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Papers: 16 Feb 2019 - 22 Feb 2019

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A new painkiller nanomedicine to bypass the blood-brain barrier and the use of morphine.

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Structures of human Na1.7 channel in complex with auxiliary subunits and animal toxins.

Voltage-gated sodium channel Na1.7 represents a promising target for pain relief. Here we report the cryo-EM structures of the human Na1.7-β1-β2 complex bound to two combinations of pore blockers and gating modifier toxins (GMTs), tetrodotoxin with Protoxin-II and saxitoxin with Huwentoxin-IV, both determined at overall resolutions of 3.2 Å. The two structures are nearly identical except for minor shifts of VSD, whose S3-S4 linker accommodates the two GMTs in a similar manner. One additional Protoxin-II sits on top of the S3-S4 linker in VSD The structures may represent an inactivated state with all four VSDs "up" and the intracellular gate closed. The structures illuminate the path toward mechanistic understanding of the function and disease of Na1.7 and establish the foundation for structure-aided development of analgesics.

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Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs.

We endeavored to identify objective blood biomarkers for pain, a subjective sensation with a biological basis, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We studied psychiatric patients, a high risk group for co-morbid pain disorders and increased perception of pain. For discovery, we used a powerful within-subject longitudinal design. We were successful in identifying blood gene expression biomarkers that were predictive of pain state, and of future emergency department (ED) visits for pain, more so when personalized by gender and diagnosis. MFAP3, which had no prior evidence in the literature for involvement in pain, had the most robust empirical evidence from our discovery and validation steps, and was a strong predictor for pain in the independent cohorts, particularly in females and males with PTSD. Other biomarkers with best overall convergent functional evidence for involvement in pain were GNG7, CNTN1, LY9, CCDC144B, and GBP1. Some of the individual biomarkers identified are targets of existing drugs. Moreover, the biomarker gene expression signatures were used for bioinformatic drug repurposing analyses, yielding leads for possible new drug candidates such as SC-560 (an NSAID), and amoxapine (an antidepressant), as well as natural compounds such as pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), and apigenin (a plant flavonoid). Our work may help mitigate the diagnostic and treatment dilemmas that have contributed to the current opioid epidemic.

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Complicated decisions on new migraine-prevention therapies.

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A Cross-Species Analysis Reveals a General Role for Piezo2 in Mechanosensory Specialization of Trigeminal Ganglia from Tactile Specialist Birds.

A major challenge in biology is to link cellular and molecular variations with behavioral phenotypes. Here, we studied somatosensory neurons from a panel of bird species from the family Anatidae, known for their tactile-based foraging behavior. We found that tactile specialists exhibit a proportional expansion of neuronal mechanoreceptors in trigeminal ganglia. The expansion of mechanoreceptors occurs via neurons with intermediately and slowly inactivating mechanocurrent. Such neurons contain the mechanically gated Piezo2 ion channel whose expression positively correlates with the expression of factors responsible for the development and function of mechanoreceptors. Conversely, Piezo2 expression negatively correlates with expression of molecules mediating the detection of temperature and pain, suggesting that the expansion of Piezo2-containing mechanoreceptors with prolonged mechanocurrent occurs at the expense of thermoreceptors and nociceptors. Our study suggests that the trade-off between neuronal subtypes is a general mechanism of tactile specialization at the level of somatosensory system.

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Synaptic Organization of VGLUT3 Expressing Low-Threshold Mechanosensitive C Fiber Terminals in the Rodent Spinal Cord.

Low-threshold mechanosensitive C fibers (C-LTMRs) that express the vesicular glutamate transporter VGLUT3 are thought to signal affective touch, and may also play a role in mechanical allodynia. However, the nature of the central termination of C-LTMRs in the dorsal horn remains largely unexplored. Here, we used light and electron microscopy in combination with VGLUT3 immunolabeling as a marker of C-LTMR terminations to investigate this issue. VGLUT3 C-LTMRs formed central terminals of Type II glomeruli in the inner part of lamina II of the dorsal horn, often establishing multiple asymmetric synapses with postsynaptic dendrites but also participating in synaptic configurations with presynaptic axons and dendrites. Unexpectedly, essentially all VGLUT3 C-LTMR terminals showed substantial VGLUT1 expression in the rat, whereas such terminals in mice lacked VGLUT1. Most VGLUT3 C-LTMR terminals exhibited weak-to-moderate VGLUT2 expression. Further, C-LTMR terminals formed numerous synapses with excitatory protein kinase Cγ (PKCγ) interneurons and inhibitory parvalbumin neurons, whereas synapses with calretinin neurons were scarce. C-LTMR terminals rarely if ever established synapses with neurokinin 1 receptor (NK1R)-possessing dendrites traversing lamina II. Thus, VGLUT3 C-LTMR terminals appear to largely correspond to neurofilament-lacking central terminals of Type II glomeruli in inner lamina II and can thus be identified at the ultrastructural level by morphological criteria. The participation of C-LTMR terminals in Type II glomeruli involving diverse populations of interneuron indicates highly complex modes of integration of C-LTMR mediated signaling in the dorsal horn. Furthermore, differences in VGLUT1 expression indicate distinct species differences in synaptic physiology of C-LTMR terminals.

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Assessment of the FDA Risk Evaluation and Mitigation Strategy for Transmucosal Immediate-Release Fentanyl Products.

Transmucosal immediate-release fentanyls (TIRFs), indicated solely for breakthrough cancer pain in opioid-tolerant patients, are subject to a US Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) to prevent them from being prescribed inappropriately.

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The impact of anxiety on chronic musculoskeletal pain and the role of astrocyte activation.

Anxiety and depression are associated with increased pain responses in chronic pain states. The extent to which anxiety drives chronic pain, or vice versa, remains an important question that has implications for analgesic treatment strategies. Here, the effect of existing anxiety on future osteoarthritis (OA) pain was investigated, and potential mechanisms were studied in an animal model. Pressure pain detection thresholds, anxiety, and depression were assessed in people with (n = 130) or without (n = 100) painful knee OA. Separately, knee pain and anxiety scores were also measured twice over 12 months in 4730 individuals recruited from the general population. A preclinical investigation of a model of OA pain in normo-anxiety Sprague-Dawley (SD) and high-anxiety Wistar Kyoto (WKY) rats assessed underlying neurobiological mechanisms. Higher anxiety, independently from depression, was associated with significantly lower pressure pain detection thresholds at sites local to (P < 0.01) and distant from (P < 0.05) the painful knee in patients with OA. Separately, high anxiety scores predicted increased risk of knee pain onset in 3274 originally pain-free people over the 1-year period (odds ratio = 1.71; 95% confidence interval = 1.25-2.34, P < 0.00083). Similarly, WKY rats developed significantly lower ipsilateral and contralateral hind paw withdrawal thresholds in the monosodium iodoacetate model of OA pain, compared with SD rats (P = 0.0005). Linear regressions revealed that baseline anxiety-like behaviour was predictive of lowered paw withdrawal thresholds in WKY rats, mirroring the human data. This augmented pain phenotype was significantly associated with increased glial fibrillary acidic protein immunofluorescence in pain-associated brain regions, identifying supraspinal astrocyte activation as a significant mechanism underlying anxiety-augmented pain behaviour.

