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Anterolateral system neurons relay pain, itch, and temperature information from the spinal cord to pain-related brain regions, but the differentiation of these neurons and their specific contribution to pain perception remain poorly defined. Here, we show that most mouse spinal neurons that embryonically express the autonomic-system-associated Paired-like homeobox 2A (Phox2a) transcription factor innervate nociceptive brain targets, including the parabrachial nucleus and the thalamus. We define the Phox2a anterolateral system neuron birth order, migration, and differentiation and uncover an essential role for Phox2a in the development of relay of nociceptive signals from the spinal cord to the brain. Finally, we also demonstrate that the molecular identity of Phox2a neurons is conserved in the human fetal spinal cord, arguing that the developmental expression of Phox2a is a prominent feature of anterolateral system neurons.
Learn More >Chronic itch represents an incapacitating burden on patients suffering from a spectrum of diseases. Despite recent advances in our understanding of the cells and circuits implicated in the processing of itch information, chronic itch often presents itself without an apparent cause. Here, we identify a spinal subpopulation of inhibitory neurons defined by the expression of Ptf1a, involved in gating mechanosensory information self-generated during movement. These neurons receive tactile and motor input and establish presynaptic inhibitory contacts on mechanosensory afferents. Loss of Ptf1a neurons leads to increased hairy skin sensitivity and chronic itch, partially mediated by the classic itch pathway involving gastrin-releasing peptide receptor (GRPR) spinal neurons. Conversely, chemogenetic activation of GRPR neurons elicits itch, which is suppressed by concomitant activation of Ptf1a neurons. These findings shed light on the circuit mechanisms implicated in chronic itch and open novel targets for therapy developments.
Learn More >Cluster headache is characterized by recurrent, unilateral attacks of excruciating pain associated with ipsilateral cranial autonomic symptoms. Although a wide array of clinical, anatomical, physiological, and genetic data have informed multiple theories about the underlying pathophysiology, the lack of a comprehensive mechanistic understanding has inhibited, on the one hand, the development of new treatments and, on the other, the identification of features predictive of response to established ones. The first-line drug, verapamil, is found to be effective in only half of all patients, and after several weeks of dose escalation, rendering therapeutic selection both uncertain and slow. Here we use high-dimensional modelling of routinely acquired phenotypic and MRI data to quantify the predictability of verapamil responsiveness and to illuminate its neural dependants, across a cohort of 708 patients evaluated for cluster headache at the National Hospital for Neurology and Neurosurgery between 2007 and 2017. We derive a succinct latent representation of cluster headache from non-linear dimensionality reduction of structured clinical features, revealing novel phenotypic clusters. In a subset of patients, we show that individually predictive models based on gradient boosting machines can predict verapamil responsiveness from clinical (410 patients) and imaging (194 patients) features. Models combining clinical and imaging data establish the first benchmark for predicting verapamil responsiveness, with an area under the receiver operating characteristic curve of 0.689 on cross-validation (95% confidence interval: 0.651 to 0.710) and 0.621 on held-out data. In the imaged patients, voxel-based morphometry revealed a grey matter cluster in lobule VI of the cerebellum (-4, -66, -20) exhibiting enhanced grey matter concentrations in verapamil non-responders compared with responders (familywise error-corrected P = 0.008, 29 voxels). We propose a mechanism for the therapeutic effect of verapamil that draws on the neuroanatomy and neurochemistry of the identified region. Our results reveal previously unrecognized high-dimensional structure within the phenotypic landscape of cluster headache that enables prediction of treatment response with modest fidelity. An analogous approach applied to larger, globally representative datasets could facilitate data-driven redefinition of diagnostic criteria and stronger, more generalizable predictive models of treatment responsiveness.
Learn More >Different pain types may be encoded in different brain circuits. Here, we examine similarities and differences in brain processing of visceral and somatic pain. We analyze data from seven fMRI studies (N = 165) and five types of pain and discomfort (esophageal, gastric, and rectal distension, cutaneous thermal stimulation, and vulvar pressure) to establish and validate generalizable pain representations. We first evaluate an established multivariate brain measure, the Neurologic Pain Signature (NPS), as a common nociceptive pain system across pain types. Then, we develop a multivariate classifier to distinguish visceral from somatic pain. The NPS responds robustly in 98% of participants across pain types, correlates with perceived intensity of visceral pain and discomfort, and shows specificity to pain when compared with cognitive and affective conditions from twelve additional studies (N = 180). Pre-defined signatures for non-pain negative affect do not respond to visceral pain. The visceral versus the somatic classifier reliably distinguishes somatic (thermal) from visceral (rectal) stimulation in both cross-validation and independent cohorts. Other pain types reflect mixtures of somatic and visceral patterns. These results validate the NPS as measuring a common core nociceptive pain system across pain types, and provide a new classifier for visceral versus somatic pain.
Learn More >The development of new analgesic drugs has been hampered by the inability to translate preclinical findings to humans. This failure is due in part to the weak connection between commonly used pain outcome measures in rodents and the clinical symptoms of chronic pain. Most rodent studies rely on the use of experimenter-evoked measures of pain and assess behavior under ethologically unnatural conditions, which limits the translational potential of preclinical research. Here, we addressed this problem by conducting an unbiased, prospective study of behavioral changes in mice within a natural homecage environment using conventional preclinical pain assays. Unexpectedly, we observed that cage lid hanging, a species-specific elective behavior, was the only homecage behavior reliably impacted by pain assays. Noxious stimuli reduced hanging behavior in an intensity-dependent manner, and the reduction in hanging could be restored by analgesics. Finally, we developed an automated approach to assess hanging behavior. Collectively, our results indicate that the depression of hanging behavior is a novel, ethologically valid, and translationally relevant pain outcome measure in mice that could facilitate the study of pain and analgesic development.
Learn More >Nerve growth factor (NGF) is a neurotrophin that activates nociceptive neurons to transmit pain signals from the peripheral to the central nervous system and that exerts its effects on neurons by signalling through tyrosine kinase receptors. Antibodies that inhibit the function of NGF and small molecule inhibitors of NGF receptors have been developed and tested in clinical studies to evaluate the efficacy of NGF inhibition as a form of analgesia in chronic pain states including osteoarthritis and chronic low back pain. Clinical studies in individuals with painful knee and hip osteoarthritis have revealed that NGF inhibitors substantially reduce joint pain and improve function compared with NSAIDs for a duration of up to 8 weeks. However, the higher tested doses of NGF inhibitors also increased the risk of rapidly progressive osteoarthritis in a small percentage of those treated. This Review recaps the biology of NGF and the studies that have been performed to evaluate the efficacy of NGF inhibition for chronic musculoskeletal pain states. The adverse events associated with NGF inhibition and the current state of knowledge about the mechanisms involved in rapidly progressive osteoarthritis are also discussed and future studies proposed to improve understanding of this rare but serious adverse event.
Learn More >This report examines the association between tetrahydrocannabinol (THC) plasma levels and pain response in a secondary analysis of data from a recent diabetic neuropathy study that demonstrated a dose-dependent reduction in spontaneous and elicited pain at specific time points. A randomized, double-blinded, placebo-controlled crossover study was conducted in sixteen patients with painful diabetic peripheral neuropathy. Subjects participated in four sessions, separated by 2 weeks, during each of which they were exposed to one of four conditions: placebo, or 1%, 4%, or 7% THC dose of cannabis. Baseline assessments of spontaneous and evoked pain were performed. Subjects were then administered aerosolized cannabis or placebo and pain intensity and cognitive testing at specific time points for 4 hours. A blood sample was drawn from the left antecubital vein for plasma assay of total THC at 0, 15, 30, 45, 60, 150, and 240 minutes. Associations were made between pain intensity, cognitive impairment and THC plasma levels in this secondary analysis. Results suggested a U-shaped relation whereby pain ratings are greatest at extreme (low and high) levels of THC. The therapeutic window appeared to fall between 16 ng/mL and 31 ng/mL THC plasma level. There was a significant linear effect of THC on only one out of the three cognitive tests. These findings stress the importance of measuring cannabinoid plasma levels when performing future research. Perspective: This analysis correlating plasma THC levels and pain reduction in diabetic neuropathy suggest a therapeutic window. Low and high THC levels had a negative association (no reduction) and THC levels within the window had a positive association (reduction). There was a minor negative linear effect of THC on cognitive function.
Learn More >The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN actively processes neuropathic pain characterized by persistent hyperalgesia with aversive emotional responses. Here we report that neuropathic pain-like hypersensitivity induced by common peroneal nerve (CPN) ligation increases nociceptive stimulation-induced responses in glutamatergic LPBN neurons. Optogenetic activation of GABAergic LPBN neurons does not affect basal nociception, but alleviates neuropathic pain-like behavior. Optogenetic activation of glutamatergic or inhibition of GABAergic LPBN neurons induces neuropathic pain-like behavior in naïve mice. Inhibition of glutamatergic LPBN neurons alleviates both basal nociception and neuropathic pain-like hypersensitivity. Repetitive pharmacogenetic activation of glutamatergic or GABAergic LPBN neurons respectively mimics or prevents the development of CPN ligation-induced neuropathic pain-like hypersensitivity. These findings indicate that a delicate balance between excitatory and inhibitory LPBN neuronal activity governs the development and maintenance of neuropathic pain.
