complex pain syndrome, and chronic headache, as well as for multimodal analgesia. However, we must note that the appropriateness of patient and dose selection should be given attention when using this drug; furthermore, patients should be observed for adverse reactions such as hypotension and bradycardia. Therefore, the safety and effectiveness of this drug for long-term use remain to be studied. In addition, basic experimental studies have also found that dexmedetomidine can protect important organs, such as the brain, heart, kidney, liver, and lung, through various mechanisms, such as antisympathetic effects, the inhibition of apoptosis and oxidative stress, and a reduction in the inflammatory response. Moreover, the neuroprotective properties of dexmedetomidine have received the most attention from scholars. Hence, in this review, we mainly focus on the characteristics and clinical applications of dexmedetomidine, especially the role of dexmedetomidine in the nervous system and the use of dexmedetomidine in the relief of neuropathic pain.
Learn More >Topical analgesics are an upcoming treatment option for neuropathic pain. In this observational study, we performed a double-blind placebo-controlled response test (DOBRET) in patients with polyneuropathy to determine the personalized analgesic effect of phenytoin 10% cream.
Learn More >Substantial evidence from preclinical models of pain suggests that basal and noxious nociceptive sensitivity, as well as antinociceptive responses to drugs, show significant heritability. Individual differences to these responses have been observed across species from rodents to humans. The use of closely related C57BL/6 inbred mouse substrains can facilitate gene mapping of acute nociceptive behaviors in preclinical pain models. In this study, we investigated behavioral differences between C57BL/6 J (B6 J) and C57BL/6 N (B6 N) substrains in the formalin test, a widely used tonic inflammatory pain model, using a battery of pain-related phenotypes, including reflexive tests, nesting, voluntary wheel running, sucrose preference and anxiety-like behavior in the light/dark test at two different time points (1-h and 24-h). Our results show that these substrains did not differ in reflexive thermal and mechanical responses at the 1-h time point. However, B6 N substrain mice showed increased sensitivity to spontaneous pain-like behaviors. In addition, B6 N substrain continued to show higher levels of mechanical hypersensitivity compared to controls at 24-h. indicating that mechanical hypersensitivity is a more persistent pain-related phenotype induced by formalin. Finally, no sex differences were observed in our outcome measures. Our results provide a comprehensive behavioral testing paradigm in response to an inflammatory agent for future mouse genetic studies in pain.
Learn More >Persistent postsurgical pain (PPSP) is a common complication of surgery that significantly affects quality of life. A better understanding of which patients are likely to develop PPSP would help to identify when perioperative and postoperative pain management may require specific attention. Quantitative sensory testing (QST) of a patient'fs preoperative pain perception is associated with acute postoperative pain, and acute postoperative pain is a risk factor for PPSP. The direct association between preoperative QST and PPSP has not been reviewed to date. In this systematic review, we assessed the relationship of preoperative QST to PPSP. We searched databases with components related to (1) preoperative QST; (2) association testing; and (3) PPSP. Two authors reviewed all titles and abstracts for inclusion. Inclusion criteria were as follows: (1) QST performed before surgery; (2) PPSP assessed ≥3 months postoperatively; and (3) the association between QST measures and PPSP is investigated. The search retrieved 905 articles; 24 studies with 2732 subjects met inclusion criteria. Most studies (22/24) had moderate to high risk of bias in multiple quality domains. Fourteen (58%) studies reported a significant association between preoperative QST and PPSP. Preoperative temporal summation of pain (4 studies), conditioned pain modulation (3 studies), and pressure pain threshold (3 studies) showed the most frequent association with PPSP. The strength of the association between preoperative QST and PPSP varied from weak to strong. Preoperative QST is variably associated with PPSP. Measurements related to central processing of pain may be most consistently associated with PPSP.
Learn More >Low back pain (LBP) is a complex and growing global health problem in need of more effective pain management strategies. Spinal mobilization (SM) is a non-pharmacological approach recommended by most clinical guidelines for LBP, but greater utilization and treatment optimization are hampered by a lack of mechanistic knowledge underlying its hypoalgesic clinical effects.
Learn More >Sex differences in pain sensitivity have been well documented, such that women often report greater sensitivity than men. However, clinical reports highlighting sex differences often equate gender and sex. This is a particularly critical oversight for those whose gender identity is different than their genetic sex.
Learn More >Chronic neuropathic pain resulting from damage to the central or peripheral nervous system is a prevalent and debilitating condition affecting 7-18% of the population. Symptoms include spontaneous pain, dysesthesia, paresthesia, allodynia and hyperalgesia. The reported sensory symptoms are comorbid with behavioral disabilities such as insomnia and depression. Neonatal anoxia, a worldwide clinical problem in both neonatal and pediatric care, causes long-term deficits similar to those mentioned. The effect of neonatal anoxia on the maturation of nociceptive pathways has been sparsely explored. To address this question and to determine whether the effects differ depending on sex, a neonatal anoxia model was used in which Wistar rat pups approximately 30 hours old and of both sexes were placed in a chamber with 100% nitrogen flow at 3.5 L/min for 25 min at 36 °C ± 1 °C. After recovery, the animals (n = 16 in each group (anoxia and control; males and females)) were returned to their mothers. The control animals were subjected to the same conditions, but no gas exchange was performed. At postnatal day (PND) 18 and PND43, the animals were subjected to pain testing by stimulation of the hind paws with von Frey monofilaments. The results revealed a significant reduction (approximately 50%) in the pain threshold in the animals exposed to anoxia in comparison with their respective controls. The pain threshold increased between PND18 and PND43. A sex-based difference was observed in the male control group at PND18. Histological analysis revealed decreased cell numbers in the ventral posterolateral thalamic nucleus (VPL), with sex differences. These results demonstrate the long-lasting negative impact of neonatal anoxia and indicate the relevance of performing suitable approaches taking in consideration the possible sex differences.
Learn More >An electrophysiological technique that can record nerve impulses from a single nerve fiber is indispensable for studying modality-specific sensory receptors such as low threshold mechanoreceptors, thermal receptors, and nociceptors. The teased-fiber single-unit recording technique has long been used to resolve impulses that are likely to be from a single nerve fiber. The teased-fiber single-unit recording technique involves tedious nerve separation procedures, causes nerve fiber impairment, and is not a true single-fiber recording method. In the present study, we describe a new and true single-fiber recording technique, the pressure-clamped single-fiber recording method. We have applied this recording technique to mouse whisker hair follicle preparations with attached whisker afferents as well as to skin-nerve preparations made from mouse hindpaw skin and saphenous nerves. This new approach can record impulses from rapidly adapting mechanoreceptors (RA), slowly adapting type 1 mechanoreceptors (SA1), and slowly adapting type 2 mechanoreceptors (SA2) in these tissue preparations. We have also applied the pressure-clamped single-fiber recordings to record impulses on Aβ-fibers, Aδ-fibers, and C-fibers. The pressure-clamped single-fiber recording technique provides a new tool for sensory physiology and pain research.