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Transcutaneous electrical nerve stimulation (TENS) for chronic pain – an overview of Cochrane Reviews.

Chronic pain, considered to be pain lasting more than three months, is a common and often difficult to treat condition that can significantly impact upon function and quality of life. Treatment typically includes pharmacological and non-pharmacological approaches. Transcutaneous electrical nerve stimulation (TENS) is an adjunct non-pharmacological treatment commonly recommended by clinicians and often used by people with pain.

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Molecular basis for pore blockade of human Na channel Na1.2 by the μ-conotoxin KIIIA.

The voltage-gated sodium channel Na1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo-electron microscopy structure of human Na1.2 bound to a peptidic pore blocker, the μ-conotoxin KIIIA, in the presence of an auxiliary subunit β2 to an overall resolution of 3.0 Å. The immunoglobulin (Ig) domain of β2 interacts with the shoulder of the pore domain through a disulfide bond. The 16-residue KIIIA interacts with the extracellular segments in repeats I to III, placing Lys7 at the entrance to the selectivity filter. Many interacting residues are specific to Na1.2, revealing a molecular basis for KIIIA specificity. The structure establishes a framework for rational design of subtype-specific blockers for Na channels.

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Sensory neuron-derived Nav1.7 contributes to dorsal horn neuron excitability.

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Role of Intraganglionic Transmission in the Trigeminovascular Pathway.

Migraine is triggered by poor air quality and odors through unknown mechanisms. Activation of the trigeminovascular pathway by environmental irritants may occur via activation of TRPA1 receptors on nasal trigeminal neurons, but how that results in peripheral and central sensitization is unclear. The anatomy of the trigeminal ganglion suggests that noxious nasal stimuli are not being transduced to the meninges by axon reflex but likely through intraganglionic transmission. Consistent with this concept, we injected CGRP, ATP or glutamate receptor antagonists or a gap junction channel blocker directly and exclusively into the trigeminal ganglion and blocked meningeal blood flow changes in response to acute nasal TRP agonists. Previously, we observed chronic sensitization of the trigeminovascular pathway after acrolein exposure, a known TRPA1 receptor agonist. To explore the mechanism of this sensitization, we utilized laser dissection microscopy to separately harvest nasal and meningeal trigeminal neuron populations in the absence or presence of acrolein exposure. mRNA levels of neurotransmitters important in migraine were then determined by RT-PCR. TRPA1 message levels were significantly increased in meningeal cell populations following acrolein exposure compared to room air exposure. This was specific to TRPA1 message in meningeal cell populations as changes were not observed in either nasal trigeminal cell populations or dorsal root ganglion populations. Taken together, this data suggests an important role for intraganglionic transmission in acute activation of the trigeminovascular pathway. It also supports a role for upregulation of TRPA1 receptors in peripheral sensitization and a possible mechanism for chronification of migraine after environmental irritant exposure.

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Nitroglycerin as a comparative experimental model of migraine pain: from animal to human and back.

Migraine is a disease for which there is still no defined pathophysiological etiology and few translational models. The organic nitrate nitroglycerin has been in use as an experimental model of migraine in both human and animal studies for several years. The drug produces a number of effects within the head, that includes blood vessels, nerves and brain areas that may produce a response similar to a migraine attack in predisposed subjects. A better understanding of the nature of these changes and how well they parallel a true migraine attack would allow for a translational model to better understand some of the mechanisms involved in the generation of a migraine attack. The present review summarizes the known body of knowledge of nitroglycerin effects evaluated in humans and animals as it relates to potential mechanisms associated with migraine headaches.

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Systematic review and neural network analysis to define predictive variables in implantable motor cortex stimulation to treat chronic intractable pain.

Implantable Motor Cortex Stimulation (iMCS) has been performed for over 25 years to treat various intractable pain syndromes. Its effectiveness shows to be highly variable and although various studies revealed predictive variables, none of these were found repeatedly. This study uses neural network analysis (NNA) to identify predictive factors of iMCS treatment of intractable pain. A systematic review provided a database of patient data on an individual level of patients who underwent iMCS to treat refractory pain between 1991 and 2017. Responders were defined as patients with a pain relief >40% as measured by numerical rating scale (NRS) score. NNA was carried out to predict outcome of iMCS and to identify predictive factors that impacted the outcome of iMCS. The outcome prediction value of the NNA was expressed as mean accuracy, sensitivity and specificity. The NNA furthermore provided the mean weight of predictive variables, which shows the impact of the predictive variable on the prediction. The mean weight was converted into the mean relative influence (M), a value that varies between 0-100%. A total of 358 patients were included (202 males (56.4%); mean age: 54.2 ±13.3), 201 of which were responders to iMCS. NNA had a mean accuracy of 66.3% and a sensitivity and specificity of 69.8% and 69.4%, respectively. NNA further identified six predictive variables that had a relatively high M: 1) the sex of the patients (M=19.7%); 2) the origin of the lesion (M=15.1%); 3) the preoperative NRS score (M= 9.2%); 4) preoperative use of rTMS (M=7.3%); 5) preoperative intake of opioids (M=7.1%) and; 6) the follow-up period (M= 13.1%). The results from the present study show that these six predictive variables influence the outcome of iMCS and that based on these variables, a fair prediction model can be built to predict outcome after iMCS surgery. PERSPECTIVE: The presented neural network analysis (NNA) analyzed the functioning of computational models and modeled non-linear statistical data. Based on this NNA, six predictive variables were identified which are suggested to be of importance in the improvement of future implantable motor cortex stimulation (iMCS) to treat chronic pain.

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Somatic symptoms in pediatric patients with chronic pain: Proposed clinical reference points for the Children’s Somatic Symptoms Inventory (formerly Children’s Somatization Inventory).