Learn More >Chronic pain, encompassing conditions, such as low back pain, arthritis, persistent post-surgical pain, fibromyalgia, and neuropathic pain disorders, is highly prevalent but remains poorly treated. The vast majority of therapeutics are directed solely at neurons, despite the fact that signaling between immune cells, glia, and neurons is now recognized as indispensable for the initiation and maintenance of chronic pain. This review highlights recent advances in understanding fundamental neuroimmune signaling mechanisms and novel therapeutic targets in rodent models of chronic pain. We further discuss new technological developments to study, diagnose, and quantify neuroimmune contributions to chronic pain in patient populations.
Learn More >To assess the safety and efficacy of AMG 301, an inhibitor of the pituitary adenylate cyclase-activating polypeptide (PACAP)-1 (PAC1) receptor, for prevention of migraine.
Learn More >Small-fiber neuropathy (SFN) has been traditionally considered as a pure disorder of peripheral nervous system, characterized by neuropathic pain and degeneration of small-diameter nerve fibers in the skin. Previous functional MRI studies revealed abnormal activations of pain networks, but the structural basis underlying such maladaptive functional alterations remains elusive. We applied diffusion tensor imaging (DTI) to explore the influences of SFN on brain microstructures. Forty-one pathology-proven SFN patients with reduced skin innervation were recruited. White matter connectivity with the thalamus as the seed was assessed using probabilistic tractography of DTI. SFN patients had reduced thalamic connectivity with the insular cortex and the sensorimotor areas including the postcentral and precentral gyri. Furthermore, the degree of skin nerve degeneration, measured by intraepidermal nerve fiber density (IENFd), was associated with the reduction of connectivity between the thalamus and pain-related areas according to different neuropathic pain phenotypes, specifically, the frontal, cingulate, motor, and limbic areas for burning, electrical shocks, tingling, mechanical allodynia, and numbness. Despite altered white matter connectivity, there was no change in white matter integrity assessed with fractional anisotropy. Our findings indicate that alterations in structural connectivity may serve as a biomarker of maladaptive brain plasticity that contributes to neuropathic pain after peripheral nerve degeneration.
Learn More >Trigeminal nerve injury-induced neuropathic pain is a debilitating chronic orofacial pain syndrome but lack of effective treatment. G protein-coupled receptors (GPCRs), especially orphan GPCRs (oGPCRs) are important therapeutic targets in pain medicine. Here we screened upregulated oGPCRs in the trigeminal ganglia (TG) after partial infraorbital nerve transection (pIONT) and found that Gpr151 was the most significantly upregulated oGPCRs. Gpr151 mRNA was increased from pIONT Day 3 and maintained for more than 21 days. Furthermore, GPR151 was expressed in the neurons of the TG after pIONT. Global mutation or knockdown of Gpr151 in the TG attenuated pIONT-induced mechanical allodynia. In addition, the excitability of TG neurons was increased after pIONT in wild-type (WT) mice, but not in Gpr151 mice. Notably, GPR151 bound to Gαi protein, but not Gαq, Gα12, or Gα13, and activated ERK through Gβγ. ERK was also activated by pIONT in the TG of WT mice, but not in Gpr151 mice. Gene microarray showed that Gpr151 mutation reduced the expression of a large number of neuroinflammation-related genes that were upregulated in WT mice after pIONT, including chemokines CCL5, CCL7, CXCL9, and CXCL10. MEK inhibitor (PD98059) attenuated mechanical allodynia and reduced the upregulation of these chemokines after pIONT. Collectively, the present study not only revealed the involvement of GPR151 in the maintenance of trigeminal neuropathic pain but also identified GPR151 as a Gαi-coupled receptor to induce ERK-dependent neuroinflammation. Thus, GPR151 may be a potential drug target for the treatment of trigeminal neuropathic pain.
Learn More >Membrane remodeling by inflammatory mediators influences the function of sensory ion channels. The capsaicin- and heat-activated TRPV1 channel contributes to neurogenic inflammation and pain hypersensitivity, in part due to its potentiation downstream of phospholipase C-coupled receptors that regulate phosphoinositide lipid content. Here, we determined the effect of phosphoinositide lipids on TRPV1 function by combining genetic dissection, diet supplementation, behavioral, biochemical, and functional analyses in As capsaicin elicits hot and pain sensation in mammals, transgenic TRPV1 worms exhibit an aversive response to capsaicin. TRPV1 worms with low levels of phosphoinositide lipids display an enhanced response to capsaicin, whereas phosphoinositide lipid supplementation reduces TRPV1-mediated responses. A worm carrying a TRPV1 construct lacking the distal C-terminal domain features an enhanced response to capsaicin, independent of the phosphoinositide lipid content. Our results demonstrate that TRPV1 activity is enhanced when the phosphoinositide lipid content is reduced, and the C-terminal domain is key to determining agonist response TRPV1 is an essential protein for the mechanism whereby noxious stimuli, such as high temperatures and chemicals, cause pain. TRPV1 undergoes sensitization, a process in which inflammatory molecules enhance its response to other stimuli, thereby promoting pain hypersensitivity. Proalgesic agents produced in response to tissue injury activate PLC-coupled receptors and alter the membrane phosphoinositide lipid content. The mechanism by which phosphoinositide lipids modulate TRPV1 function has remained controversial. Determining whether membrane phosphoinositides are positive or negative regulators of TRPV1 function is critical for developing therapeutic strategies to ameliorate TRPV1-mediated inflammatory pain. We address the role of phosphoinositide lipids on TRPV1 function using an approach and report that phosphoinositide lipids reduce TRPV1 activity .
Learn More >TACAN (Tmem120A), a mechanotransducing ion channel highly expressed in a subset of nociceptors, has recently been shown to contribute to detection of noxious mechanical stimulation. In the present study we evaluated its role in sensitization to mechanical stimuli associated with preclinical models of inflammatory and chemotherapy-induced neuropathic pain (CIPN). Intrathecal administration of an oligodeoxynucleotide antisense (AS-ODN) to TACAN mRNA attenuated TACAN protein expression in rat dorsal root ganglia (DRG). While TACAN AS-ODN produced only a modest increase in mechanical nociceptive threshold, it markedly reduced mechanical hyperalgesia produced by intradermal administration of prostaglandin E (PGE), tumor necrosis factor alpha (TNFα) and low molecular weight hyaluronan (LMWH), and systemic administration of lipopolysaccharide (LPS), compatible with a prominent role of TACAN in mechanical hyperalgesia produced by inflammation. In contrast, TACAN AS-ODN had no effect on mechanical hyperalgesia associated with CIPN produced by oxaliplatin or paclitaxel. Our results provide evidence that TACAN plays a role in mechanical hyperalgesia induced by pronociceptive inflammatory mediators, but not CIPN, compatible with multiple mechanisms mediating mechanical nociception, and sensitization to mechanical stimuli in preclinical models of inflammatory versus CIPN. PERSPECTIVE: We evaluated the role of TACAN, a mechanotransducing ion channel in nociceptors, in preclinical models of inflammatory and chemotherapy-induced neuropathic pain. Attenuation of TACAN expression reduced hyperalgesia produced by inflammatory mediators but had not chemotherapeutic agents. Our findings support the presence of multiple mechanotransducers in nociceptors.
Learn More >Many primary care clinics are resistant to accept new patients taking prescription opioids for chronic pain. It is unclear how much of this practice is specific to individuals who may be perceived to have aberrant opioid use. This study sought to determine whether clinics are more or less willing to accept and prescribe opioids to patients depending on whether their history is more or less suggestive of aberrant opioids use by conducting an audit survey of primary care clinics in 9 states from May to July 2019. Simulated patients taking opioids for chronic pain called each clinic twice, giving one of two scenarios for needing a new provider: their previous physician had either 1) retired or 2) stopped prescribing opioids for unspecified reasons. Clinic willingness to continue prescribing opioids and accept the patient for general primary care were assessed. Of 452 clinics responding to both scenarios (904 calls), 193 (43%) said their providers would not prescribe opioids in either scenario, 146 (32%) said their providers might prescribe in both, and 113 (25%) responded differently to each scenario. Clinics responding differently had greater odds (OR=1.83 CI[1.23,2.76]) of willingness to prescribe when the previous doctor retired than when the doctor had stopped prescribing. These findings suggest that primary care access is limited for patients taking opioids for chronic pain, and differentially further reduced for patients whose histories are suggestive of aberrant use. This denial of care could lead to unintended harms such as worsened pain or conversion to illicit substances.
Learn More >The COVID-19 pandemic has had a tremendous impact, including on individuals with chronic pain. The social distancing policies necessary to slow the spread of SARS-CoV-2 have involved increased levels of social isolation. This cross-sectional survey study examined pain severity and interference among individuals with chronic pain during an early phase of social distancing mandates, and identified characteristics of individuals who were most impacted. Approximately 4-8 weeks after social distancing mandates commenced in the state of Massachusetts, 150 patients with fibromyalgia, chronic spine and postsurgical pain completed demographic, pain, social distancing, and validated psychosocial questionnaires. Patients self-reported an overall significant increase in pain severity and pain interference, compared to before social distancing, although both pain severity and interference were quite variable among individuals under conditions of social distancing. Several demographic, socioeconomic, and psychosocial factors were associated with greater pain severity and interference during social distancing. Multivariable linear regression demonstrated that female gender, non-white race, lower education, disability, fibromyalgia, and higher pain catastrophizing were independently associated with greater pain severity, while female gender and pain catastrophizing were independently associated greater pain interference. The findings suggest that individual differences among chronic pain patients should be considered in the planning, development, and prioritization of interventions to improve pain care and to prevent worsening of symptoms during the continuing COVID-19 pandemic.