Learn More >Joint pain is the major clinical symptom of arthritis that affects millions of people. Controlling the excitability of knee-innervating dorsal root ganglion (DRG) neurons (knee neurons) could potentially provide pain relief. Therefore, our objective was to evaluate whether the newly engineered adeno-associated virus (AAV) serotype, AAV-PHP.S, can deliver functional artificial receptors to control knee neuron excitability following intra-articular knee injection.
Learn More >Meniscal injury is a common prelude to post-traumatic osteoarthritis (PTOA). Joint nerves can become damaged in arthritic joints leading to the manifestation of neuropathic pain. Both PTOA and neuropathic pain are more common in females; however, it is unknown whether the neural processing of joint pain is sex-specific.
Learn More >Although it has been suggested that the different cultural and social environments between countries contribute to variations in pain catastrophizing (PC), an international comparison of PC in patients with chronic pain has not yet been reported. Prior to undertaking this comparison, a cross-cultural assessment of the pain catastrophizing scale (PCS) was undertaken to explore the different factor-structures among each translated version of the PCS.
Learn More >Whereas impaired multisensory processing of bodily stimuli and distorted body representation are well-established in various chronic pain disorders, such research has focused on exteroceptive bodily cues and neglected bodily signals from the inside of the body (or interoceptive signals). Extending existing basic and clinical research, we investigated for the first time interoception and its neurophysiological correlates in patients with complex regional pain syndrome (CRPS). In three different experiments, including a total of 36 patients with CRPS and 42 aged-gender matched healthy controls, we measured interoceptive sensitivity (heart beat counting task, HBC) and neural responses to heartbeats (heartbeat evoked potentials, HEP). As hypothesized, we observed reduced sensitivity in perceiving interoceptive bodily stimuli, i.e. their heartbeat, in two independent samples of CRPS patients (studies 1 and 2). Moreover, the cortical processing of their heartbeat, i.e. the HEP, was reduced compared to controls (study 3) and reduced interoceptive sensitivity and HEPs were related to CRPS patients' motor impairment and pain duration. By providing consistent evidence for impaired processing of interoceptive bodily cues in CRPS, this study shows that the perceptual changes occurring in chronic pain include signals originating from the visceral organs, suggesting changes in the neural body representation, that includes next to exteroceptive, also interoceptive bodily signals. By showing that impaired interoceptive processing is associated with clinical symptoms, our findings also encourage the use of interoceptive-related information in future rehabilitation for chronic pain.
Learn More >The frequent use of medication to treat migraine attacks can lead to an increase in migraine frequency and is called medication-overuse headache (MOH).
Learn More >To provide an updated review of the pathophysiology, diagnosis, and management of migraine with aura.
Learn More >Neck pain is a global burdensome problem, with a large proportion of neck pain cases becoming chronic. Although physical exercise is a commonly prescribed treatment, the evidence on the effectiveness of isolated exercise interventions remains limited. Traditional pairwise randomised controlled trials (RCTs) and meta-analyses are limited in only comparing two interventions. This protocol describes the design of a network meta-analysis, which enables a comparative investigation of all physical exercise interventions for which RCTs are available. We aim to systematically compare the effectiveness of different types of physical exercise in people with chronic non-specific neck pain.
Learn More >Central post-stroke pain (CPSP) can arise after lesions anywhere in the central somatosensory pathways, essentially within the spinothalamic system (STS). Although the STS can be selectively injured in the mesencephalon, CPSP has not been described in pure midbrain infarcts.
Learn More >Develop a translational assay of Transient Receptor Potential Ankyrin 1 (TRPA1) activity for use as a preclinical and clinical biomarker.
Learn More >Protocol for a pragmatic randomized controlled trial (the Exercise guideline Promotion and Implementation in Chronic SCI [EPIC-SCI] Trial).
Learn More >Recent years have seen an increase in the adoption of cannabinoid medicines, which have demonstrated effectiveness for the treatment of chronic pain. However, the extent to which frequent cannabis use (CU) influences sensitivity to acute pain has not been systematically examined. Such a determination is clinically relevant in light of hypersensitivity to pain associated with prolonged use of other analgesics such as opioids, and reports of increased pain sensitivity to experimentally induced pain during acute cannabis intoxication. This study will explore differences on measures of pain intensity and tolerance. We hypothesize that individuals who report frequent CU will demonstrate greater experimental pain sensitivity.
Learn More >The opioid epidemic is a significant public health problem that is associated with overdose and death. The increase in opioid-related problems can largely be attributed to increases in opioid prescriptions for the treatment of chronic pain. Unfortunately, there is not a consensus on a definition of opioid misuse in the context of chronic pain, making measurement a challenge. One commonly used measure to assess opioid misuse in the context of chronic pain is the Current Opioid Misuse Measure (COMM). The COMM was designed to assess opioid misuse generally, as captured by psychiatric symptoms and aberrant drug use behaviors. Although studies have examined cross-validation using correlations, little psychometric work has been conducted, and therefore it is currently unknown what domains the measure is assessing.
Learn More >Neuropathic pain (NP) is caused by primary or secondary impairment of the peripheral or central nervous systems. Its etiology is complex and involves abnormal patterns of gene expression and pathway activation. Using bioinformatics analysis, we aimed to identify NP-associated changes in genes and pathways in L4 and L5 dorsal root ganglia (DRG) in a rat model of NP induced by chronic compression of the DRG (CCD). Genome-wide transcriptional analyses were used to elucidate the molecular mechanisms underlying NP. We screened differentially expressed genes (DEGs) 7 days after CCD in comparison with sham-operated controls. Quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting were used to confirm the presence of key DEGs. Kyoto Encyclopedia of Genes and Genomes (KEGG)-pathway analysis of DEGs and global signal transduction network analysis of DEGs were also conducted. The CCD group developed clear mechanical and thermal allodynia in the ipsilateral hind paw compared with the sham group. This comparison identified 1,887 DEGs, with 1156 upregulated and 731 downregulated DEGs, and 123 DEG-enriched pathways. We identified the key candidate genes that might play a role in the development of NP, namely (), , (), (), (), and () by analyzing the global signal transduction network. RT-qPCR and western blot analysis confirmed the microarray results. The DEGs , , , , and , and the cytokine signaling pathway, the neuroactive ligand-receptor interaction, the toll-like receptor signaling pathway, and the PI3K-Akt signaling pathway may have decisive modulatory roles in both nerve regeneration and NP. These results provide deeper insight into the mechanism underlying NP and promising therapeutic targets for its treatment.
Learn More >Chronic pain is common in adolescents. Evidence-based guidelines recommend interdisciplinary treatment, but access is limited by geography. The development of hybrid programs utilizing both face-to-face and videoconference treatment may help overcome this. We developed a 7-week hybrid pediatric interdisciplinary pain program (Hybrid-PIPP) and wished to compare it to individual face-to-face sessions (Standard Care). Our objective was to test the feasibility of a protocol that used a matched pair un-blinded randomized controlled design to investigate the efficacy and cost-effectiveness of the Hybrid-PIPP compared to Standard Care.