Among youth with chroic pain, elevated somatic symptoms across multiple body systems have been associated with greater emotional distress and functional disability and could represent poor adaptation to pain. The Children's Somatic Symptoms Inventory (formerly the Children's Somatization Inventory) is commonly used to assess somatic symptoms in children. However, no studies have evaluated the clinical utility of the measure in the assessment of pediatric patients with chronic pain. This study evaluated the factor structure and clinical relevance of the 24-item Children's Somatic Symptoms Inventory (CSSI-24) in youth (n = 1150) with mixed chronic pain complaints presenting to a tertiary pain clinic. CSSI-24 total scores were equal or superior to factor scores as indicators of patients' clinical characteristics (functional disability, pain catastrophizing, fear of pain, anxiety and depressive symptoms) and parental catastrophizing and protective responses. Tertile-derived clinical reference points for the CSSI-24 total score (<18: low, 19 – 31: moderate, ≥ 32: high) significantly differed on measures of clinical characteristics and parent factors. Controlling for age, sex, pain intensity and primary pain complaint, the high somatic symptoms group exhibited significantly greater health care utilization compared to the moderate and low groups. Assessment of somatic symptoms in pediatric patients with chronic pain may provide useful information regarding patients' psychosocial risk and tendency to access health services. Perspective: Clinical reference points based on the CSSI-24 total scores meaningfully differentiated youth with chronic pain on measures of emotional distress, functioning, parent catastrophizing and protective responses, and health care utilization. Assessing somatic symptoms could provide useful information regarding a pediatric patient's psychosocial risk, tendency to access health services, and need for enhanced care coordination.

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Neural network-based alterations during repeated heat pain stimulation in major depression.

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Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain.

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A Cost-Effectiveness Analysis of Vaccination for Prevention of Herpes Zoster and Related Complications: Input for National Recommendations.

The U.S. Advisory Committee on Immunization Practices recently developed recommendations for use of a new recombinant zoster vaccine (RZV).

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Commentary: Flipping the switch on chronic pain.

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Central sensitization increases the pupil dilation elicited by mechanical pinprick stimulation.

High frequency electrical stimulation (HFS) of skin nociceptors triggers central sensitization (CS), manifested as increased pinprick sensitivity of the skin surrounding the site of HFS. Our aim was to assess the effect of CS on pinprick-evoked pupil dilation responses (PDRs) and pinprick-evoked brain potentials (PEPs). We hypothesized that the increase in the positive wave of PEPs following HFS would result from an enhanced pinprick-evoked phasic response of the locus coeruleus-noradrenergic system (LC-NS), indicated by enhanced PDRs. In fourteen healthy volunteers, 64 and 96 mN pinprick stimuli were delivered to the left and right forearms, before and twenty minutes after applying HFS to one of the two forearms. Both PEPs and pinprick-evoked PDRs were recorded. After HFS, pinprick stimuli were perceived as more intense at the HFS treated arm compared to baseline and control site, and this increase was similar for both stimulation intensities. Importantly, the pinprick-evoked PDR was also increased and the increase was stronger for 64 as compared to 96 mN stimulation. This is in line with our previous results showing a stronger increase of the PEP positivity at 64 vs. 96 mN stimulation and suggests that the increase in PEP positivity observed in previous studies could relate, at least in part, to enhance LC-NS activity. However, there was no increase of the PEP positivity in the present study, indicating that enhanced LC-NS activity is not the only determinant of the HFS-induced enhancement of PEPs. Altogether, our results indicate that PDRs are more sensitive for detecting CS than PEPs.

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Sex differences in gene regulation in the dorsal root ganglion after nerve injury.

Pain is a subjective experience derived from complex interactions among biological, environmental, and psychosocial pathways. Sex differences in pain sensitivity and chronic pain prevalence are well established. However, the molecular basis underlying these sex dimorphisms are poorly understood particularly with regard to the role of the peripheral nervous system. Here we sought to identify shared and distinct gene networks functioning in the peripheral nervous systems that may contribute to sex differences of pain in rats after nerve injury.

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CRPS: what’s in a name? Taxonomy, epidemiology, neurologic, immune and autoimmune considerations.

This account of the condition now termed complex regional pain syndrome (CRPS) spans approximately 462 years since a description embodying similar clinical features was described by Ambroise Paré in 1557. While reviewing its historical origins, the text describes why it became necessary to change the taxonomies of two clinical syndromes with similar pathophysiologies to one which acknowledges this aspect but does not introduce any mechanistic overtones. Discussed at length is the role of the sympathetic component of the autonomic nervous system (ANS) and why its dysfunction has both directly and indirectly influenced our understanding of the inflammatory aspects of CRPS. As the following article will show, our knowledge has expanded in an exponential fashion to include musculoskeletal, immune, autoimmune, central and peripheral nervous system and ANS dysfunction, all of which increase the complexity of its clinical management. A burgeoning literature is beginning to shed light on the mechanistic aspects of these syndromes and the increasing evidence of a genetic influence on such factors as autoimmunity, and its importance is also discussed at length. An important aspect that has been missing from the diagnostic criteria is a measure of disease severity. The recent validation of a CRPS Severity Score is also included.

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Persistent autonomic dysfunction and bladder sensitivity in primary dysmenorrhea.

Menstrual pain, also known as dysmenorrhea, is a leading risk factor for bladder pain syndrome (BPS). A better understanding of the mechanisms that predispose dysmenorrheic women to BPS is needed to develop prophylactic strategies. Abnormal autonomic regulation, a key factor implicated in BPS and chronic pain, has not been adequately characterized in women with dysmenorrhea. Thus, we examined heart rate variability (HRV) in healthy (n = 34), dysmenorrheic (n = 103), and BPS participants (n = 23) in their luteal phase across a bladder-filling task. Both dysmenorrheic and BPS participants reported increased bladder pain sensitivity when compared to controls (p's < 0.001). Similarly, dysmenorrheic and BPS participants had increased heart rate (p's < 0.01), increased diastolic blood pressure (p's < 0.01), and reduced HRV (p's < 0.05) when compared to controls. Dysmenorrheic participants also exhibited little change in heart rate between maximum bladder capacity and after micturition when compared to controls (p = 0.013). Our findings demonstrate menstrual pain's association with abnormal autonomic activity and bladder sensitivity, even two weeks after menses. Our findings of autonomic dysfunction in both early episodic and chronic visceral pain states points to an urgent need to elucidate the development of such imbalance, perhaps beginning in adolescence.

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P2Y12 regulates microglia activation and excitatory synaptic transmission in spinal lamina II neurons during neuropathic pain in rodents.

Peripheral nerve injury causes neuropathic pain and microglia activation. P2Y12 receptors on microglia are thought to be a key player in the surveillance of the local environment, but whether or how these receptors are engaged in the cross-talk between microglia and neurons of the dorsal horn remain ambiguous. Using a rodent model of nerve injury-induced pain, we investigated the roles of P2Y12 in microglia activation, excitatory synaptic transmission, and nociceptive allodynia. We found that spinal nerve ligation (SNL) significantly increased the level of P2Y12 receptors specifically in the microglia of the ipsilateral dorsal horn. Injections of P2Y12 antagonists (MRS2395 or clopidogrel) attenuated microglia activation and increased the paw withdrawal latency in response to thermal stimuli on the ipsilateral side without affecting the basal threshold on the contralateral side. These effects on pain behaviors were replicated in P2Y12 knockout mice. Patch-clamp recordings further revealed that partial sciatic nerve ligation (PSNL)-induced excessive miniature excitatory postsynaptic currents (mEPSCs) were significantly attenuated in P2Y12 knockout mice. Moreover, we found that SNL activates the GTP-RhoA/ROCK2 signaling pathway and elevates the level of phosphorylated p38 mitogen-activated protein kinase (MAPK), which was inhibited by the P2Y12 antagonist. The phosphorylation of p38 MAPK was inhibited by a ROCK inhibitor, but not vice versa, suggesting that p38 MAPK is downstream of ROCK activation. Our findings suggest that nerve injury engages the P2Y12 receptor-dependent GTP-RhoA/ROCK2 signaling pathway to upregulate excitatory synaptic transmission in the dorsal horn. This cross-talk ultimately participates in the manifestation of nociceptive allodynia, implicating P2Y12 receptor as a potential target for alleviating neuropathic pain.