Learn More >Our knowledge of the prevalence, impact, and outcomes of chronic pain in the general population is predominantly based on studies over relatively short periods of time. The aim of this study was to identify and describe trajectories of chronic pain status over a period of 21 years. Self-reported population data (n=1858) from five timepoints were analyzed. Pain was categorized by: no chronic pain (NCP); chronic regional pain (CRP); and chronic widespread pain (CWP). Latent Class Growth Analysis was carried out for identification of trajectories, and logistic regression analysis for identification of predictors for pain prognosis. Five trajectories were identified: 1) Persistent NCP (57%); 2) Migrating from NCP to CRP or CWP (5%), 3) Persistent CRP or Migration between CRP and NCP (22%); 4) Migration from CRP to CWP (10%); 5) Persistent CWP (6%). Age, sleeping problems, poor vitality and physical function at baseline were associated with pain progression from NCP. Female gender, seeking care for pain, lack of social support, poor physical function, vitality, and mental health predicted poor pain prognosis among those with CRP. In conclusion chronic pain was common in the population including 6 % reporting persistent CWP, although the majority persistently reported no chronic pain. Most people had stable pain status, but some had ongoing change in pain status over time including people who improved from chronic pain. It was possible to identify clinically relevant factors, characterizing trajectories of chronic pain development, that can be useful for identifying individuals at risk and potential targets for intervention.
Learn More >The striking difference between men and women in headache prevalence is suggested to develop in adolescence. Although headaches are common and affect quality of life and daily functioning, the evidence needed to develop effective counselling and preventive approaches is still limited.Using data collected at age 11, 14, 17 and 20 years in the Dutch PIAMA birth cohort study (n=3064 with > 1 questionnaire), we assessed headache prevalence and incidence in girls and boys and explored associations with early life, environmental, lifestyle, health and psychosocial factors. Associations were analysed longitudinally with generalized linear mixed models and discrete time hazard models.From age 11 to 20, the prevalence of headache increased from 9.4% to 19.8% in girls and hardly changed in boys (7.6% to 6.1%). Headache commonly co-occurred with other unfavorable health and psychosocial conditions. 88% of the girls and 76% of boys with headache also reported at least one of the following at age 17: sleeping problems, asthma, hay fever, musculoskeletal complaints, fatigue, low mental health or worrying. Results suggest higher headache prevalence in adolescents following lower educational tracks, in those who skip breakfast >2 days per week and in boys exposed to tobacco smoke in infancy. In girls, sleeping problems and musculoskeletal complaints were associated with higher odds of incident headache and residential greenness with lower odds of incident headache.The high prevalence and strong female predominance of headache, already in adolescence and often with comorbidities deserve recognition by professionals in (preventive) health care settings and schools.
Learn More >Pain experience can change the central processing of nociceptive inputs, resulting in persistent allodynia and hyperalgesia. However, the underlying circuit mechanisms remain underexplored. Here, we focus on pain-induced remodeling of the projection from the mediodorsal thalamus (MD) to anterior cingulate cortex (ACC), a projection that relays spinal nociceptive input for central processing. Using optogenetics combined with slice electrophysiology, we detected in male mice that 7 days of chronic constriction injury (CCI; achieved by loose ligation of the sciatic nerve) generated AMPA receptor (AMPAR)-silent glutamatergic synapses within the contralateral MD-to-ACC projection. AMPAR-silent synapses are typically GluN2B-enriched nascent glutamatergic synapses that mediate the initial formation of neural circuits during early development. During development, some silent synapses mature and become 'unsilenced' by recruiting and stabilizing AMPARs, consolidating and strengthening the newly formed circuits. Consistent with these synaptogenic features, pain-induced generation of silent synapses was accompanied by increased densities of immature dendritic spines in ACC neurons and increased synaptic weight of GluN2B-containing NMDA receptors (NMDARs) in the MD-to-ACC projection. After prolonged (∼30 days) CCI, injury-generated silent synapses declined to low levels, which likely resulted from a synaptic maturation process that strengthens AMPAR-mediated MD-to-ACC transmission. Consistent with this hypothesis, viral-mediated knockdown of GluN2B in ACC neurons, which prevented pain-induced generation of silent synapses and silent synapse-mediated strengthening of MD-to-ACC projection after prolonged CCI, prevented the development of allodynia. Taken together, our results depict a silent synapse-mediated mechanism through which key supraspinal neural circuits that regulate pain sensitivity are remodeled to induce allodynia and hyperalgesia.
Learn More >The full utility of an acute treatment requires examination of the entire time course of effect during a migraine attack. Here the time course of effect of ubrogepant is evaluated.
Learn More >Human models of migraine have been used for the past 30 years to test putative 'trigger' molecules and ascertain whether they induce migraine attacks in humans. However, nocebo effects using this model have never been systematically explored.
Learn More >To compare spatial pain modulation capabilities between adolescents with and without migraine.
Learn More >Among youth with chronic non-cancer pain, 50% have parents with chronic pain. These youth report significantly more pain interference and posttraumatic stress symptoms (PTSS), and worse health-related quality of life (HRQL) than youth whose parents do not have chronic pain. Additionally, parent chronic pain is linked to increased child anxiety and depressive symptoms. Survivors of childhood cancer (SCCs) are at risk of pain and negative psychosocial outcomes and therefore may be especially vulnerable if their parents have chronic pain. Thus, the aims of the current study were to (1) identify rates of chronic pain among parents of SCCs, (2) test group differences in psychological symptoms in parents with chronic pain versus without, and (3) test group differences in pain interference, HRQL, anxiety, depression, and PTSS in SCCs with parents with chronic pain versus without.
Learn More >Pain is a common but potentially debilitating symptom, often requiring complex management strategies. To understand the molecular dynamics of peripheral inflammation and nociceptive pain, we investigated longitudinal changes in behavior, tissue structure, and transcriptomic profiles in the rat carrageenan-induced peripheral inflammation model. Sequential changes in the number of differentially expressed genes are consistent with temporal recruitment of key leukocyte populations, mainly neutrophils and macrophages with each wave being preceded by upregulation of the cell-specific chemoattractants, Cxcl1 and Cxcl2, and Ccl2 and Ccl7, respectively. We defined 12 temporal gene clusters based on expression pattern. Within the patterns we extracted genes comprising the inflammatory secretome and others related to nociceptive tissue remodeling and to sensory perception of pain. Structural tissue changes, involving upregulation of multiple collagens occurred as soon as 1-hour post-injection, consistent with inflammatory tissue remodeling. Inflammatory expression profiling revealed a broad-spectrum, temporally orchestrated molecular and cellular recruitment process. The results provide numerous potential targets for modulation of pain and inflammation. PERSPECTIVE: This study investigates the highly orchestrated biological response during tissue inflammation with precise assessment of molecular dynamics at the transcriptional level. The results identify transcriptional changes that define an evolving inflammatory state in rats. This study provides foundational data for identifying markers of, and potential treatments for, inflammation and pain in patients.
Learn More >Maladaptive defensive responses such as excessive avoidance behavior have received increasing attention as a main mechanism for the development and maintenance of chronic pain complaints. However, another defensive response which is commonly studied in animals as a proxy for fear is freezing behavior. No research to date has investigated human freezing behavior in the context of pain. In addition, there is an increasing realization that social context can affect pain-relevant processes such as pain experience and pain behavior but less is known about the effects of social context on defensive responses to pain. Hence, this study investigated freezing behavior and facial pain expression in the context of pain, and their modulation by social context.
Learn More >Neural precursor cell-expressed developmentally downregulated protein 4-2 (Nedd4-2) is a member of the E3 ubiquitin ligase family that is highly expressed in sensory neurons and involved in pain modulation via downregulation of ion channels in excitable membranes. Ubiquitination involving Nedd4-2 is regulated by adenosine monophosphate-activated protein kinase (AMPK), which is impaired in the dorsal root ganglion (DRG) neurons of db/db mice. AMPK negatively regulates the expression of transient receptor potential ankyrin 1 (TRPA1), a recognised pain sensor expressed on the membrane of DRG neurons, consequently relieving mechanical allodynia in db/db mice. Herein, we studied the involvement of Nedd4-2 in painful diabetic neuropathy and observed that Nedd4-2 negatively regulated diabetic mechanical allodynia. Nedd4-2 was co-expressed with TRPA1 in mouse DRG neurons. Nedd4-2 was involved in TRPA1 ubiquitination, this ubiquitination, as well as Nedd4-2-TRPA1 interaction, was decreased in db/db mice. Moreover, Nedd4-2 levels were decreased in db/db mice, while an abnormal intracellular distribution was observed in short-term high glucose-cultured DRG neurons. AMPK activators not only restored Nedd4-2 distribution but also increased Nedd4-2 expression. These findings demonstrate that Nedd4-2 is a potent regulator of TRPA1, and that the abnormal expression of Nedd4-2 in DRG neurons contributes to diabetic neuropathic pain.