Learn More >The purpose of this study was to explore the role and mechanism of the PI3K/AKT/mTOR signaling pathway in painful diabetic neuropathy (PDN). The diabetes mellitus (DM) model was established by intraperitoneal injection of streptozocin into SD rats. After 3 weeks of modeling, the DM + LY group was treated with PI3K inhibitor, the DM + vehicle group was treated with DMSO, and the DM group was untreated. The paw mechanical withdrawal thresholds (MWT) was measured by Von Frey filaments, and the expression of PI3K/AKT/mTOR pathway-related proteins and autophagy marker proteins were analyzed by Western blotting. We found that 3 weeks after modeling, the MWT values of diabetic rats were significantly reduced, p-PI3K, p-AKT and p-mTOR proteins expression in the spinal cord was increased, and Beclin1 and LC3-II expressions were reduced (P < 0.05). After administration of PI3K inhibitor, the MWT values in DM + LY group were improved, and the expressions of p-PI3K, p-AKT and p-mTOR proteins in the spinal cord were decreased significantly, and the expressions of Beclin1 and LC3-II were increased (P < 0.05). However, there were no significant changes in the DM + vehicle group compared with the DM group (P > 0.05). Therefore, we conclude that activation of the PI3K/AKT/mTOR pathway and impaired autophagy may be key factors that cause PDN. Inhibition of the PI3K/AKT/mTOR pathway could promote autophagy activity and alleviate PDN.
Learn More >Cannabidiol (CBD), the major non-psychoactive constituent of L., has gained traction as a potential treatment for intractable chronic pain in many conditions. Clinical evidence suggests that CBD provides therapeutic benefit in certain forms of epilepsy and imparts analgesia in certain conditions, and improves quality of life. CBD continues to be Schedule I or V on the list of controlled substances of the Drug Enforcement Agency of the United States. However, preparations labeled CBD are available publicly in stores and on the streets. However, use of CBD does not always resolve pain. CBD purchased freely entails the risk of adulteration by potentially hazardous chemicals. As well, CBD use by pregnant women is rising and poses a major health-hazard for future generations. In this mini-review, we present balanced and unbiased pre-clinical and clinical findings for the beneficial effects of CBD treatment on chronic pain and its deleterious effects on prenatal development.
Learn More >Cervical dystonia is the most common form of focal idiopathic dystonia and is frequently associated with pain. Headaches are not considered to be more prevalent amongst patients presenting with cervical dystonia, and headaches attributed to craniocervical dystonia are considered to be a rare disorder, despite the lack of studies and clinical information regarding the subject.
Learn More >Capsaicin is the most abundant pungent molecule identified in red chili peppers, and it is widely used for food flavoring, in pepper spray for self-defense devices and recently in ointments for the relief of neuropathic pain. Capsaicin and several other related vanilloid compounds are secondary plant metabolites. Capsaicin is a selective agonist of the transient receptor potential channel, vanilloid subfamily member 1 (TRPV1). After exposition to vanilloid solution, Caenorhabditis elegans wild type (N2) and mutants were placed on petri dishes divided in quadrants for heat stimulation. Thermal avoidance index was used to phenotype each tested C. elegans experimental groups. The data revealed for the first-time that capsaicin can impede nocifensive response of C. elegans to noxious heat (32-35 °C) following a sustained exposition. The effect was reversed 6 h post capsaicin exposition. Additionally, we identified the capsaicin target, the C. elegans transient receptor potential channel OCR-2 and not OSM-9. Further experiments also undoubtedly revealed anti-nociceptive effect for capsaicin analogues, including olvanil, gingerol, shogaol and curcumin.
Learn More >Nucleoside reverse transcriptase inhibitors (NRTIs) are associated with the development of painful neuropathies and may further aggravate sensory neuropathy produced by HIV-1 infection, leading to discontinuation of NRTI therapy by HIV patients. Following antiretroviral-induced peripheral neuropathy, c-Jun N-terminal kinase (JNK) is activated in the dorsal root ganglia (DRG) and spinal cord. However, the contribution of individual JNK genes remains unknown. Here, we have tested the behavioural mechanical sensitivity of JNK1, JNK2 and JNK3 knockout (KO) mice in the von Frey test after treatment with 2',3'-dideoxycytidine (ddC). Protein expression was investigated in the spinal cord of wild type (wt) and KO mice by western blotting. The onset of neuropathic pain was prevented by the deletion of JNK3, leading us to hypothesize that JNK3 protein plays a major role in the regulation of pain threshold in antiretroviral neuropathy. The growth-associated protein 43 (GAP-43) and the transcription factor c-Jun are involved in regeneration processes. This study revealed an up-regulation of GAP-43 and c-Jun protein, 14 days after ddC administration. JNK1 deletion induced a significant reduction in c-Jun phosphorylation and GAP-43 protein contents. In contrast, there was no difference in ddC-induced reduction of hind paw intraepidermal nerve fibre density in all JNK KO mice. Overall, these findings indicate that JNK3 plays a critical role in regulating ddC neurotoxicity-induced mechanical pain hypersensitivity, while JNK1 is important for activation of c-Jun and GAP-43 as a critical pathway of a regeneration program. These data highlight the impact of individual JNK isoforms on antiretroviral neurotoxicity and neuro-regeneration processes.
Learn More >Oxaliplatin, a platinum-based chemotherapeutic agent, is widely used to treat colorectal cancer, but it induces peripheral neuropathy as a serious dose-limiting side effect. Recently, thrombomodulin alfa, a recombinant human soluble thrombomodulin, was reported to prevent oxaliplatin-induced peripheral neuropathy in a clinical phase 2 study. Here we conducted preclinical pharmacology studies. Rats were given oxaliplatin (6 mg/kg) intravenously to induce mechanical hyperalgesia associated with peripheral neuropathy. Single intravenous administration of thrombomodulin alfa (0.1, 0.3, 1 mg/kg) dose dependently prevented the development of oxaliplatin-induced mechanical hyperalgesia, with no sex difference in the efficacy. The preventative effect of thrombomodulin alfa on mechanical hyperalgesia was attenuated by antithrombin or carboxypeptidase inhibitor. In addition, carboxypeptidase B, a homolog of activated thrombin-activatable fibrinolysis inhibitor (TAFI) and human-derived activated protein C, prevented mechanical hyperalgesia, whereas antithrombin or other anti-coagulants did not. These results suggest that thrombomodulin alfa prevents sensory symptoms of oxaliplatin-induced peripheral neuropathy through the activation of TAFI and protein C by modulating thrombin activity, but the effects are independent of an anticoagulant effect. On the other hand, thrombomodulin alfa did not affect the anti-cancer activity of oxaliplatin on human colon cancer cell lines or mice transplanted with HCT116 cells. These results indicate that thrombomodulin alfa prevents sensory symptoms of oxaliplatin-induced peripheral neuropathy without affecting the anti-tumor activity of oxaliplatin. Therefore, thrombomodulin alfa is a promising drug to prevent the symptoms of oxaliplatin-induced peripheral neuropathy.