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Employing pain and mindfulness to understand consciousness: a symbiotic relationship.

Consciousness, defined here as the quality of awareness of self and the corresponding sensory environment, is considered to be one of most enigmatic and contentious areas of scholarly dissection and investigation. The subjective experience of pain is constructed and modulated by a myriad of sensory, cognitive and affective dimensions. Thus, the study of pain can provide many inroads to a concept like consciousness that the traditional sense modalities do not. Mindfulness defined here as non-reactive awareness of the present moment, can uniquely control and/or modulate particular substrates of conscious experience. Thus, in combination with brain imaging methodologies, we propose that the interactions between pain and mindfulness could serve as a more comprehensive platform to disentangle the biological and psychological substrates of conscious experience. The present review provides a brief synopsis on how combining the study of pain and mindfulness can inform the study of consciousness, delineates the multiple, unique brain mechanisms supporting mindfulness-based pain relief, and describes how mindfulness uniquely improves the affective dimension of pain, an important consideration for the treatment of chronic pain.

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Age-related differences in patient-reported and objective measures of chemotherapy-induced peripheral neuropathy among cancer survivors.

While older adults with cancer are more likely to develop chemotherapy-induced peripheral neuropathy (CIPN), the study aimed to determine if patient-reported and objective measures of CIPN differ by age among cancer survivors.

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Identification of mineralocorticoid and glucocorticoid receptors on peripheral nociceptors: translation of experimental findings from animal to human biology.

Evidence is accumulating that activation of mineralocorticoid (MR) and glucocorticoid (GR) receptors on peripheral sensory neurons modulates pain sensation. While the expression and exact anatomical localization of MR and GR in the various subpopulations of peripheral sensory neurons has been shown in animals, it is still unknown for the human skin. Therefore, we aimed to identify MR and GR mRNA and protein as well as the exact subpopulations of sensory neurons in human versus rat skin. Tissue samples from rat and human skin were subjected to RT-PCR, Western blot and double immunofluorescence confocal analysis of MR and GR with the neuronal markers calcitonin gene-related peptide (CGRP), neurofilament 200 (NF200) and tyrosine hydroxylase (TH). Using RT-PCR we were able to isolate MR as well as GR specific transcripts from human skin. Consistently, Western blot analysis identified MR- as well as GR- specific protein bands at the expected molecular weights of 110 and 87 kD, respectively. Double immunofluorescence confocal microscopy of human skin revealed that MR predominantly colocalized with calcitonin-gene-related peptide (CGRP)-immunoreactive (IR) nociceptive neurons – similar to rat skin – underscoring a pivotal role for MR in the modulation of pain. The majority of GR-immmunoreactivity was localized in peripheral peptidergic CGRP-IR sensory nerve fibers, but in addition on TH-IR sympathetic postganglionic, and NF200-IR myelinated mechanoreceptive nerve fibers, both within human and rat skin. Moreover, GR but not MR were localized in keratinocytes of the epidermal layer of human and rat skin. Overall, our results indicate considerable overlap in sensory neuron expression of MR and GR in humans and rats endorsing a common systems approach in mammals that may modulate the transmission of sensory information by MR and GR activation.

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Mechanosensitive meningeal nociception via Piezo channels: Implications for pulsatile pain in migraine?

Recent discovery of mechanosensitive Piezo receptors in trigeminal ganglia suggested the novel molecular candidate for generation of migraine pain. However, the contribution of Piezo channels in migraine pathology was not tested yet. Therefore, in this study, we explored a potential involvement of Piezo channels in peripheral trigeminal nociception implicated in generation of migraine pain.

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Dynamic Role of the G Protein in Stabilizing the Active State of the Adenosine A Receptor.

Agonist binding in the extracellular region of the G protein-coupled adenosine A2A receptor increases its affinity to the G proteins in the intracellular region, and vice versa. The structural basis for this effect is not evident from the crystal structures of AR in various conformational states since it stems from the receptor dynamics. Using atomistic molecular dynamics simulations on four different conformational states of the adenosine A receptor, we observed that the agonists show decreased ligand mobility, lower entropy of the extracellular loops in the active-intermediate state compared with the inactive state. In contrast, the entropy of the intracellular region increases to prime the receptor for coupling the G protein. Coupling of the G protein to AR shrinks the agonist binding site, making tighter receptor agonist contacts with an increase in the strength of allosteric communication compared with the active-intermediate state. These insights provide a strong basis for structure-based ligand design studies.

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Role of regional anesthesia and analgesia in the opioid epidemic.

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The contributions of mTOR activation-mediated upregulation of synapsin II and neurite outgrowth to hyperalgesia in STZ-induced diabetic rats.

Painful diabetic neuropathy (PDN) is among the common complications in diabetes mellitus (DM), with its underlying mechanisms largely unknown. Synapsin II is primarily expressed in the spinal dorsal horn, and its upregulation mediates a superfluous release of glutamate and a deficiency of GABAergic interneuron synaptic transmission, which is directly implicated in the facilitation of pain signals in the hyperalgesic nociceptive response. Recently, synapsin II has been revealed to be associated with the modulation of neurite outgrowth, whereas the process of this neuronal structural neuroplasticity following neuronal hyperexcitability still remains unclear. In this study, we found that under conditions of elevated glucose, TNF-α induced the activation of mTOR, mediating the upregulation of synapsin II and neurite outgrowth in dorsal horn neurons. In vivo, we demonstrated that mTOR and synapsin II were upregulated and co-expressed in the spinal dorsal horn neurons in rats with streptozotocin (STZ)-induced diabetes. Furthermore, the intrathecal administration of the mTOR inhibitor rapamycin or synapsin II shRNA significantly diminished the expression of synapsin II, effectively mitigating hyperalgesia in PDN rats. We are the first to discover that in STZ-induced diabetic rats the activation of mTOR mediates the upregulation of synapsin II and neurite outgrowth, both contributing to hyperalgesia. These findings may benefit the clinical therapy of PDN by provision of a novel target.