Learn More >Monoclonal antibodies to calcitonin gene-related peptide or its receptor have clinical trial evidence in adults with headache, but data are lacking in adolescents. The objective of this study was to describe the safety and efficacy of calcitonin gene-related peptide monoclonal antibody treatment in adolescents with chronic headache disorders.
Learn More >Enhancing the efficacy of spinal cord stimulation (SCS) is needed to alleviate the burden of chronic pain and dependence on opioids. Present SCS therapies are characterized by the delivery of constant stimulation in the form of trains of tonic pulses (TPs). We tested the hypothesis that modulated SCS using novel time-dynamic pulses (TDPs) leads to improved analgesia and compared the effects of SCS using conventional TPs and a collection of TDPs in a rat model of neuropathic pain according to a longitudinal, double-blind, and crossover design. We tested the effects of the following SCS patterns on paw withdrawal threshold and resting state EEG theta power as a biomarker of spontaneous pain: Tonic (conventional), amplitude modulation, pulse width modulation, sinusoidal rate modulation, and stochastic rate modulation. Results demonstrated that under the parameter settings tested in this study, all tested patterns except pulse width modulation, significantly reversed mechanical hypersensitivity, with stochastic rate modulation achieving the highest efficacy, followed by the sinusoidal rate modulation. The anti-nociceptive effects of sinusoidal rate modulation on EEG outlasted SCS duration on the behavioral and EEG levels. These results suggest that TDP modulation may improve clinical outcomes by reducing pain intensity and possibly improving the sensory experience.
Learn More >A small number of studies have supported the efficacy of open-label placebos (OLPs) in reducing pain. However, research comparing the effectiveness of OLPs with deceptive placebos (DPs) is limited, and the relative impact on pain tolerance versus intensity are not yet understood. This study therefore, examined the effectiveness of a nasal placebo administered openly and deceptively on pain intensity and tolerance during a cold pressor test (CPT).
Learn More >Atopic dermatitis (AD) is a common skin disease characterized by chronic inflammation and itchiness. Although skin barrier dysfunction and immune abnormalities are thought to contribute to the development of AD, the precise pathogenic mechanism remains to be elucidated. We have developed a unique, diet-induced AD mouse model based on the findings that deficiencies of certain polyunsaturated fatty acids and starches cause AD-like symptoms in hairless mice. Here, we present a protocol and tips for establishing an AD mouse model using a custom diet modified from a widely used standard diet (AIN-76A Rodent Diet). We also describe methods for evaluating skin barrier dysfunction and analyzing itch-related scratching behavior. This model can be used not only to investigate the complex pathogenic mechanism of human AD but also to study the puzzling relationship between nutrition and AD development.
Learn More >In the field of pain, virtual reality (VR) technology has been increasingly common in the context of procedural pain management. As an interactive technology tool, VR has the potential to be extended beyond acute pain management to chronic pain rehabilitation with a focus on increasing engagement with painful or avoided movements.
Learn More >There is growing interest in the potential of internet-delivered pain management programs (PMPs) to increase access to care for people with chronic pain. However, very few economic evaluations of these interventions have been reported. Using existing data, the current study examined the cost-effectiveness of an internet-delivered PMP for a mixed group chronic pain patients (n = 490) provided with different levels of clinician support. The findings indicated that each additional clinical outcome (defined as a ≥ 30% reduction in disability, depression, anxiety and pain) was associated with cost-savings when the intervention was provided in a self-guided format (ICER range: -$404 to -$808 AUD) or an optional-guided format (ICER range: -$314 to -$541 AUD), and a relatively small fixed cost when provided in the clinician-guided format (ICER range: $88 to $225 AUD). The results were driven by a reduction in service use costs among the treatment groups, which offset the costs of providing the internet-delivered PMP in the self-guided and optional-guided formats. The same general pattern of results was found when more stringent clinical outcomes (defined as a ≥ 50% reduction) were employed. These findings suggest that carefully developed and administered internet-delivered PMPs, provided with different levels of clinician support, can be highly cost effective for patients with a broad range of pain conditions. PERSPECTIVE: This study examines the cost-effectiveness of an internet-delivered pain management program provided to adults with a broad range of chronic pain conditions. Evidence of cost-effectiveness was found across a broad range of clinical outcomes and with different levels of clinician support.
Learn More >Small fiber neuropathy (SFN) is a prevalent neurologic syndrome. Testing methods have emerged in recent years to better diagnose it, including autonomic tests and skin punch biopsy. SFN can present in a non-length-dependent fashion and can be mistaken for syndromes such as fibromyalgia and complex regional pain syndrome. SFN is caused by a variety of metabolic, infectious, genetic, and inflammatory diseases. Recently treatments have emerged for TTR amyloid neuropathy and Fabry disease, and novel biomarkers have been found both in genetic and inflammatory SFN syndromes. Ongoing trials attempt to establish the efficacy of intravenous immunoglobulin in inflammatory SFN syndromes.
Learn More >Neuropathic pain (NP) is a common complication that negatively affects the lives of patients with spinal cord injury (SCI). The disruption in the balance of excitatory and inhibitory neurons in the spinal cord dorsal horn contributes to the development of SCI and induces NP. The calcium-binding protein (CaBP) calbindin-D 28K (CaBP-28K) is highly expressed in excitatory interneurons, and the CaBP parvalbumin (PV) is present in inhibitory neurons in the dorsal horn. To better define the changes in the CaBPs contributing to the development of SCI-induced NP, we examined the changes in CaBP-28K and PV staining density in the lumbar (L4-6) lamina I and II, and their relationship with NP after mild spinal cord contusion injury in mice. We additionally examined the effects of alternate thermal stimulation (ATS). Compared with sham mice, injured animals developed mechanical allodynia in response to light mechanical stimuli and exhibited mechanical hyporesponsiveness to noxious mechanical stimuli. The decreased response latency to heat stimuli and increased response latency to cold stimuli at 7 days post injury suggested that the injured mice developed heat hyperalgesia and cold hypoalgesia, respectively. Temperature preference tests showed significant warm allodynia after injury. Animals that underwent ATS (15-18 and 35-40°C; +5 minutes/stimulation/day; 5 days/week) displayed significant amelioration of heat hyperalgesia, cold hypoalgesia, and warm allodynia after 2 weeks of ATS. In contrast, mechanical sensitivity was not influenced by ATS. Analysis of the CaBP-28K positive signal in L4-6 lamina I and II indicated an increase in staining density after SCI, which was associated with an increase in the number of CaBP-28K-stained L4-6 dorsal root ganglion (DRG) neurons. ATS decreased the CaBP-28K staining density in L4-6 spinal cord and DRG in injured animals, and was significantly and strongly correlated with ATS alleviation of pain behavior. The expression of PV showed no changes in lamina I and II after ATS in SCI animals. Thus, ATS partially decreases the pain behavior after SCI by modulating the changes in CaBP-associated excitatory-inhibitory neurons.
Learn More >The discovery of calcitonin gene-related peptide (CGRP) and its role in migraine has promoted a new era in migraine treatment: CGRP antagonism. Two classes of medications are currently available: small molecules targeting the CGRP receptor and monoclonal antibodies targeting the CGRP receptor or CGRP ligand. The revolution of these medications is represented by blurring the borders between acute and preventive treatments, episodic and chronic migraine, naïve and refractory patients and even between migraine and other headache disorders.
Learn More >In the present study, we demonstrated that there is a direct relationship between scratching behaviors induced by itch and functional changes in the brain reward system. Using a conditional place preference test, the rewarding effect was clearly evoked by scratching under both acute and chronic itch stimuli. The induction of ΔFosB, a member of the Fos family of transcription factors, was observed in dopamine transporter (DAT)-positive dopamine neurons in the ventral tegmental area (VTA) of mice suffering from a chronic itch sensation. Based on a cellular analysis of scratching-activated neurons, these neurons highly expressed tyrosine hydroxylase (TH) and DAT genes in the VTA. Furthermore, in an in vivo microdialysis study, the levels of extracellular dopamine in the nucleus accumbens (NAcc) were significantly increased by transient scratching behaviors. To specifically suppress the mesolimbic dopaminergic pathway using pharmacogenetics, we used the TH-cre/hM4Di mice. Pharmacogenetic suppression of mesolimbic dopaminergic neurons significantly decreased scratching behaviors. Under the itch condition with scratching behaviors restricted by an Elizabethan collar, the induction of ΔFosB was found mostly in corticotropin-releasing hormone (CRH)-containing neurons of the hypothalamic paraventricular nucleus (PVN). These findings suggest that repetitive abnormal scratching behaviors under acute and chronic itch stimuli may activate mesolimbic dopamine neurons along with pleasant emotions, while the restriction of such scratching behaviors may initially induce the activation of PVN-CRH neurons associated with stress.