Learn More >Clinical guidelines and systematic reviews recommend exercise in the management of chronic non-specific neck pain. Although exercise training programmes that consist of both motor control exercise and exercises for the superficial cervical muscles (segmental exercises) are effective, the exercise variables including dosage vary considerably across trials or are poorly reported. This study aims to gain expert consensus on these exercise variables so that they can be described clearly using intervention reporting checklists to inform clinical practice and future clinical trials.
Learn More >Atopic dermatitis is a prevalent inflammatory skin condition characterized by itch and dry skin, which affects 15-20% of children and 3-5% of adults. This article reviews epidemiological, clinical and experimental data to provide an overview of the most important disease mechanisms in atopic dermatitis. Genetic predisposition, environmental insults, atopic triggers, complex host immune response and skin barrier changes, and altered skin microbiota are discussed. Whilst our understanding of atopic dermatitis has improved dramatically in recent years, many basic aspects are still not understood. Further research is needed to fully understand this complex skin disease.
Learn More >The treatment of noncancer pain in the United States and globally is met with significant challenges, resulting in profound physical, emotional, and societal costs. Based on this need, numerous modalities have been proposed to manage chronic pain, including opioid and nonopioid interventions as well as surgical approaches. Thus, the future of pain management continues to be mired in evolving concepts and constant debates. Consequently, it is crucial to understand the past as we move towards the future. The evolution of lessons for better pain management at present and for the future starting from the 1990s to the present date are reviewed and emphasized with a focus on learning from the past for the future. This review summarizes the evolution of multiple modalities of treatments, including multidisciplinary programs, multimodal therapy, interventional techniques, opioid therapy, other conservative modalities, and surgical interventions. This review emphasizes the individual, patient-centered development of an effective pain treatment plan after proper evaluation to establish a diagnosis. It includes measurable outcomes that focus on improvements in the quality of life and activities of daily living, as well as improvement in pain and function and, most importantly, return to productive citizenship. It is crucial that the knowledge of best practices be advanced, along with emphasis on lessons learned in the past to provide best practices for better pain management.
Learn More >Morphine is frequently used for pain relief, but long-term morphine therapy in patients with chronic pain results in analgesic tolerance and hyperalgesia. There are no effective therapeutic treatments that limit these detrimental side effects. We found pretreatment with melatonin could decrease morphine-induced analgesic tolerance. There was a significant activation of the NLRP3 inflammasome in the prefrontal cortex and the peripheral blood of morphine-treated mice compared to control animals, which could be blocked by melatonin. The inflammasome activation induced by morphine was mediated by the microglia. SiRNA knockdown or pharmacological inhibition of the NLRP3 abolished the morphine-induced inflammasome activation. Co-administration of melatonin and low-dose morphine had better analgesia effects in the murine models of pain and led to a lower NLRP3 inflammasome activity in brain tissues. Mice deficient for Nlrp3 had a higher nociceptive threshold and were less sensitive to develop morphine-induced analgesic tolerance and acetic acid-induced pain relative to wild-type animals. Concordantly, we observed a significantly elevated level of serum IL-1β, which indicates an increase of NLRP3 inflammasome activity associated with the reduced level of serum melatonin, in heroin-addicted patients relative to healthy individuals. Our results provide a solid basis for conducting a clinical trial with the co-administration of melatonin and morphine for the relief of severe pain.
Learn More >Chronic itch can be a debilitating medical condition with clinical characteristics and impact akin to chronic pain. Itch severity is subjective and clinicians depend on patient reported numerical ratings scales (NRS); most commonly 24-hour worst itch (WI-NRS) has been validated including large scale studies. WI-NRS does not attempt to take into account itch duration or the variability that is often experienced throughout the day and night by chronic itch patients.
Learn More >Opioid receptors are widely distributed in the central and peripheral nervous systems and non-neuronal tissues. Numerous researchers have noted the pivotal role of peripheral opioid receptors (PORs) in analgesia. Accumulating evidence has shown the existence of PORs in the trigeminal nerve system, indicating that PORs may be involved in the modulation of orofacial pain. In this review, we summarise the recent evidence for the role of PORs in orofacial pain and discuss the possible cellular mechanisms.
Learn More >Atopic dermatitis (AD) is associated with itch, pain, and sleep disturbance, all of which may contribute toward cognitive dysfunction.
Learn More >Pruritus in atopic dermatitis has been studied extensively; however, evaluation of skin pain has been very limited. The aim of this study was to evaluate the presence, frequency and characteristics of skin pain in patients with atopic dermatitis. A survey was conducted of a representative sample of 5,000 18-80-year-old individuals selected from the French population according to sex, age, geographical area and socioprofessional status. Data on socio-demographic status and the presence of any skin disease were collected. Pain in the past month and health-related quality of life were evaluated. Average intensity of skin pain during the previous month was assessed with a horizontal visual analogue scale (0-10). Skin pain was reported by more than half of the patients with atopic dermatitis, at a pain intensity of almost 6/10. A neuropathic component was suggested by the Douleur Neuropathique – 4 questions (DN4) questionnaire (a tool for detection of neuropathic pain), as well as the presence of pain inside and outside of skin lesions. Severe alterations to health-related quality of life were assessed with the Dermatology Life Quality Index and Short Form 12 Health Survey (SF-12). Pain is reported frequently by patients with atopic dermatitis. Healthcare professionals should question patients about pain and provide effective treatments. Future clinical trials must take skin pain into account.
Learn More >Oxidative stress induced post-translational protein modifications are associated with the development of inflammatory hypersensitivities. At least 90% of cellular reactive oxygen species (ROS) are produced in the mitochondria, where the mitochondrial antioxidant, manganese superoxide dismutase (MnSOD), is located. MnSOD's ability to reduce ROS is enhanced by the mitochondrial NAD-dependent deacetylase sirtuin (SIRT3). SIRT3 can reduce ROS levels by deacetylating MnSOD and enhancing its ability to neutralize ROS or by enhancing the transcription of MnSOD and other oxidative stress-responsive genes. SIRT3 can be post-translationally modified through carbonylation which results in loss of activity. The contribution of post-translational SIRT3 modifications in central sensitization is largely unexplored. Our results reveal that SIRT3 carbonylation contributes to spinal MnSOD inactivation during carrageenan-induced thermal hyperalgesia in rats. Moreover, inhibiting ROS with natural and synthetic antioxidants, prevented SIRT3 carbonylation, restored the enzymatic activity of MnSOD, and blocked the development of thermal hyperalgesia. These results suggest that therapeutic strategies aimed at inhibiting post-translational modifications of SIRT3 may provide beneficial outcomes in pain states where ROS have been documented to play an important role in the development of central sensitization.