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Cross-Sectional Evaluation of the Psychometric Properties of the Headache-Specific Locus of Control Scale in People With Migraine.

This study aims to investigate the psychometric properties (component structure, reliability, and construct validity) of the Headache-Specific Locus of Control scale in several clinical migraine populations.

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Clinical Course and Impact of Complex Regional Pain Syndrome Confined to the Knee.

Although complex regional pain syndrome (CRPS) of the knee is comparable to CRPS of the ankle/foot at time of diagnosis, no reports are available concerning the course of knee CRPS. Therefore, this study investigated the clinical course in terms of the symptoms and signs, health-related quality of life (HR-QoL), and work status of patients diagnosed with CRPS of the knee.

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PI3K/Akt Signaling Pathway may be involved in MCP-1-induced P2X4R Expression in cultured microglia and Cancer-induced Bone Pain Rats.

P2X4 receptor (P2X4R), a subtype of P2 purinergic receptors, is an ATP-gated receptor through which activity of spinal microglia instigates pain hypersensitivity in various pain conditions. Accumulating evidence indicates that monocyte chemoattractant protein-1 (MCP-1) plays an important role in chronic pain facilitation, and it could stimulate microglia activation and involve in regulating P2X4R expression. However, the mechanism of MCP-1 in regulating the expression of P2X4R in microglia is poorly understood, and whether MCP-1 can aggravate pain via up-regulating spinal P2X4R expression in Cancer-induced Bone Pain (CIBP) remains unclear. In this study, we observed that Iba-1 and P2X4R expression is increased in microglia treated with MCP-1, and blockade with a selective CCR2 antagonist RS-504393 suppressed microglia activation and reduced P2X4R expression in cultured microglia. In response to MCP-1, the expression level of p-Akt was also increased and RS-504393 inhibited the increase. Besides, PI3K inhibitor LY 294002 could attenuate MCP-1-induced P2X4R expression in cultured microglia. MCP-1 was found to be associated with P2X4R expression and mechanical allodynia induced by CIBP in vivo since the expression of MCP-1 was increased in CIBP and RS-504393 alleviated the P2X4R expression and mechanical allodynia in CIBP. Moreover, RS-504393 also reduced the increase of p-Akt induced by CIBP. Inhibition of PI3K/Akt pathway may partly reduce MCP-1/CCR2-induced expression of P2X4R and mechanical allodynia in CIBP rats.

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A narrative review of data collection and analysis guidelines for comparative effectiveness research in chronic pain using patient-reported outcomes and electronic health records.

Chronic pain is a widespread and complex set of conditions that are often difficult and expensive to treat. Comparative effectiveness research (CER) is an evolving research method that is useful in determining which treatments are most effective for medical conditions such as chronic pain. An underutilized mechanism for conducting CER in pain medicine involves combining patient-reported outcomes (PROs) with electronic health records (EHRs). Patient-reported pain and mental and physical health outcomes are increasingly collected during clinic visits, and these data can be linked to EHR data that are relevant to the treatment of a patient's pain, such as diagnoses, medications ordered, and medical comorbidities. When aggregated, this information forms a data repository that can be used for high-quality CER. This review provides a blueprint for conducting CER using PROs combined with EHRs. As an example, the University of Pittsburgh's patient outcomes repository for treatment is described. This system includes PROs collected via the Collaborative Health Outcomes Information Registry software and cross-linked data from the University of Pittsburgh Medical Center EHR. The requirements, best practice guidelines, statistical considerations, and caveats for performing CER with this type of data repository are also discussed.

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Effects of long non-coding RNA uc.48+ on pain transmission in trigeminal neuralgia.

Trigeminal neuralgia (TN) is the most common neuropathic pain in the facial area, for which the effective therapy is unavailable. Long non-coding RNA (lncRNA) such as lncRNA uc.48+ is involved in diabetic neuropathic pain and may affect purinergic signaling in ganglia of diabetic rats. In this research, chronic constriction injury of the infraorbital nerve (CCI-ION) was applied to establish a rat model of TN. Five days after local injection of siRNA targeting the lncRNA uc.48+ in trigeminal ganglia (TGs), the upregulated uc.48+ expression and the reduced mechanical withdrawal threshold (MWT) in the TN rats were significantly reversed. The expression of P2X receptor in TGs was increased in the TN group compared with the sham group, but uc.48+ siRNA treatment mitigated this effect. The phosphorylation of ERK1/2 in TGs of TN rats was significantly enhanced compared with the sham group, while uc.48+ siRNA treatment reversed this change. In addition, injection of the lncRNA uc.48+ overexpression plasmid in TGs of control rats significantly reduced the MWT but elevated the expression of P2X in TGs; the phosphorylation of ERK1/2 in TGs in these uc.48+-overexpressed rats was significantly higher, similar to the observations in rats of TN model. The interaction between uc.48+ and the P2X receptor was detected by RNA binding protein immunoprecipitation (RIP), indicating that P2X receptor could specifically bind to uc.48 + . In summary, knockdown of lncRNA uc.48+ by siRNA could inhibit transduction of TN signals, whereas uc.48+ overexpression promoted TN signal transduction. LncRNA uc.48+ may interact with P2X receptor to upregulate expression of P2X receptor and furthermore enhance the phosphorylation of ERK1/2 in TGs, thereby participating in pain transmission in TN.

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Parkinson’s disease and pain: Modulation of nociceptive circuitry in a rat model of nigrostriatal lesion.

Parkinson's disease (PD) is a neurodegenerative disorder that causes progressive dysfunction of dopaminergic and non-dopaminergic neurons, generating motor and nonmotor signs and symptoms. Pain is reported as the most bothersome nonmotor symptom in PD; however, pain remains overlooked and poorly understood. In this study, we evaluated the nociceptive behavior and the descending analgesia circuitry in a rat model of PD. Three independent experiments were performed to investigate: i) thermal nociceptive behavior; ii) mechanical nociceptive behavior and dopaminergic repositioning; and iii) modulation of the pain control circuitry. The rat model of PD, induced by unilateral striatal 6-hydroxydopamine (6-OHDA), did not interfere with thermal nociceptive responses; however, the mechanical nociceptive threshold was decreased bilaterally compared to that of naive or striatal saline-injected rats. This response was reversed by apomorphine or levodopa treatment. Striatal 6-OHDA induced motor impairments and reduced dopaminergic neuron immunolabeling as well as the pattern of neuronal activation (c-Fos) in the substantia nigra ipsilateral (IPL) to the lesion. In the midbrain periaqueductal gray (PAG), 6-OHDA-induced lesion increased IPL and decreased contralateral PAG GABAergic labeling compared to control. In the dorsal horn of the spinal cord, lesioned rats showed bilateral inhibition of enkephalin and μ-opioid receptor labeling. Taken together, we demonstrated that the unilateral 6-OHDA-induced PD model induces bilateral mechanical hypernociception, which is reversed by dopamine restoration, changes in the PAG circuitry, and inhibition of spinal opioidergic regulation, probably due to impaired descending analgesic control. A better understanding of pain mechanisms in PD patients is critical for developing better therapeutic strategies to improve their quality of life.