Learn More >Ongoing activity in nociceptors, a driver of spontaneous pain, can be generated in dorsal root ganglion neurons in the absence of sensory generator potentials if one or more of three neurophysiological alterations occur – prolonged depolarization of resting membrane potential (RMP), hyperpolarization of action potential (AP) threshold, and/or increased amplitude of depolarizing spontaneous fluctuations of membrane potential (DSFs) to bridge the gap between RMP and AP threshold. Previous work showed that acute, sustained exposure to serotonin (5-HT) hyperpolarized AP threshold and potentiated DSFs, leading to ongoing activity if a separate source of maintained depolarization was present. Cellular signaling pathways that increase DSF amplitude and promote ongoing activity acutely in nociceptors are not known for any neuromodulator. Here, isolated DRG neurons from male rats were used to define the pathway by which low concentrations of 5-HT enhance DSFs, hyperpolarize AP threshold, and promote ongoing activity. A selective 5-HT receptor antagonist blocked these 5-HT-induced hyperexcitable effects, while a selective 5-HT agonist mimicked the effects of 5-HT. Inhibition of cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), attenuated 5-HT's hyperexcitable effects, but a blocker of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels had no significant effect. 5-HT-dependent PKA activation was specific to DRG neurons that bind isolectin B4 (a nonpeptidergic nociceptor marker). 5-HT's effects on AP threshold, DSFs, and ongoing activity were mimicked by a cAMP analog. Sustained exposure to 5-HT promotes ongoing activity in nonpeptidergic nociceptors through the G-coupled 5-HT receptor and downstream cAMP signaling involving both PKA and EPAC.
Learn More >Persistent post-traumatic headache (PTH) is a common sequela of mild traumatic brain injury (TBI) and retrospective assessments have found a migraine-like phenotype to be very frequent. This has raised a discussion of shared underlying mechanisms and whether persistent PTH is simply trauma-triggered migraine.
Learn More >Clinically, pain has an uneven incidence throughout lifespan and impacts more on the elderly. In contrast, preclinical models of pathological pain have typically used juvenile or young adult animals to highlight the involvement of glial populations, proinflammatory cytokines, and chemokines in the onset and maintenance of pathological signalling in the spinal dorsal horn. The potential impact of this mismatch is also complicated by the growing appreciation that the aged central nervous system exists in a state of chronic inflammation because of enhanced proinflammatory cytokine/chemokine signalling and glial activation. To address this issue, we investigated the impact of aging on the expression of genes that have been associated with neuropathic pain, glial signalling, neurotransmission and neuroinflammation. We used qRT-PCR to quantify gene expression and focussed on the dorsal horn of the spinal cord as this is an important perturbation site in neuropathic pain. To control for global vs region-specific age-related changes in gene expression, the ventral half of the spinal cord was examined. Our results show that expression of proinflammatory chemokines, pattern recognition receptors, and neurotransmitter system components was significantly altered in aged (24-32 months) versus young mice (2-4 months). Notably, the magnitude and direction of these changes were spinal-cord region dependent. For example, expression of the chemokine, Cxcl13, increased 119-fold in dorsal spinal cord, but only 2-fold in the ventral spinal cord of old versus young mice. Therefore, we propose the dorsal spinal cord of old animals is subject to region-specific alterations that prime circuits for the development of pathological pain, potentially in the absence of the peripheral triggers normally associated with these conditions.
Learn More >Botulinum neurotoxin (BoNT) is an effective treatment for many neurologic disorders. This article gives a comprehensive overview of the clinical applications of BoNT across the field of neurology.
Learn More >Itch is an unpleasant and aversive somatosensory experience. These negative emotions significantly affect mental health in chronic itch patients. Therefore, it is important to understand the brain mechanism of negative emotions due to itch. The amygdala is an important hub of network to regulate negative emotions due to itch. However, the exact network remains unknown. Thus, using functional magnetic resonance imaging, we investigated what network the amygdala constitutes for processing itch in human brains. Twenty-five healthy subjects participated in the present study. Brain activity during electrical itch stimuli was measured by using functional magnetic resonance imaging. The amygdala exhibited increased functional connectivity during itch stimuli with key brain regions of the serotonergic system responsible for negative emotions (the medial habenula, median raphe nucleus) and the memory system to consolidate emotional experiences (the parahippocampus, perirhinal cortex). These systems may become therapeutic targets to prevent or reduce diminished mental health commonly seen in chronic itch patients.
Learn More >Interdisciplinary multimodal pain therapy (IMPT) programs for chronic back pain are effective and recommended. The patient-centered and biopsychosocial nature of IMPT is grounded in contemporary understanding that chronic pain states reflect heightened sensitization of the nervous system rather than an issue in the tissue. Teaching patients about pain is part of IMPT programs, though a clinical guideline is lacking. This study aims to answer the following question: Does the addition of an evidence-based pain neuroscience education (PNE) lecture for patients, into an IMPT program, produce superior results than the IMPT program itself?
Learn More >Complex regional pain syndrome (CRPS) is characterized by chronic, spontaneous and provoked pain of the distal extremities whose severity is disproportionate to the triggering event. Diagnosis and treatment are still debated and multidisciplinary. The purpose of this systematic review is to analyze the available literature to provide an update on the latest evidence related to the treatment of CRPS in growing age.
Learn More >Postherpetic neuralgia (PHN) is the most common complication of herpes zoster, but the mechanism of PHN is still unclear. Activation of spinal astrocytes is involved in PHN. Our study aims to explore whether lncRNA KCNA2 antisense RNA (KCNA2-AS) regulates spinal astrocytes in PHN through signal transducers and activators of transcription 3 (STAT3).
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating side effect that worsens quality of life and increases the risk of falls in cancer survivors. Evidence of yoga's safety and efficacy in treating CIPN is lacking.
Learn More >Oral amitriptyline hydrochloride (amitriptyline) is ineffective against some forms of chronic pain and is often associated with dose-limiting adverse events. We evaluated the potential effectiveness of high-dose topical amitriptyline in a preliminary case series of chemotherapy-induced peripheral neuropathy (CIPN) patients and investigated whether local or systemic adverse events associated with the use of amitriptyline were present in these patients. We also investigated the mechanism of action of topically administered amitriptyline in mice. Our case series suggested that topical 10% amitriptyline treatment was associated with pain relief in CIPN patients, without the side effects associated with systemic absorption. Topical amitriptyline significantly increased mechanical withdrawal thresholds when applied to the hind paw of mice, and inhibited the firing responses of C-, Aβ- and Aδ-type peripheral nerve fibers in ex vivo skin-saphenous nerve preparations. Whole-cell patch-clamp recordings on cultured sensory neurons revealed that amitriptyline was a potent inhibitor of the main voltage-gated sodium channels (Nav1.7, Nav1.8 and Nav1.9) found in nociceptors. Calcium imaging showed that amitriptyline activated the transient receptor potential cation channel, TRPA1. Our case series indicated that high-dose 10% topical amitriptyline could alleviate neuropathic pain without adverse local or systemic effects. This analgesic action appeared to be mediated through local inhibition of voltage-gated sodium channels. PERSPECTIVE: Our preliminary case series suggested that topical amitriptyline could provide effective pain relief for chemotherapy-induced peripheral neuropathy patients without any systemic or local adverse events. Investigation of the mechanism of this analgesic action in mice revealed that this activity was mediated through local inhibition of nociceptor Nav channels.
Learn More >"Deep brain stimulation is a safe and effective therapy for the management of a variety of neurologic conditions with Food and Drug Administration or humanitarian exception approval for Parkinson disease, dystonia, tremor, and obsessive-compulsive disorder. Advances in neurophysiology, neuroimaging, and technology have driven increasing interest in the potential benefits of neurostimulation in other neuropsychiatric conditions including dementia, depression, pain, Tourette syndrome, and epilepsy, among others. New anatomic or combined targets are being investigated in these conditions to improve symptoms refractory to medications or standard stimulation."
Learn More >Microglia play an important role in the central sensitization and chronic pain. However, a direct connection between microglial function and pain development in vivo remains incompletely understood. To address this issue, we applied chemogenetic approach by using CXCR1:R26 transgenic mice to enable expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (Gi DREADD) in microglia. We found that microglial Gi DREADD activation inhibited spinal nerve transection (SNT)-induced microglial reactivity as well as chronic pain in both male and female mice. Gi DREADD activation downregulated the transcription factor interferon regulatory factor 8 (IRF8) and its downstream target pro-inflammatory cytokine interleukin 1 beta (IL-1β). Using in vivo spinal cord recording, we found that activation of microglial Gi DREADD attenuated synaptic transmission following SNT. Our results demonstrate that microglial Gi DREADD reduces neuroinflammation, synaptic function and neuropathic pain after SNT. Thus, chemogenetic approaches provide a potential opportunity for interrogating microglial function and neuropathic pain treatment.
Learn More >Alcohol Use Disorder (AUD) is a chronic relapsing disorder characterized by compulsive alcohol intake, loss of control over alcohol intake, and a negative emotional state when access to alcohol is prevented. AUD is also closely tied to pain, as repeated alcohol drinking leads to increased pain sensitivity during withdrawal. The sigma-2 receptor, recently identified as transmembrane protein 97 (σ2R/TMEM97), is an integral membrane protein involved in cholesterol homeostasis and lipid metabolism. Selective σ2R/Tmem97 modulators have been recently shown to relieve mechanical hypersensitivity in animal models of neuropathic pain as well as to attenuate alcohol withdrawal signs in C. elegans and to reduce alcohol drinking in rats, suggesting a potential key role for this protein in alcohol-related behaviors. In this study, we tested the effects of a potent and selective σ2R/TMEM97 ligand, JVW-1034, on heavy alcohol drinking and alcohol-induced heightened pain states in mice using an intermittent access model. Administration of JVW-1034 decreased both ethanol intake and preference for ethanol, without affecting water intake, total fluid intake, or food intake. Notably, this effect was specific for alcohol, as JVW-1034 had no effect on sucrose intake. Furthermore, JVW-1034 reduced both thermal hyperalgesia and mechanical hypersensitivity in ethanol withdrawn mice. Our data provide important evidence that modulation of σ2R/TMEM97 with small molecules can mediate heavy alcohol drinking as well as chronic alcohol-induced heightened pain sensitivity, thereby identifying a promising novel pharmacological target for AUD and associated pain states.