Learn More >The Sigma-1 receptor (σR) is highly expressed in the primary sensory neurons (PSNs) that are the critical site of initiation and maintenance of pain following peripheral nerve injury. By immunoblot and immunohistochemistry, we observed increased expression of both σR and σR-binding immunoglobulin protein (BiP) in the lumbar (L) dorsal root ganglia (DRG) ipsilateral to painful neuropathy induced by spared nerve injury (SNI). To evaluate the therapeutic potential of PSN-targeted σR inhibition at a selected segmental level, we designed a recombinant adeno-associated viral (AAV) vector expressing a small hairpin RNA (shRNA) against rat σR. Injection of this vector into the L4/L5 DRGs induced downregulation of σR in DRG neurons of all size groups, while expression of BiP was not affected. This was accompanied by attenuation of SNI-induced cutaneous mechanical and thermal hypersensitivity. Whole-cell current-clamp recordings of dissociated neurons showed that knockdown of σR suppressed neuronal excitability, suggesting that σR silencing attenuates pain by reversal of injury-induced neuronal hyperexcitability. These findings support a critical role of σR in modulating PSN nociceptive functions, and that the nerve injury-induced elevated σR activity in the PSNs can be a significant driver of neuropathic pain. Further understanding the role of PSN-σR in pain pathology may open routes to exploit this system for DRG-targeted pain therapy.
Learn More >Aim was to stratify the knee MRIs of the Foundation for National Institutes of Health Osteoarthritis Biomarkers Consortium (FNIH) cohort into distinct structural phenotypes based on semiquantitative assessment and to determine risk for pain and structural progression over 48 months.
Learn More >Comorbid posttraumatic stress disorder (PTSD) in patients with chronic pain may have a negative effect on the course and outcome of both disorders. Nevertheless, the co-occurrence of the two conditions is often overlooked in clinical settings. Further, little is known about how PTSD is associated with biopsychosocial characteristics in this patient group. The first objective was to assess the prevalence of posttraumatic stress symptoms (PTSS) in patients with chronic pain in a Norwegian university hospital outpatient pain clinic. The second objective was to investigate possible associations between PTSS and adverse outcomes such as pain intensity, disability, and distress. The third objective was to compare the PTSS prevalence rates between primary versus secondary pain conditions.
Learn More >Dihydroergotamine (DHE) is an ergot alkaloid derivative of substances produced by rye fungus. Ergotamine was first used in the field of gynecology and obstetrics, then used for migraine treatment a few years later. DHE was developed as a derivative of ergotamine. DHE, when compared to ergotamine, demonstrates greater alpha-adrenergic antagonist activity, lower arterial vasoconstriction, less dopaminergic agonism, and lower emetic potential. DHE can be delivered via several routes including intravenous (IV), intramuscular (IM), subcutaneous (SC), intranasal (IN), oral, and orally inhaled (although the latter two are not available in the USA and the last remains experimental only). DHE can be used in an outpatient basis in infusion centers, emergency departments, and urgent care centers, as well as inpatient treatment for admitted patients. There are protocols for adults as well as pediatric migraine treatment. DHE and other ergot alkaloids are considered contraindicated in pregnant women as they decrease uterine blood flow and increase uterine muscle contractility predisposing to spontaneous abortion. DHE during lactation is also not recommended as it can lead to gastrointestinal distress and weakness in infants; it can also suppress milk production. Caution should be taken before administering DHE in patients with cardiovascular risk factors. DHE is an older drug with an interesting history, yet it is still clinically useful today for patients with migraine attacks not responsive to triptans, who have a greater burden from migraine, and in refractory migraine.
Learn More >Long non-coding RNAs (lncRNAs) are a group of non-coding RNAs longer than 200 nucleotides, which are defined as transcripts. The lncRNAs are involved in regulating gene expression at epigenetic, transcriptional, and post-transcriptional levels. Recent studies have found that lncRNA is closely related to many diseases like neurological diseases, endocrine and metabolic disorders. Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes mellitus. In this review, we highlight the latest research related to lncRNAs in DPN.
Learn More >Hemiplegic migraine (HM) is a clinically and genetically heterogeneous condition with attacks of headache and motor weakness which may be associated with impaired consciousness, cerebellar ataxia and intellectual disability. Motor symptoms usually last <72 hours and are associated with visual or sensory manifestations, speech impairment or brainstem aura. HM can occur as a sporadic HM or familiar HM with an autosomal dominant mode of inheritance. Mutations in CACNA1A, ATP1A2 and SCN1A encoding proteins involved in ion transport are implicated. The pathophysiology of HM is close to the process of typical migraine with aura, but appearing with a lower threshold and more severity. We reviewed epidemiology, clinical presentation, diagnostic assessment, differential diagnosis and treatment of HM to offer the best evidence of this rare condition. The differential diagnosis of HM is broad, including other types of migraine and any condition that can cause transitory neurological signs and symptoms. Neuroimaging, cerebrospinal fluid analysis and electroencephalography are useful, but the diagnosis is clinical with a genetic confirmation. The management relies on the control of triggering factors and even hospitalisation in case of long-lasting auras. As HM is a rare condition, there are no randomised controlled trials, but the evidence for the treatment comes from small studies.
Learn More >The P2X receptor family of ATP-gated cation channels are attractive drug targets for pain and inflammatory disease, but no subtype-selective agonists, and few partially selective agonists have been described to date. As proof-of-concept for the discovery of novel P2X receptor agonists, here we demonstrate the use of Drosophila taste neurons heterologously expressing rat P2X2 receptors as a screening platform. We demonstrate that wild-type rat P2X2 expressed in Drosophila is fully functional (ATP EC 8.7 µM), and that screening of small (2 µl) volumes of a library of 80 adenosine nucleotide analogues is rapid and straightforward. We have determined agonist potency and specificity profiles for rat P2X2 receptors; triphosphate-bearing analogues display broad activity, tolerating a number of substitutions, and diphosphate and monophosphate analogues display very little activity. While several ATP analogues gave responses of similar magnitude to ATP, including the previously identified agonists ATPγS and ATPαS, we were also able to identify a novel agonist, the synthetic analogue 2-fluoro-ATP, and to confirm its agonist activity on rat P2X2 receptors expressed in human cells. These data validate our Drosophila platform as a useful tool for the analysis of agonist structure-activity relationships, and for the screening and discovery of novel P2X receptor agonists.
Learn More >Sensory neurons respond to noxious stimuli by relaying information from the periphery to the central nervous system via action potentials driven by voltage-gated sodium channels, specifically Nav1.7 and Nav1.8. These channels play a key role in the manifestation of inflammatory pain. The ability to screen compounds that modulate voltage-gated sodium channels using cell-based assays assumes that key channels present in vivo is maintained in vitro. Prior electrophysiological work in vitro utilized acutely dissociated tissues, however, maintaining this preparation for long periods is difficult. A potential alternative involves multi-electrode arrays which permit long-term measurements of neural spike activity and are well suited for assessing persistent sensitization consistent with chronic pain. Here, we demonstrate that the addition of two inflammatory mediators associated with chronic inflammatory pain, nerve growth factor (NGF) and interleukin-6 (IL-6), to adult DRG neurons increases their firing rates on multi-electrode arrays in vitro. Nav1.7 and Nav1.8 proteins are readily detected in cultured neurons and contribute to evoked activity. The blockade of both Nav1.7 and Nav1.8, has a profound impact on thermally evoked firing after treatment with IL-6 and NGF. This work underscores the utility of multi-electrode arrays for pharmacological studies of sensory neurons and may facilitate the discovery and mechanistic analyses of anti-nociceptive compounds.