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N/OFQ-NOP System in Peripheral and Central Immunomodulation.

Classical opioids (μ: mu, MOP; δ: delta, DOP and κ: kappa, KOP) variably affect immune function; they are immune depressants and there is good clinical evidence in the periphery. In addition, there is evidence for a central role in the control of a number of neuropathologies, e.g., neuropathic pain. Nociceptin/Orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide receptor, NOP; peripheral and central activation can modulate immune function. In the periphery, NOP activation generally depresses immune function, but unlike classical opioids this is in part driven by NOP located on circulating immune cells. Peripheral activation has important implications in pathologies like asthma and sepsis. NOP is expressed on central neurones and glia where activation can modulate glial function. Microglia, as resident central 'macrophages', increase/infiltrate in pain and following trauma; these changes can be reduced by N/OFQ. Moreover, the interaction with other glial cell types such as the ubiquitous astrocytes and their known cross talk with microglia open a wealth of possibilities for central immunomodulation. At the whole animal level, clinical ligands with wide central and peripheral distribution have the potential to modulate immune function, and defining the precise nature of that interaction is important in mitigating or even harnessing the adverse effect profile of these important drugs.

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Psychological and work-related outcomes after inpatient multidisciplinary rehabilitation of chronic low back pain: a prospective randomized controlled trial.

This study investigated the long-term effects (12 months post-rehabilitation) of a standard inpatient multidisciplinary rehabilitation program for patients with chronic low back pain (CLBP), in which a control group (CG) received pain competence training and an intervention group (IG) received combined pain competence and depression prevention training.

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Acute postoperative pain is an independent predictor of chronic postsurgical pain following total knee arthroplasty at 6 months: a prospective cohort study.

Approximately 15% of patients report persistent knee pain despite surgical success following total knee arthroplasty (TKA). The purpose of this study was to determine the association of acute-postsurgical pain (APSP) with chronic postsurgical pain (CPSP) 6 months after TKA controlling for patient, surgical and psychological confounding factors.

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Descriptors of Vulvodynia: A Multisocietal Definition Consensus (International Society for the Study of Vulvovaginal Disease, the International Society for the Study of Women Sexual Health, and the International Pelvic Pain Society).

Three scientific societies, the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS) developed the "2015 ISSVD, ISSWSH, and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia" (referred to as the "2015 consensus terminology").The terminology included 11 descriptors of vulvodynia. However, the definitions of the descriptors were not included in the 2015 consensus terminology publications. The objective of this article was to provide these definitions.

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American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Perioperative Management of Patients on Preoperative Opioid Therapy.

Enhanced recovery pathways have quickly become part of the standard of care for patients undergoing elective surgery, especially in North America and Europe. One of the central tenets of this multidisciplinary approach is the use of multimodal analgesia with opioid-sparing and even opioid-free anesthesia and analgesia. However, the current state is a historically high use of opioids for both appropriate and inappropriate reasons, and patients with chronic opioid use before their surgery represent a common, often difficult-to-manage population for the enhanced recovery providers and health care team at large. Furthermore, limited evidence and few proven successful protocols exist to guide providers caring for these at-risk patients throughout their elective surgical experience. Therefore, the fourth Perioperative Quality Initiative brought together an international team of multidisciplinary experts, including anesthesiologists, nurse anesthetists, surgeons, pain specialists, neurologists, nurses, and other experts with the objective of providing consensus recommendations. Specifically, the goal of this consensus document is to minimize opioid-related complications by providing expert-based consensus recommendations that reflect the strength of the medical evidence regarding: (1) the definition, categorization, and risk stratification of patients receiving opioids before surgery; (2) optimal perioperative treatment strategies for patients receiving preoperative opioids; and (3) optimal discharge and continuity of care management practices for patients receiving opioids preoperatively. The overarching theme of this document is to provide health care providers with guidance to reduce potentially avoidable opioid-related complications including opioid dependence (both physical and behavioral), disability, and death. Enhanced recovery programs attempt to incorporate best practices into pathways of care. By presenting the available evidence for perioperative management of patients on opioids, this consensus panel hopes to encourage further development of pathways specific to this high-risk group to mitigate the often unintentional iatrogenic and untoward effects of opioids and to improve perioperative outcomes.

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Volume alterations of brainstem subregions in migraine with aura.

The brainstem plays a significant role in migraine pathogenesis, but a relationship between volume alterations of brainstem subregions and migraine aura characteristics has not been sufficiently investigated. The aim of this study is to compare the volume of the brainstem, and its subregions, between patients with a migraine with aura (MwA) and healthy controls (HC), and also to correlate characteristics of MwA and the volume of the brainstem subregions.

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A Phase 3, Randomized, Placebo-Controlled Evaluation of the Safety of Intravenous Meloxicam Following Major Surgery.

An intravenous (IV) formulation of meloxicam is being studied for moderate to severe pain management. This phase 3, randomized, multicenter, double-blind, placebo-controlled trial evaluated the safety of once-daily meloxicam IV 30 mg in subjects following major elective surgery. Eligible subjects were randomized (3:1) to receive meloxicam IV 30 mg or placebo administered once daily. Safety was evaluated via adverse events, clinical laboratory tests, vital signs, wound healing, and opioid consumption. The incidence of adverse events was similar between meloxicam IV- and placebo-treated subjects (63.0% versus 65.0%). Investigators assessed most adverse events as mild or moderate in intensity and unrelated to treatment. Adverse events of interest (injection-site reactions, bleeding, cardiovascular, hepatic, renal, thrombotic, and wound-healing events) were similar between groups. Over the treatment period, meloxicam IV was associated with a 23.6% (P = .0531) reduction in total opioid use (9.2 mg morphine equivalent) compared to placebo-treated subjects. The results suggest that meloxicam IV had a safety profile similar to that of placebo with respect to numbers and frequencies of adverse events and reduced opioid consumption in subjects with moderate to severe postoperative pain following major elective surgery.

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Attachment insecurity as a vulnerability factor in the development of chronic whiplash associated disorder – A prospective cohort study.

Attachment theory represents a dynamic model for understanding how pre-existing personality factors may contribute to the development of chronic pain and disability after whiplash injury. The aim of the present study was to investigate the impact of attachment insecurity on disability 6-months post-injury. It was hypothesized that: (1) levels of attachment insecurity assessed at baseline would predict levels of disability six months post-injury, and (2) both attachment dimensions (anxiety and avoidance) would moderate associations between pain and disability, and psychological distress and disability.

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Assessing discrepancies in outcomes of pain rehabilitation: “these questionnaires don’t measure results that are relevant to me”.