Learn More >Neuropathic pain often accompanies the functional deficits associated with spinal cord injury (SCI) and further reduces a patient's quality of life. Clinical and pre-clinical research is beginning to highlight the beneficial role that rehabilitative therapies such as locomotor training can have not only on functional recovery but also on chronic pain management. Our group has previously developed an intensive locomotor training (ILT) treadmill protocol in a rat that reduced SCI neuropathic pain symptoms for at least 3 months. We have extended these findings in the current study to evaluate the ability of regular ILT regimen over a 2 year period post-SCI to maintain neuropathic pain reduction. To assess this, the rat clip compression SCI model (T7/8) was used and treadmill training initiated starting 4 weeks after SCI and continuing through the duration of the study. Results showed continued suppression of SCI neuropathic pain responses (reduced mechanical, heat, and cold hypersensitivity throughout the entire time course of the study. In contrast, non-exercised rats showed consistent and sustained neuropathic pain responses during this period. In addition, prolonged survival and improved locomotor outcomes were observed in rats undergoing ILT as the study longevity progressed. Potential contributory mechanisms underlying beneficial effects of ILT include reduced inflammation and restoration of antinociceptive inhibitory processes as indicated by neurochemical assays in spinal tissue of remaining rats at 2 years post-SCI. The benefits of chronic ILT suggest long-term physical exercise therapy can produce powerful and prolonged management of neuropathic pain, partly through sustained reduction of spinal pathological processes.
Learn More >Orthodontic force produces mechanical irritation and localized inflammation in the periodontium, which causes pain in most patients. Nocifensive behaviors resulting from orthodontic force in mice can be substantially attenuated by intraganglionic injection of resiniferatoxin (RTX), a neurotoxin that specifically ablates a subset of neurons expressing transient receptor potential vanilloid 1 (TRPV1). In the current study, we determined changes in the transcriptomic profiles in the trigeminal ganglia (TG) following the application of orthodontic force, and assessed the roles of TRPV1-expressing afferents in these transcriptomic changes. RTX or vehicle was injected into the TG of mice a week before the placement of an orthodontic spring exerting 10 g of force. After 2 days, the TG were collected for RNA sequencing. The application of orthodontic force resulted in 1279 differentially expressed genes (DEGs) in the TG. Gene ontology analysis showed downregulation of gliogenesis and ion channel activities, especially of voltage-gated potassium channels. DEGs produced by orthodontic force correlated more strongly with DEGs resulting from nerve injury than from inflammation. Orthodontic force resulted in the differential expression of multiple genes involved in pain regulation, including upregulation of , , , and , and downregulation of , , , and . Orthodontic force-induced DEGs correlated with DEGs specific to multiple neuronal and non-neuronal subtypes following nerve injury. These transcriptomic changes were abolished in the mice that received the RTX injection. These results suggest that orthodontic force produces transcriptomic changes resembling nerve injury in the TG and that nociceptive inputs through TRPV1-expressing afferents leads to subsequent changes in gene expression not only in TRPV1-positive neurons, but also in TRPV1-negative neurons and non-neuronal cells throughout the ganglia. Orthodontic force-induced transcriptomic changes might be an active regenerative program of trigeminal ganglia in response to axonal injury following orthodontic force.
Learn More >To investigate quality of life (QOL) and functionality changes in chronic pain during tapentadol prolonged release (PR) treatment. analysis of data from three Phase III trials in patients with osteoarthritis knee pain or low back pain. QOL and functionality changes were assessed by SF-36 scores. All SF-36 subdomain scores improved progressively to week 3 of tapentadol titration and were sustained during 12-week maintenance treatment. Improvements in SF-36 scores were similar between tapentadol dose groups (e.g., 200 to <300 mg vs ≥500 mg), with no greater effect from higher doses. QOL and functionality improvements were consistently greater with tapentadol PR than oxycodone controlled release. Tapentadol PR provides consistent, clinically relevant improvements in QOL and functionality in chronic pain.
Learn More >To determine whether high school start time is associated with headache frequency in adolescents with migraine.
Learn More >Inflammatory pain is the most common type of pain treated clinically. However, the currently available treatments for inflammatory pain have limited effects and can cause severe side effects. The aim of this study is to describe the effect of miRNA-485-5p on osteoarthritis-related inflammatory pain.
Learn More >Preoperative patient-specific risk factors may elucidate the mechanisms leading to the persistence of pain and opioid use after surgery. This study aimed to determine whether similar or discordant preoperative factors were associated with the duration of postoperative pain and opioid use.
Learn More >The purpose of the present study was to explore whether and to what extent the neuroimaging markers could predict the relief of the symptoms of patients with migraine without aura (MWoA) following a 4-week acupuncture treatment period. In study 1, the advanced multivariate pattern analysis was applied to perform a classification analysis between 40 patients with MWoA and 40 healthy subjects (HS) based on the z-transformed amplitude of low-frequency fluctuation (zALFF) maps. In study 2, the meaningful classifying features were selected as predicting features and the support vector regression models were constructed to predict the clinical efficacy of acupuncture in reducing the frequency of migraine attacks and headache intensity in 40 patients with MWoA. In study 3, a region of interest-based comparison between the pre- and post-treatment zALFF maps was conducted in 33 patients with MwoA to assess the changes in predicting features after acupuncture intervention. The zALFF value of the foci in the bilateral middle occipital gyrus, right fusiform gyrus, left insula, and left superior cerebellum could discriminate patients with MWoA from HS with higher than 70% accuracy. The zALFF value of the clusters in the right and left middle occipital gyrus could effectively predict the relief of headache intensity ( = 0.38 ± 0.059, mean squared error = 2.626 ± 0.325) and frequency of migraine attacks ( = 0.284 ± 0.072, mean squared error = 20.535 ± 2.701) after the 4-week acupuncture treatment period. Moreover, the zALFF values of these two clusters were both significantly reduced after treatment. The present study demonstrated the feasibility and validity of applying machine learning technologies and individual cerebral spontaneous activity patterns to predict acupuncture treatment outcomes in patients with MWoA. The data provided a quantitative benchmark for selecting acupuncture for MWoA.
Learn More >Oxidative stress can be induced by various stimuli and altered in certain conditions, including exercise and pain. Although many studies have investigated oxidative stress in relation to either exercise or pain, the literature presents conflicting results. Therefore, this review critically discusses existing literature about this topic, aiming to provide a clear overview of known interactions between oxidative stress, exercise, and pain in healthy people as well as in people with chronic pain, and to highlight possible confounding factors to keep in mind when reflecting on these interactions. In addition, autonomic regulation and epigenetic mechanisms are proposed as potential mechanisms of action underlying the interplay between oxidative stress, exercise, and pain. This review highlights that the relation between oxidative stress, exercise, and pain is poorly understood and not straightforward, as it is dependent on the characteristics of exercise, but also on which population is investigated. To be able to compare studies on this topic, strict guidelines should be developed to limit the effect of several confounding factors. This way, the true interplay between oxidative stress, exercise, and pain, and the underlying mechanisms of action can be revealed and validated via independent studies.
Learn More >This study is a systematic review of interventions to improve adherence to guideline recommendations for prescribing opioids for chronic noncancer pain.
Learn More >Among the five KCNQ channels, also known as the K7 voltage-gated potassium (K) channels, KCNQ2-KCNQ5 control neuronal excitability. Dysfunctions of KCNQ2-KCNQ5 are associated with neurological disorders such as epilepsy, deafness, and neuropathic pain. Here, we report the cryoelectron microscopy (cryo-EM) structures of human KCNQ4 and its complexes with the opener retigabine or the blocker linopirdine at overall resolutions of 2.5, 3.1, and 3.3 Å, respectively. In all structures, a phosphatidylinositol 4,5-bisphosphate (PIP) molecule inserts its head group into a cavity within each voltage-sensing domain (VSD), revealing an unobserved binding mode for PIP. Retigabine nestles in each fenestration, inducing local shifts. Instead of staying within the central pore, linopirdine resides in a cytosolic cavity underneath the inner gate. Electrophysiological analyses of various mutants corroborated the structural observations. Our studies reveal the molecular basis for the modulatory mechanism of neuronal KCNQ channels and provide a framework for structure-facilitated drug discovery targeting these important channels.
Learn More >To assess the role of momentary pain on opioid craving and illicit opioid use among individuals receiving opioid agonist treatment.
Learn More >To improve understanding of current practices in the treatment of children and adolescents with chronic pain in Spain.