Learn More >Deafferentation pain (DP), a typical neuropathic pain, occurs due to peripheral or central sensory nerve injury, which causes abnormal discharge of the upstream neurons or C fibers. Current treatment methods for DP have multiple side effects. Bone marrow mesenchymal stem cells (BMSC) have been used to treat neuropathic pain because of their ability to regulate neuroinflammation. Glial cell-derived neurotrophic factor (GDNF) is a neurotrophic mediator that exerts neuroprotective effects in neurological diseases. In this study, we investigated whether DP could be alleviated by BMSCs and the underlying mechanism. In vitro study, microglia was stimulated by lipopolysaccharide and then co-cultured with BMSC, GDNF or siRNA GDNF-BMSC. In vivo study, BMSC or siRNA GDNF-BMSC was transplanted intramedullarily on the 21st day after DP surgery. The expression of inflammatory-related factors were detected by RT-PCR and ELISA, RT-PCR,flow cytometry and immunofluorescence staining were performed to detect the expression of microglial surface markers, and Western blot was used to detect the expression levels of p-NF-kb, pPI3K, and pAKT. The pain-related behavioral changes were detected 7 days after transplantation. ELISA and RT-PCR results showed that the production of inflammatory cytokines in lipopolysaccharide-stimulated microglia and DP model plasma was downregulated, while anti-inflammatory mediators were upregulated significantly following pretreatment with BMSCs or GDNF. Flow cytometry, immunofluorescence staining, and RT-PCR results showed that BMSCs inhibited the microglial M1 phenotype and promoted the M2 phenotype by secreting GDNF. Furthermore, modulation functions of BMSCs involve inhibiting NF-κB while promoting PI3K /AKT signaling pathway activation. We found that our in vivo DP model was completely deafferent and BMSC administration clearly alleviated symptoms of DP. This function was also, at least partly, achieved by GDNF. The present studies demonstrate that BMSC can inhibit neuroinflammation by transforming microglial destructive M1 phenotype into regenerative M2 phenotype, and thus alleviate DP,likely by suppressing the NF-κB signaling pathway while promoting the PI3K/AKT signaling pathway activation through producing GDNF. The present findings are in support of the potential therapeutic application of BMSCs and the pharmaceutical application of GDNF for DP.
Learn More >Chemotherapy-induced neuropathic pain is a common dose-limiting side effect of cancer treatment but the underlying mechanisms are largely unknown. Here, we used a whole genome expression microarray and gene ontology analysis to identify the upregulation of a sequence-specific DNA-binding protein, HOXA6, in the spinal dorsal horn on day 10 after injection of rats with oxaliplatin. Genetic disruption of HOXA6 with siRNAs alleviated mechanical allodynia after oxaliplatin administration. Reduced representation bisulfite sequencing assays indicated that oxaliplatin decreased the methylation levels of the SOX10 promoter but not of HOXA6. TET1 was also upregulated by oxaliplatin. Genetic disruption of TET1 with siRNA blocked the promoter demethylation of SOX10 and the upregulation of HOXA6 and SOX10. Importantly, inhibition of SOX10 by intrathecal application of SOX10 siRNA ameliorated the mechanical allodynia induced by oxaliplatin and downregulated the expression of HOXA6. Consistently, overexpression of SOX10 through intraspinal injection of AAV-SOX10-EGFP produced mechanical allodynia and upregulated the expression of spinal dorsal horn HOXA6. Moreover, chromatin immunoprecipitation assays demonstrated that oxaliplatin increased the binding of SOX10 to the promoter region of HOXA6. Taken together, our data suggest that HOXA6 upregulation through the TET1-mediated promoter demethylation of SOX10 may contribute to oxaliplatin-induced neuropathic pain. This article is protected by copyright. All rights reserved.
Learn More >Pain resilience, one's ability to maintain behavioral engagement and adaptively regulate cognitions and emotions despite intense or prolonged pain, has been shown to protect against negative pain-related outcomes in experimental settings. A weakness of this research, and much of experimental pain research in general, has been the lack of rationale behind the selection of noxious stimuli which can activate different nociceptive fibers. The present study sought to determine if the relationship between pain resilience and pain ratings differed across stimuli based on the stimulated nociceptors.
Learn More >Among 170 adults with sickle cell disease, we evaluated chronic pain impact and disability prevalence, assessed age and gender differences, and identified psychosocial predictors of chronic pain intensity and disability. Most participants had a high level of disability. Chronic pain intensity and disability were significantly associated with pain catastrophizing and chronic pain self-efficacy, and worsened with age. Further research is needed to confirm study findings and develop interventions, including palliative care approaches that address catastrophizing and disability, particularly for young women and middle-aged adults with sickle cell disease. Moreover, consistent clinical assessment of chronic pain and psychosocial health should be implemented.
Learn More >Galcanezumab, along with three other monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, represents the latest disease-specific and mechanism-based treatment for the prophylaxis of migraine. Galcanezumab shares data also for the prophylaxis of cluster headache.
Learn More >Cluster headache (CH) is considered to be a catastrophic disease presenting the most severe human pain condition. Available pharmacological treatments are hampered by unwanted side effects, and there is an urgent need for non-pharmacological treatment alternatives. We present a novel therapeutic approach for chronic CH, having evolved from an episodic CH, using a non-invasive percutaneous bioelectric current stimulation (PBCS), which generates static electric fields in the range of the naturally occurring electric potentials.
Learn More >Allergic contact dermatitis is a skin inflammatory disease manifested with itch and pain symptom around the inflamed area. Chemokines such as CXCL12 are involved in the pathophysiology of allergic contact dermatitis, but little has been known about the effect of CXCL12/CXCR4 signaling for nociceptive sensation accompanying allergic contact dermatitis. Our study showed that CXCL12 and CXCR4 were upregulated in trigeminal ganglion with the progression of allergic contact dermatitis through western blotting and immunofluorescence. CXCL12 and CXCR4 were mainly upregulated in small-diameter neurons, which were co-localized with nociceptive markers in trigeminal ganglion. CXCR4 and CXCL12 were also expressed in trigeminal ganglion neurons retrograded from the skin lesion. Intradermal injection of CXCL12 enhanced the itch- and pain-like behavior which could be relieved by AMD3100, a CXCR4 antagonist, without changes of mast cells. Our findings suggested that blockade of CXCL12/CXCR4 signaling pathway might be beneficial to relieve itch and pain sensation accompanying allergic contact dermatitis.