Pain rehabilitation programs are recommended interventions for patients with chronic pain. Average effect sizes are moderate. Physiatrists, based on clinical experience, argue that the present outcome measures underestimate the outcome of pain rehabilitation programs.

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Multicenter cross-sectional study of the clinical features and types of treatment of spinal cord-related pain syndrome.

We termed chronic neuropathic pain (NeP) in patients with diseases associated with spinal cord damage as "spinal cord-related pain syndrome". We conducted a survey of patients with the syndrome to assess the type and severity of NeP and its effect on QOL, and treatment modalities.

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Utilization of pain medications and its effect on quality of life, health care utilization and associated costs in individuals with chronic back pain.

Pain medications are widely prescribed to treat chronic back pain (CBP). However, the effect of using pain medications on individuals with CBP has received very little attention.

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Pain experiences and intrapersonal change among patients with chronic non-cancer pain after using a pain diary: a mixed-methods study.

Pain diaries are a valuable self-assessment tool; however, their use in chronic non-cancer pain has received limited attention. In this study, we examined the effect of pain diary use on pain intensity, interference, and intrapersonal change in patients with chronic non-cancer pain.

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General practitioners and management of chronic noncancer pain: a cross-sectional survey of influences on opioid deprescribing.

General practitioners' (GPs) views about deprescribing prescription opioid analgesics (POAs) may influence the care provided for patients experiencing chronic noncancer pain (CNCP). There are limited data addressing GPs' beliefs about deprescribing, including their decisions to deprescribe different types of POAs.

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Hyperbaric oxygen relieves neuropathic pain through AKT/TSC2/mTOR pathway activity to induce autophagy.

Our previous study suggested that HBO treatment attenuated neuropathic pain by inhibiting mTOR to induce autophagy in SNL neuropathic pain model. The aim of this study was to evaluate the role of AKT/TSC2/mTOR pathway in SNL and autophagy and determine whether HBO treatment could relieve neuropathic pain via modulating AKT/TSC2/mTOR pathway.

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Association between MRI findings and back pain after osteoporotic vertebral fractures: a multicenter prospective cohort study.

Osteoprotic vertebral fractures(OFV) are common in elderly people. The association between back pain due to OVF with MRI signal change is unclear. In this study we hypothesized that MRI findingswould be a predictive factor for back pain measured by VAS at 6 months follow-up.

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Exploring anxiety sensitivity in the relationship between pain intensity and opioid misuse among opioid-using adults with chronic pain.

Opioid misuse is a significant public health problem. Chronic pain is one highly prevalent factor that is strongly associated with increased risk for opioid misuse. Anxiety sensitivity (fear of anxiety related physical sensations) is an individual difference factor consistently linked to pain experience, and separately, heroin use. The present study examined if anxiety sensitivity may be one factor related to the relationship between pain intensity and opioid misuse among opioid-using adults with chronic pain. Results indicated that anxiety sensitivity total score was significantly associated with the relationship between pain intensity and current opioid misuse, as well as pain intensity and severity of opioid dependence. Overall, results suggest that anxiety sensitivity may be an important assessment and intervention target to ultimately reduce the rates of opioid misuse among adults with chronic pain.

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A Quantitative Sensory Testing Approach to Pain in Autism Spectrum Disorders.

Sensory abnormalities in autism has been noted clinically, with pain insensitivity as a specified diagnostic criterion. However, there is limited research using psychophysically robust techniques. Thirteen adults with ASD and 13 matched controls completed an established quantitative sensory testing (QST) battery, supplemented with measures of pain tolerance and central modulation. The ASD group showed higher thresholds for light touch detection and mechanical pain. Notably, the ASD group had a greater range of extreme scores (the number of z-scores outside of the 95% CI > 2), dynamic mechanical allodynia and paradoxical heat sensation; phenomena not typically seen in neurotypical individuals. These data support the need for research examining central mechanisms for pain in ASD and greater consideration of individual difference.

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MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis.

The efficacy of mesenchymal stem cell (MSC) therapies is increasingly attributed to paracrine secretion, particularly exosomes. In this study, we investigated the role of MSC exosomes in the regulation of inflammatory response, nociceptive behaviour, and condylar cartilage and subchondral bone healing in an immunocompetent rat model of temporomandibular joint osteoarthritis (TMJ-OA). We observed that exosome-mediated repair of osteoarthritic TMJs was characterized by early suppression of pain and degeneration with reduced inflammation, followed by sustained proliferation and gradual improvements in matrix expression and subchondral bone architecture, leading to overall joint restoration and regeneration. Using chondrocyte cultures, we could attribute some of the cellular activities during exosome-mediated joint repair to adenosine activation of AKT, ERK and AMPK signalling. Specifically, MSC exosomes enhanced s-GAG synthesis impeded by IL-1β, and suppressed IL-1β-induced nitric oxide and MMP13 production. These effects were partially abrogated by inhibitors of adenosine receptor activation, AKT, ERK and AMPK phosphorylation. Together, our observations suggest that MSC exosomes promote TMJ repair and regeneration in OA through a well-orchestrated mechanism of action that involved multiple cellular processes to restore the matrix and overall joint homeostasis. This study demonstrates the translational potential of a cell-free ready-to-use exosome-based therapeutic for treating TMJ pain and degeneration.

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Biomarker Analysis of Orally Dosed, Dual Active, Matrix Metalloproteinase (MMP)-2 and MMP-9 Inhibitor, AQU-118, in the Spinal Nerve Ligation (SNL) Rat Model of Neuropathic Pain.

There is an unmet medical need for the development of non-addicting pain therapeutics with enhanced efficacy and tolerability. The current study examined the effects of AQU-118, an orally active inhibitor of metalloproteinase-2 (MMP-2) and MMP-9, in the spinal nerve ligation (SNL) rat model of neuropathic pain. Mechanical allodynia and the levels of various biomarkers were examined within the dorsal root ganglion (DRG) before and after oral dosing with AQU-118. The rats that received the SNL surgery exhibited significant mechanical allodynia as compared to sham controls. Animals received either vehicle, positive control (gabapentin), or AQU-118. After SNL surgery, the dorsal root ganglion (DRG) of those rats dosed with vehicle had elevated messenger RNA (mRNA) expression levels for MMP-2, IL1-β &amp; IL-6 and elevated protein levels for caspase-3 while exhibiting decreased protein levels for myelin basic protein (MBP) &amp; active IL-β as compared to sham controls. Rats orally dosed with AQU-118 exhibited significantly reduced mechanical allodynia and decreased levels of caspase-3 in the DRG as compared to vehicle controls. Results demonstrate that oral dosing with the dual active, MMP-2/-9 inhibitor, AQU-118, attenuated mechanical allodynia while at the same time significantly reduced the levels of caspase-3 in the DRG.