Learn More >A better understanding of neural pain processing and of the development of pain over time, is critical to identify objective measures of pain and to evaluate the effect of pain alleviation therapies. One issue is, that the brain areas known to be related to pain processing are not exclusively responding to painful stimuli, and the neuronal activity is also influenced by other brain areas. Functional connectivity reflects synchrony or covariation of activation between groups of neurons. Previous studies found changes in connectivity days or weeks after pain induction. However, less in known on the temporal development of pain. Our objective was therefore to investigate the interaction between the anterior cingulate cortex (ACC) and primary somatosensory cortex (SI) in the hyperacute (minute) and sustained (hours) response in an animal model of neuropathic pain. Intra-cortical local field potentials (LFP) were recorded in 18 rats. In 10 rats the spared nerve injury model was used as an intervention. The intra-cortical activity was recorded before, immediately after, and three hours after the intervention. The interaction was quantified as the calculated correlation and coherence. The results from the intervention group showed a decrease in correlation between ACC and SI activity, which was most pronounced in the hyperacute phase but a longer time frame may be required for plastic changes to occur. This indicated that both SI and ACC are involved in hyperacute pain processing.
Learn More >Dorsal root ganglion stimulation (DRG-S) involves the electrical modulation of the somata of afferent neural fibers to treat chronic pain. DRG-S has demonstrated clinical efficacy at frequencies lower than typically used with spinal cord stimulation (SCS). In a clinical study, we found that the frequency of DRG-S can be tapered to a frequency as low as 4 Hz with no loss of efficacy. This review discusses possible mechanisms of action underlying effective pain relief with very low-frequency DRG-S.
Learn More >Trigeminal neuralgia (TN) is a chronic neuropathic pain that seriously affects the daily life of patients. There is increasing evidence that microRNAs (miRNAs) play an important role in the development of neuropathic pain.In this study, the TaqMan Low Density Array (TLDA) was used to analyze the serum miRNA levels of 28 TN patients, and 31 healthy people without any neuropathic pain were used as controls.The results showed that the expression profile of serum miRNA in TN patients was different from that in healthy controls. Compared with the control group, 13 miRNAs in the serum of TN patients were up-regulated and 115 miRNAs were down-regulated by >2 times. Quantitative reverse transcription PCR (RT-qPCR) analysis and receiver operating characteristic (ROC) curve were performed. The analysis further confirmed that the expression levels of 4 miRNAs, including miR-132-3p, miR-146b-5p, miR-155-5p, and miR-384, were significantly higher than those of healthy controls, and the difference was statistically significant.This study preliminarily confirmed the changes of serum miRNA expression profile in TN patients. Among them, 4 kinds of serum miRNA are likely to be related to the occurrence and development of TN.
Learn More >Low intensity, high-frequency transcranial alternating current stimulation (tACS) applied over the motor cortex decreases the amplitude of motor evoked potentials. This double-blind, placebo-controlled parallel group study aimed to test the efficacy of this method for acute management of migraines. The patients received either active (0.4 mA, 140 Hz) or sham stimulation for 15 min over the visual cortex with the number of terminated attacks two hours post-stimulation as the primary endpoint, as a home therapy option. They were advised to treat a maximum of five migraine attacks over the course of six weeks. From forty patients, twenty-five completed the study, sixteen in the active and nine in the sham group with a total of 102 treated migraine attacks. The percentage of terminated migraine attacks not requiring acute rescue medication was significantly higher in the active (21.5%) than in the sham group (0%), and the perceived pain after active stimulation was significantly less for 2-4 h post-stimulation than after sham stimulation. tACS over the visual cortex has the potential to terminate migraine attacks. Nevertheless, the high drop-out rate due to compliance problems suggests that this method is impeded by its complexity and time-consuming setup.
Learn More >The Cannabis sativa plant contains more than 120 cannabinoids. With the exceptions of ∆-tetrahydrocannabinol (∆-THC) and cannabidiol (CBD), comparatively little is known about the pharmacology of the less-abundant plant-derived (phyto) cannabinoids. The best-studied transducers of cannabinoid-dependent effects are type 1 and type 2 cannabinoid receptors (CB1R, CB2R). Partial agonism of CB1R by ∆-THC is known to bring about the 'high' associated with Cannabis use, as well as the pain-, appetite-, and anxiety-modulating effects that are potentially therapeutic. CB2R activation by certain cannabinoids has been associated with anti-inflammatory activities. We assessed the activity of 8 phytocannabinoids at human CB1R, and CB2R in Chinese hamster ovary (CHO) cells stably expressing these receptors and in C57BL/6 mice in an attempt to better understand their pharmacodynamics. Specifically, ∆-THC, ∆-tetrahydrocannabinolic acid (∆-THCa), ∆-tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDa), cannabidivarin (CBDV), cannabigerol (CBG), and cannabichromene (CBC) were evaluated. Compounds were assessed for their affinity to receptors, ability to inhibit cAMP accumulation, βarrestin2 recruitment, receptor selectivity, and ligand bias in cell culture; and cataleptic, hypothermic, anti-nociceptive, hypolocomotive, and anxiolytic effects in mice. Our data reveal partial agonist activity for many phytocannabinoids tested at CB1R and/or CB2R, as well as in vivo responses often associated with activation of CB1R. These data build on the growing body of literature showing cannabinoid receptor-dependent pharmacology for these less-abundant phytocannabinoids and are critical in understanding the complex and interactive pharmacology of Cannabis-derived molecules.
Learn More >Dorsal root ganglion neurostimulation (DRG-S) is effective in treating various refractory chronic pain syndromes. In preclinical studies, DRG-S at very low frequencies (<5 Hz) reduces excitatory output in the superficial dorsal horn. Clinically, we have also observed the effectiveness of DRG-S at low frequencies. We conducted a case series to describe the effect of very low-frequency DRG-S stimulation on clinical outcomes.
Learn More >Trajectory studies suggest considerable stability of persistent or recurrent pain in adolescence. This points to the first decade of life as an important aetiologic window for shaping future pain, where the potential for prevention may be optimised.
Learn More >Disturbed sleep and use of opioid pain medication are common among individuals with chronic pain. Anecdotally, opioids are thought to promote sleep by relieving pain. This study aimed to determine whether opioid use is associated with daily sleep parameters (and vice versa) among adults with comorbid symptoms of insomnia and fibromyalgia.
Learn More >Pain is a complex, multidimensional experience but often is measured as a unidimensional experience. This study aimed to separately assess the sensory and affective components of pain and identify their relations to important pain-related outcomes, particularly in terms of opioid misuse risk and emotion dysregulation among patients with chronic pain receiving treatment in Appalachia. Two hundred and twelve patients presenting to a multidisciplinary pain center completed the Difficulties in Emotion Regulation Scale (DERS-18), Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), and short-form McGill Pain Questionnaire (SF-MPQ). The sensory experience of pain was unrelated to emotion dysregulation ( = 0.06, = 0.57) and weakly related to opioid misuse risk ( = 0.182, < 0.05). In contrast, the affective experience of pain was moderately related to emotion dysregulation ( = 0.217, < 0.05) and strongly related to opioid misuse risk ( = 0.37, < 0.01). In addition, emotion dysregulation predicted variance in opioid misuse risk above and beyond the affective and sensory experiences of pain (( = 0.693, < 0.001). The results suggest patients with a strong affective experience versus sensory experience of pain and challenges with emotion regulation may require a more comprehensive intervention to address these underlying components in order to reduce their risk of misusing opioid medications.
Learn More >Alterations of the expression of microRNAs (miRNAs) in chronic pain models seem to play a crucial role in the development of neuropathic pain, with microRNA-1 (miR-1) being of particular interest. Recently, we were able to show that decreased miR-1 levels were associated with increased expression of brain-derived neurotrophic factor (BDNF) and Connexin 43 (Cx43). We hypothesized that miR-1 mimetic nucleotides could alleviate neuropathic pain caused by chronic constriction injury in rats.
Learn More >IMT504 is a non-CPG, non-coding synthetic oligodeoxinucleotide (ODN) with immunomodulatory properties and a novel inhibitory role in pain transmission, exerting long-lasting analgesic effects upon multiple systemic administrations. However, its mechanisms of anti-nociceptive action are still poorly understood. In the present study in male adult rats undergoing complete Freund's adjuvant-induced hindpaw inflammation, we focused in the analysis of the immunomodulatory role of IMT504 over the cellular infiltrate, the impact on the inflammatory milieu, and the correlation with its anti-allodynic role. By means of behavioral analysis, we determined that a single subcutaneous administration of 6 mg/kg of IMT504 is sufficient to exert a 6-week-long full reversal of mechanical and cold allodynia, compromising neither acute pain perception nor locomotor activity. Importantly, we found that the anti-nociceptive effects of systemic IMT504, plus quick reductions in hindpaw edema, were associated with a modulatory action upon cellular infiltrate of B-cells, macrophages and CD8 T-cells populations. Accordingly, we observed a profound downregulation of several inflammatory leukocyte adhesion proteins, chemokines and cytokines, as well as of β-endorphin and an increase in the anti-inflammatory cytokine, interleukin-10. Altogether, we demonstrate that at least part of the anti-nociceptive actions of IMT504 relate to the modulation of the peripheral immune system at the site of injury, favoring a switch from pro- to anti-inflammatory conditions, and provide further support to its use against chronic inflammatory pain. Graphical abstract GA short description – IMT504 systemic Administration. Systemic administration of the non-CpG ODN IMT504 results in a 6-week long blockade of pain-like behavior in association with anti-inflammatory responses at the site of injury. These include modulation of lymphoid and myeloid populations plus downregulated expression levels of multiple pro-inflammatory cytokines and β-endorphin. Nocifensive responses and locomotion remain unaltered.