Learn More >Neuropathic pain is one of the most frequently stated complications after spinal cord injury. In post-spinal cord injury, the decrease of gamma aminobutyric acid synthesis within the distal spinal cord is one of the main causes of neuropathic pain. The predominant research question of this study was whether exercise training may promote the expression of glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67, which are key enzymes of gamma aminobutyric acid synthesis, within the distal spinal cord through tropomyosin-related kinase B signaling, as its synthesis assists to relieve neuropathic pain after spinal cord injury. Animal experiment was conducted, and all rats were allocated into five groups: Sham group, SCI/PBS group, SCI-TT/PBS group, SCI/tropomyosin-related kinase B-IgG group, and SCI-TT/tropomyosin-related kinase B-IgG group, and then T10 contusion SCI model was performed as well as the tropomyosin-related kinase B-IgG was used to block the tropomyosin-related kinase B activation. Mechanical withdrawal thresholds and thermal withdrawal latencies were used for assessing pain-related behaviors. Western blot analysis was used to detect the expression of brain-derived neurotrophic factor, tropomyosin-related kinase B, CREB, p-REB, glutamic acid decarboxylase-65, and glutamic acid decarboxylase-67 within the distal spinal cord. Immunohistochemistry was used to analyze the distribution of CREB, p-CREB, glutamic acid decarboxylase-65, and glutamic acid decarboxylase-67 within the distal spinal cord dorsal horn. The results showed that exercise training could significantly mitigate the mechanical allodynia and thermal hyperalgesia in post-spinal cord injury and increase the synthesis of brain-derived neurotrophic factor, tropomyosin-related kinase B, CREB, p-CREB, glutamic acid decarboxylase-65, and glutamic acid decarboxylase-67 within the distal spinal cord. After the tropomyosin-related kinase B signaling was blocked, the analgesic effect of exercise training was inhibited, and in the SCI-TT/tropomyosin-related kinase B-IgG group, the synthesis of CREB, p-CREB, glutamic acid decarboxylase-65, and glutamic acid decarboxylase-67 within the distal spinal cord were also significantly reduced compared with the SCI-TT/PBS group. This study shows that exercise training may increase the glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67 expression within the spinal cord dorsal horn through the tropomyosin-related kinase B signaling, and this mechanism may play a vital role in relieving the neuropathic pain of rats caused by incomplete SCI.
Learn More >OnabotulinumtoxinA is an effective preventive treatment for chronic migraine. In chronic migraine, besides a reduction in headache frequency, a decreased reliance on oral prophylactics is also indicative of treatment effectiveness. This study aimed to quantify the change in the use of oral prophylactics after treatment with onabotulinumtoxinA in patients with chronic migraine.
Learn More >Osteoarthritis (OA) is one of the most debilitating diseases and is associated with a high personal and socioeconomic burden. So far, there is no therapy available that effectively arrests structural deterioration of cartilage and bone or is able to successfully reverse any of the existing structural defects. Efforts to identify more tailored treatment options led to the development of strategies that enabled the classification of patient subgroups from the pool of heterogeneous phenotypes that display distinct common characteristics. To this end, the classification differentiates the structural endotypes into cartilage and bone subtypes, which are predominantly driven by structure-related degenerative events. In addition, further classifications have highlighted individuals with an increased inflammatory contribution (inflammatory phenotype) and pain-driven phenotypes as well as senescence and metabolic syndrome phenotypes. Most probably, it will not be possible to classify individuals by a single definite subtype, but it might help to identify groups of patients with a predominant pathology that would more likely benefit from a specific drug or cell-based therapy. Current clinical trials addressed mainly regeneration/repair of cartilage and bone defects or targeted pro-inflammatory mediators by intra-articular injections of drugs and antibodies. Pain was treated mostly by antagonizing nerve growth factor (NGF) activity and its receptor tropomyosin-related kinase A (TrkA). Therapies targeting metabolic disorders such as diabetes mellitus and senescence/aging-related pathologies are not specifically addressing OA. However, none of these therapies has been proven to modify disease progression significantly or successfully prevent final joint replacement in the advanced disease stage. Within this review, we discuss the recent advances in phenotype-specific treatment options and evaluate their applicability for use in personalized OA therapy.
Learn More >Chronic low back pain (CLBP) is a highly prevalent and disabling condition in the elderly, and yet it is undertreated and understudied in this patient population. Tapentadol is a central analgesic with an improved tolerability profile that may be particularly beneficial to the elderly CLBP.
Learn More >Bearing in mind that pain and major depressive disorder (MDD) often share biological pathways, this condition is classified as depression-pain syndrome. Mounting evidence suggests that oxidative stress is implicated in the pathophysiology of this syndrome. The development of effective pharmacological interventions for the depression-pain syndrome is of particular importance as clinical treatments for this comorbidity have shown limited efficacy. Therefore, the present study aimed to evaluate whether the 3,5-dimethyl-1-phenyl-4-(phenylselanyl)-1H-pyrazole (SePy) was able to reverse the depression-pain syndrome induced by intracerebroventricular (i.c.v) streptozotocin (STZ) in mice and the possible modulation of oxidative and nitrergic pathways in its effect. The treatment with SePy (1 and 10 mg/kg) administered intragastrically (i.g.) reversed the increased immobility time in the tail suspension test, decreased grooming time in the splash test, latency time to nociceptive response in the hot plate test, and the response frequency of Von Frey hair (VFH) stimulation induced by STZ (0.2 mg/4 μl/per mouse). Additionally, SePy (10 mg/kg, i.g.) reversed STZ-induced alterations in the levels of reactive oxygen species, nitric oxide, and lipid peroxidation and the superoxide dismutase and catalase activities in the prefrontal cortices (PFC) and hippocampi (HC) of mice. Treatment with SePy (10 mg/kg, i.g.) also reversed the STZ-induced increased expression of inducible nitric oxide synthase (iNOS) and glycogen synthase kinase 3 beta (GSK3β) in the PFC and HC. An additional molecular docking investigation found that SePy binds to the active site of iNOS and GSK3β. Altogether, these results indicate that the antidepressant-like effect of SePy is accompanied by decreased hyperalgesia and mechanical allodynia, which were associated with its antioxidant effect.
Learn More >Among patients with cervical myelopathy who were diagnosed with neuropathic pain (NP) by the LANSS test, the study participants were randomly assigned to one of the two study groups. The participants in one study group received opioids only, while those in the other group received opioids and pregabalin. Thirty-nine patients were analyzed in the study (20 patients in the opioid-only group and 19 in the pregabalin add-on group). The LANSS, neck pain, and arm pain scores in the pregabalin add-on group improved significantly compared with those in the opioid-only group after the first 4 weeks (p = 0.005, 0.001 and 0.035, respectively), but there was no significant difference between the two groups during the next 4 weeks (p = 0.615, 0.377 and 0.716, respectively). There was no significant difference in the neck disability index and EuroQol-5Dimension scores after four weeks and eight weeks of follow-up. Adverse events were reported by four patients (20.0%) in the opioid-only group and five patients (26.3%) in the pregabalin add-on group (p = 0.716). However, over time, the occurrence of side effects and dropouts increased in the pregabalin add-on group. This exploratory pilot study suggests that pregabalin add-on treatment is more efficient than the use of opioids alone at the beginning of NP treatment in cervical myelopathy patients. However, prescribing pregabalin add-on treatment for more than four weeks should be done cautiously.