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Neurons and Microglia; A Sickly-Sweet Duo in Diabetic Pain Neuropathy.

Diabetes is a common condition characterized by persistent hyperglycemia. High blood sugar primarily affects cells that have a limited capacity to regulate their glucose intake. These cells include capillary endothelial cells in the retina, mesangial cells in the renal glomerulus, Schwann cells, and neurons of the peripheral and central nervous systems. As a result, hyperglycemia leads to largely intractable complications such as retinopathy, nephropathy, hypertension, and neuropathy. Diabetic pain neuropathy is a complex and multifactorial disease that has been associated with poor glycemic control, longer diabetes duration, hypertension, advanced age, smoking status, hypoinsulinemia, and dyslipidemia. While many of the driving factors involved in diabetic pain are still being investigated, they can be broadly classified as either neuron -intrinsic or -extrinsic. In neurons, hyperglycemia impairs the polyol pathway, leading to an overproduction of reactive oxygen species and reactive nitrogen species, an enhanced formation of advanced glycation end products, and a disruption in Na/K ATPase pump function. In terms of the extrinsic pathway, hyperglycemia leads to the generation of both overactive microglia and microangiopathy. The former incites a feed-forward inflammatory loop that hypersensitizes nociceptor neurons, as observed at the onset of diabetic pain neuropathy. The latter reduces neurons' access to oxygen, glucose and nutrients, prompting reductions in nociceptor terminal expression and losses in sensation, as observed in the later stages of diabetic pain neuropathy. Overall, microglia can be seen as potent and long-lasting amplifiers of nociceptor neuron activity, and may therefore constitute a potential therapeutic target in the treatment of diabetic pain neuropathy.

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Perioperative Pharmacological Sleep-Promotion and Pain Control: A Systematic Review.

Sleep macrostructure is commonly disturbed after surgery. Postoperative pain control remains challenging. Given the bidirectional interaction between sleep and pain, understanding the role of modulation of sleep during the perioperative period on postoperative pain is needed.

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An investigation of healthcare utilization and its association with levels of health literacy in individuals with chronic pain.

Chronic pain patients are frequent and recurrent users of health services, which may have an impact on levels of health literacy (HL). Therefore, the aim of the present study was to investigate associations between healthcare utilization and varying levels of HL in individuals with and without chronic pain.

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A comprehensive review of hormonal and biological therapies for endometriosis: latest developments.

Endometriosis is a chronic benign estrogen dependent disease characterized by the presence of endometriotic glands and stroma outside the uterine cavity. Although combined hormonal contraceptives and progestins, currently available first-line treatments for endometriosis, are efficacious and well tolerated for treating disease-related pain, some women experience partial or no improvement of pain or its recurrence is frequent after discontinuation of the therapies. For these reasons, new drugs are under investigation for the treatment of endometriosis. Areas covered: This review aims to give to the reader a complete and updated overview on hormonal and biological therapies for the treatment of endometriosis, underlining the latest developments in this field of research. Expert opinion: Among the new drugs investigated, late clinical trials on gonadotropin-releasing hormone (GnRH) antagonists and aromatase inhibitors (AIs) have demonstrated the most promising results. For this reason, elagolix, a new GnRH-antagonist, recently received the approval by the Food and Drug Administration (FDA) for treating pain associated to endometriosis. Other drugs with innovative targets have been identified, but the majority of these compounds have only been evaluated in pre-clinical studies or early clinical trials. Thus, a further extensive clinical research is necessary to better elucidate their pharmacologic characteristics, their efficacy and safety for the treatment of this benign chronic disease.

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Mechanism of persistent hyperalgesia in neuropathic pain caused by chronic constriction injury.

Transmembrane member 16A (TMEM16A) is involved in many physiological functions, such as epithelial secretion, sensory conduction, nociception, control of neuronal excitability, and regulation of smooth muscle contraction, and may be important in peripheral pain transmission. To explore the role of TMEM16A in the persistent hyperalgesia that results from chronic constriction injury-induced neuropathic pain, a rat model of the condition was established by ligating the left sciatic nerve. A TMEM16A selective antagonist (10 μg T16Ainh-A01) was intrathecally injected at L5-6. For measurement of thermal hyperalgesia, the drug was administered once at 14 days and thermal withdrawal latency was recorded with an analgesia meter. For measurement of other indexes, the drug was administered at 12 days, once every 6 hours, totally five times. The measurements were performed at 14 days. Western blot assay was conducted to analyze TMEM16A expression in the L4-6 dorsal root ganglion. Immunofluorescence staining was used to detect the immunoreactivity of TMEM16A in the L4-6 dorsal root ganglion on the injured side. Patch clamp was used to detect electrophysiological changes in the neurons in the L4-6 dorsal root ganglion. Our results demonstrated that thermal withdrawal latency was shortened in the model rats compared with control rats. Additionally, TMEM16A expression and the number of TMEM16A positive cells in the L4-6 dorsal root ganglion were higher in the model rats, which induced excitation of the neurons in the L4-6 dorsal root ganglion. These findings were inhibited by T16Ainh-A01 and confirm that TMEM16A plays a key role in persistent chronic constriction injury-induced hyperalgesia. Thus, inhibiting TMEM16A might be a novel pharmacological intervention for neuropathic pain. All experimental protocols were approved by the Animal Ethics Committee at the First Affiliated Hospital of Shihezi University School of Medicine, China (approval No. A2017-170-01) on February 27, 2017.

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The hypothalamic-spinal dopaminergic system: a target for pain modulation.

Nociceptive signals conveyed to the dorsal horn of the spinal cord by primary nociceptors are subject to extensive modulation by local neurons and by supraspinal descending pathways to the spinal cord before being relayed to higher brain centers. Descending modulatory pathways to the spinal cord comprise, among others, noradrenergic, serotonergic, γ-aminobutyric acid (GABA)ergic, and dopaminergic fibers. The contributions of noradrenaline, serotonin, and GABA to pain modulation have been extensively investigated. In contrast, the contributions of dopamine to pain modulation remain poorly understood. The focus of this review is to summarize the current knowledge of the contributions of dopamine to pain modulation. Hypothalamic A11 dopaminergic neurons project to all levels of the spinal cord and provide the main source of spinal dopamine. Dopamine receptors are expressed in primary nociceptors as well as in spinal neurons located in different laminae in the dorsal horn of the spinal cord, suggesting that dopamine can modulate pain signals by acting at both presynaptic and postsynaptic targets. Here, I will review the literature on the effects of dopamine and dopamine receptor agonists/antagonists on the excitability of primary nociceptors, the effects of dopamine on the synaptic transmission between primary nociceptors and dorsal horn neurons, and the effects of dopamine on pain in rodents. Published data support both anti-nociceptive effects of dopamine mediated by D2-like receptors and pro-nociceptive effects mediated by D1-like receptors.

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