Learn More >There is wide discrepancy on how to perform clinical assessment of oxaliplatin-induced peripheral neuropathy. In this scenario, the Electronic von Frey (EVF), which evaluates pain objectively based upon mechanical pain thresholds (MPTs), may be a valuable tool. The present study aims to quantify hyperalgesia in the hands and feet of patients treated with oxaliplatin and to propose a novel method to classify the degree of neurotoxicity using EVF-derived measures as cut-off points.
Learn More >Adenosine is a purine nucleoside, responsible for the regulation of multiple physiological and pathological cellular and tissue functions by activation of four G protein-coupled receptors (GPCR), namely A, A, A, and A adenosine receptors (ARs). In recent years, extensive progress has been made to elucidate the role of adenosine in pain regulation. Most of the antinociceptive effects of adenosine are dependent upon AAR activation located at peripheral, spinal, and supraspinal sites. The role of AAR and AAR is more controversial since their activation has both pro- and anti-nociceptive effects. AAR agonists are emerging as promising candidates for neuropathic pain. Although their therapeutic potential has been demonstrated in diverse preclinical studies, no AR ligands have so far reached the market. To date, novel pharmacological approaches such as adenosine regulating agents and allosteric modulators have been proposed to improve efficacy and limit side effects enhancing the effect of endogenous adenosine. This review aims to provide an overview of the therapeutic potential of ligands interacting with ARs and the adenosinergic system for the treatment of acute and chronic pain.
Learn More >The pharmacodynamics of opioids for chronic peripheral neuropathic pain are complex and likely extend beyond classical opioid receptor theory. Preclinical evidence of opioid modulation of central immune signalling has not been identified in vivo in humans. Examining the cerebrospinal fluid (CSF) of patients medicated with opioids is required to identify potential pharmacodynamic mechanisms. We compared CSF samples of chronic peripheral neuropathic pain patients receiving opioids (n = 7) versus chronic peripheral neuropathic pain patients not taking opioids (control group, n = 13). Baseline pain scores with demographics were recorded. Proteome analysis was performed using mass spectrometry and secreted neuropeptides were measured by enzyme-linked immunosorbent assay. Based on Gene Ontology analysis, proteins involved in the positive regulation of nervous system development and myeloid leukocyte activation were increased in patients taking opioids versus the control group. The largest decrease in protein expression in patients taking opioids were related to neutrophil mediated immunity. In addition, notably higher expression levels of neural proteins (85%) and receptors (80%) were detected in the opioid group compared to the control group. This study suggests modulation of CNS homeostasis, possibly attributable to opioids, thus highlighting potential mechanisms for the pharmacodynamics of opioids. We also provide new insights into the immunomodulatory functions of opioids in vivo.
Learn More >Examine factors associated with post-procedure opioid receipt and persistent opioid use among opioid-naïve patients in a nationally representative sample SUMMARY BACKGROUND DATA:: We used panels 18-20 in the Medical Expenditures Panel Survey (MEPS) between the years 2013 to 2015. Respondents ages 18 and over with any self-reported procedure in the previous year with complete data on the outcome variables for the remainder of the two-year study period.
Learn More >There is a growing body of literature implicating angiotensin II in the modulation of tumour-associated inflammation and pain. However, the impact of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) on pain and inflammation has not yet been studied in oral cancers. The objective is to investigate the role of ACEi and ARB pharmacotherapy on preoperative pain and inflammatory biomarkers, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR), in patients with oral cancer.
Learn More >Neurological disorders, including Parkinson's disease (PD), have increased in prevalence and are expected to further increase in the coming decades. In this regard, PD affects around 3% of the population by age 65 and up to 5% of people over the age of 85. PD is a widely described, physically and mentally disabling neurodegenerative disorder. One symptom often poorly recognized and under-treated by health care providers despite being reported as the most common non-motor symptom is the finding of chronic pain. Compared to the general population of similar age, PD patients suffer from a significantly higher level and prevalence of pain. The most common form of pain reported by Parkinson's patients is of musculoskeletal origin. One of the most used combination drugs for PD is Levodopa-Carbidopa, a dopamine precursor that is converted to dopamine by the action of a naturally occurring enzyme called DOPA decarboxylase. Pramipexole, a D2 dopamine agonist, and apomorphine, a dopamine agonist, and Rotigotine, a dopamine receptor agonist, have showed efficacy on PD-associated pain. Other treatments that have shown efficacy in treating pain of diverse etiologies are acetaminophen, Nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors. Opioids and opioid-like medications such as oxycodone, morphine, tramadol, and codeine are also commonly employed in treatment of chronic pain in PD. Other opioid related medications such as Tapentadol, a central-acting oral analgesic with combined opioid and noradrenergic properties, and Targinact, a combination of the opioid agonist oxycodone and the opioid antagonist naloxone have shown improvement in pain. Anticonvulsants such as gabapentin, pregabalin, lamotrigine, carbamazepine and tricyclic antidepressants (TCAs) can be trialed when attempting to manage chronic pain in PD. The selective serotonin and noradrenaline reuptake inhibitors (SNRIs) also possess pain relieving and antidepressant properties, but carry less of the risk of anticholinergic side effects seen in TCAs. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown in multiple studies to be effective against various types of PD associated pain symptoms. Massage therapy (MT) is one of the most common forms of complementary and alternative medicine. Studies have shown that pressure applied during MT may stimulate vagal activity, promoting reduced anxiety and pain, as well as increasing levels of serotonin. In a survey study of PD patients, rehabilitative therapy and physical therapy were rated as the most effective for pain reduction, though with only temporary relief but these studies were uncontrolled. Yoga has been studied for patients with a wide array of neurological disorders. In summary, PD pathology is thought to have a modulating effect on pain sensation, which could amplify pain. This could help explain a portion of the higher incidence of chronic pain felt by PD patients. A treatment plan can be devised that may include dopaminergic agents, acetaminophen, NSAIDs, opioids, antidepressants, physical therapies, DBS and other options discussed in this review. A thorough assessment of patient history and physical examination should be made in patients with PD so chronic pain may be managed effectively.
Learn More >A national primary and secondary healthcare-level study in the Czech Republic has not yet been conducted to evaluate the prevalence of migraine. We analyzed the current treatment patterns (acute and prophylactic) in migraine patients and the number of migraine patients potentially eligible for treatment with recent calcitonin gene-related peptide (CGRP) pathway-targeted therapies.
Learn More >In the last decade, machine learning has been widely used in different fields, especially because of its capacity to work with complex data. With the support of machine learning techniques, different studies have been using data-driven approaches to better understand some syndromes like mild cognitive impairment, Alzheimer's disease, schizophrenia, and chronic pain. Chronic pain is a complex disease that can recurrently be misdiagnosed due to its comorbidities with other syndromes with which it shares symptoms. Within that context, several studies have been suggesting different machine learning algorithms to classify or predict chronic pain conditions. Those algorithms were fed with a diversity of data types, from self-report data based on questionnaires to the most advanced brain imaging techniques. In this study, we assessed the sensitivity of different algorithms and datasets classifying chronic pain syndromes. Together with this assessment, we highlighted important methodological steps that should be taken into account when an experiment using machine learning is conducted. The best results were obtained by ensemble-based algorithms and the dataset containing the greatest diversity of information, resulting in area under the receiver operating curve (AUC) values of around 0.85. In addition, the performance of the algorithms is strongly related to the hyper-parameters. Thus, a good strategy for hyper-parameter optimization should be used to extract the most from the algorithm. These findings support the notion that machine learning can be a powerful tool to better understand chronic pain conditions.
Learn More >Administrations of intravenous immunoglobulin (IVIG), an immune-modulating blood-derived product, may be beneficial for managing neuropathic pain. Here, we review previous studies to investigate the effectiveness of IVIG in managing neuropathic pain due to various neurological disorders. The electronic databases PubMed, Scopus, Embase, and the Cochrane Library were searched for studies published up to February 2020. Two reviewers independently assessed the studies using strict inclusion criteria. Ten studies were included and qualitatively analyzed. The review included patients with pain due to complex regional pain syndrome (CRPS), diabetic polyneuropathy, and others, such as postherpetic neuralgia and trigeminal neuralgia. We found that IVIG may be one of the beneficial options for managing neuropathic pain from various neurological disorders. In the four articles reviewed, no major adverse effects were reported, and the trend was toward a positive pain-reducing effect in eight articles. However, to confirm the benefits of IVIG on reducing neuropathic pain, more high-quality studies are required.
Learn More >Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain condition that significantly affects patient quality of life. We investigated whether receiving a formal medical diagnosis of IC/BPS was perceived by patients to improve symptoms and disease-specific quality of life.
Learn More >Human immunodeficiency virus type-1 (HIV-1) and opiates cause long-term inflammatory insult to the central nervous system (CNS) and worsen disease progression and HIV-1-related neuropathology. The combination of these proinflammatory factors reflects a devastating problem as opioids have high abuse liability and continue to be prescribed for certain patients experiencing HIV-1-related pain.
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