Learn More >The Medial Prefrontal Cortex as a Central Hub for Mental Comorbidities Associated with Chronic Pain.
Chronic pain patients frequently develop and suffer from mental comorbidities such as depressive mood, impaired cognition, and other significant constraints of daily life, which can only insufficiently be overcome by medication. The emotional and cognitive components of pain are processed by the medial prefrontal cortex, which comprises the anterior cingulate cortex, the prelimbic, and the infralimbic cortex. All three subregions are significantly affected by chronic pain: magnetic resonance imaging has revealed gray matter loss in all these areas in chronic pain conditions. While the anterior cingulate cortex appears hyperactive, prelimbic, and infralimbic regions show reduced activity. The medial prefrontal cortex receives ascending, nociceptive input, but also exerts important top-down control of pain sensation: its projections are the main cortical input of the periaqueductal gray, which is part of the descending inhibitory pain control system at the spinal level. A multitude of neurotransmitter systems contributes to the fine-tuning of the local circuitry, of which cholinergic and GABAergic signaling are particularly emerging as relevant components of affective pain processing within the prefrontal cortex. Accordingly, factors such as distraction, positive mood, and anticipation of pain relief such as placebo can ameliorate pain by affecting mPFC function, making this cortical area a promising target region for medical as well as psychosocial interventions for pain therapy.
Learn More >Acceptance and commitment therapy (ACT) has accrued a growing evidence-base for a wide variety of psychological difficulties. Given that ACT promotes broad and flexible repertoires of behaviour as well as neutralizing the ubiquitous psychological processes theorized to be responsible for much human suffering, such an approach may hold promise. The use of ACT-informed parenting interventions offers another alternative to solely behavioural approaches but it remains relatively understudied and in need of further exploration.
Learn More >Tonic spinal cord stimulation (SCS) has been used as a treatment for chronic neuropathic pain ever since its discovery late 1960's. Despite its clinical successes in a subset of chronic neuropathic pain syndromes, several limitations such as insufficient pain relief and uncomfortable paresthesias, have led to the development of new targets, the dorsal root ganglion, and new stimulation waveforms, such as burst and high frequency. The aim of this review is to provide a brief overview of the main mechanisms behind the mode of action of the different SCS paradigms. Tonic SCS mainly acts via a segmental spinal mechanism where it induces GABA-release from inhibitory interneurons in the spinal dorsal horn. Tonic SCS concurrently initiates neuropathic pain modulation through a supraspinal-spinal feedback loop and serotonergic descending fibers. Mechanisms of stimulation of the DRG as well as those related to new SCS paradigms are now under investigation, where it seems that burst SCS not only stimulates sensory, discriminative aspects of pain (like Tonic-SCS) but also emotional, affective and motivational aspects of pain. Initial long-term study results on closed-loop SCS systems hold promise for improvement of future SCS treatment.
Learn More >After the emergence of a novel coronavirus named SARS-CoV-2, coronavirus disease 2019 (COVID-19) was initially characterized by fever, sore throat, cough and dyspnea, mainly manifestations of respiratory system. However, other manifestations such as headache, abdominal pain, diarrhea, loss of taste and smell were added to the clinical spectrum, during the course of the COVID-19 pandemic. The reports on the neurological findings are increasing rapidly and headache seems to be the leader on the symptom list. Headache was reported in 11-34% of the hospitalized COVID-19 patients, but clinical features of these headaches were totally missing in available publications. According to our initial experience, significant features of headache presentation in the symptomatic COVID-19 patients were new onset, moderate-severe, bilateral headache with pulsating or pressing quality in the temporo-parietal, forehead or periorbital region. The most striking features of the headache were sudden to gradual onset and poor response to common analgesics, or high relapse rate, that was limited to the active phase of the COVID-19. Symptomatic COVID-19 patients, around 6-10%, also reported headache as a presenting symptom. The possible pathophysiological mechanisms of headache include activation of peripheral trigeminal nerve endings by the SARS-CoV2 directly or through the vasculopathy and/or increased circulating pro-inflammatory cytokines and hypoxia. We concluded that as a common non-respiratory symptom of COVID-19, headache should not be overlooked, and its characteristics should be recorded with scrutiny.
Learn More >Neuropathic pain is a pathological condition induced by a lesion or disease affecting the somatosensory system, with symptoms like allodynia and hyperalgesia. It has a multifaceted pathogenesis as it implicates several molecular signaling pathways involving peripheral and central nervous systems. Affective and cognitive dysfunctions have been reported as comorbidities of neuropathic pain states, supporting the notion that pain and mood disorders share some common pathogenetic mechanisms. The understanding of these pathophysiological mechanisms requires the development of animal models mimicking, as far as possible, clinical neuropathic pain symptoms. Among them, the Spared Nerve Injury (SNI) model has been largely characterized in terms of behavioral and functional alterations. This model is associated with changes in neuronal firing activity at spinal and supraspinal levels, and induces late neuropsychiatric disorders (such as anxious-like and depressive-like behaviors, and cognitive impairments) comparable to an advanced phase of neuropathy. The goal of this review is to summarize current findings in preclinical research, employing the SNI model as a tool for identifying pathophysiological mechanisms of neuropathic pain and testing pharmacological agent.
Learn More >High-density surface electromyography (HDEMG) is an electrophysiological technique that can be used to quantify the spatial distribution of activity within muscles. When pain-free individuals perform sustained or repetitive tasks, different regions within a muscle become progressively more active; this is thought to reflect a strategy to redistribute the load to different regions, thus limiting localised muscle fatigue. The use of HDEMG has revealed that when people with musculoskeletal pain perform the same tasks, the distribution of activity within the same muscle is usually different, and the same muscle region tends to be active throughout the whole task without progressive activation of different muscle regions. This potentially results in a focal overload of a muscle region, and may contribute to fatigue, localised muscle pain and potentially pain persistence and/or recurrence over time. Interestingly, not all patients with musculoskeletal pain present with this regional alteration in muscle activation, reflecting the heterogeneity of patient presentations. This article will briefly review the technique of HDEMG followed by a review of studies demonstrating spatial redistribution of muscle activity in asymptomatic people during both isometric and dynamic conditions, including functional tasks. Lastly, the article will provide a review of HDEMG studies with a focus on changes in the behaviour of the lumbar erector spine and upper trapezius in people with spinal pain. These studies have revealed subtle changes in the distribution of muscle activity in people with spinal pain, which may have relevance for onset, persistence or recurrence of symptoms and could become a target of novel therapeutic approaches.
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