Papers: 17 Dec 2022 - 23 Dec 2022

The primary motor cortex (M1) is involved in the control of voluntary movements and is extensively mapped in this capacity. Although the M1 is implicated in modulation of pain, the underlying circuitry and causal underpinnings remain elusive. We unexpectedly unraveled a connection from the M1 to the nucleus accumbens reward circuitry through a M1 layer 6-mediodorsal thalamus pathway, which specifically suppresses negative emotional valence and associated coping behaviors in neuropathic pain. By contrast, layer 5 M1 neurons connect with specific cell populations in zona incerta and periaqueductal gray to suppress sensory hypersensitivity without altering pain affect. Thus, the M1 employs distinct, layer-specific pathways to attune sensory and aversive-emotional components of neuropathic pain, which can be exploited for purposes of pain relief.

Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we reveal that intestinal GUCY2C is selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2CHigh neuropod cells associate with co-cultured dorsal root ganglia neurons and induce hyperexcitability, reducing the rheobase and increasing the resulting number of evoked action potentials. Conversely, the GUCY2C agonist linaclotide eliminated neuronal hyperexcitability produced by GUCY2C-sufficient, but not GUCY2C-deficient, neuropod cells, an effect independent of bulk epithelial cells or extracellular cGMP. Genetic elimination of intestinal GUCY2C amplified nociceptive signaling and VP that was comparable to chemically-induced VP but refractory to linaclotide. Importantly, eliminating GUCY2C selectively in neuropod cells also increased nociceptive signaling and VP that was refractory to linaclotide. In the context of loss of GUCY2C hormones in patients with VP, these observations suggest a specific role for neuropod GUCY2C signaling in the pathophysiology and treatment of these pain syndromes.

Neuronal N-type (CaV2.2) voltage-gated calcium channels are essential for neurotransmission from primary afferent terminals in the dorsal horn. In this study we have utilized a knock-in mouse expressing CaV2.2 with an inserted extracellular hemagglutinin-tag (CaV2.2_HA), to visualise the distribution of endogenous CaV2.2 in dorsal root ganglion (DRG) neurons and their primary afferents in the dorsal horn. We examined the effect of partial sciatic nerve ligation (PSNL) and found an increase in CaV2.2_HA only in large and medium dorsal root ganglion neurons, and also in deep dorsal-horn synaptic terminals. Furthermore, there is a parallel increase in co-expression with GFRα1, present in a population of low threshold mechanoreceptors, both in large DRG neurons and in their terminals. The increased expression of CaV2.2_HA in these DRG neurons and their terminals is dependent on the presence of the auxiliary subunit α2δ-1, which is required for channel trafficking to the cell surface and to synaptic terminals, and likely contributes to enhanced synaptic transmission at these synapses following PSNL. In contrast the increase of GFRα1 is not altered in α2δ-1 knockout mice. We also found following PSNL there is patchy loss of glomerular synapses immunoreactive for CaV2.2_HA and CGRP or IB4, restricted to the superficial layers of the dorsal horn. This reduction is not dependent on α2δ-1, and likely reflects partial deafferentation of C-nociceptor presynaptic terminals. Therefore, we can distinguish in this pain model two different events affecting specific DRG terminals, with opposite consequences for CaV2.2_HA expression and function in the dorsal horn.

Somatosensory neurons are highly heterogeneous with distinct types of neural cells responding to specific stimuli. However, the distribution and roles of cell-type-specific long intergenic noncoding RNAs (lincRNAs) in somatosensory neurons remain largely unexplored. Here, by utilizing droplet-based single-cell RNA-seq (scRNA-seq) and full-length Smart-seq2, we show that lincRNAs, but not coding mRNAs, are enriched in specific types of mouse somatosensory neurons. Profiling of lincRNAs from single neurons located in dorsal root ganglia (DRG) identifies 200 lincRNAs localized in specific types or subtypes of somatosensory neurons. Among them, the conserved cell-type-specific lincRNA CLAP associates with pruritus and is abundantly expressed in somatostatin (SST)-positive neurons. CLAP knockdown reduces histamine-induced Ca influx in cultured SST-positive neurons and in vivo reduces histamine-induced scratching in mice. In vivo knockdown of CLAP also decreases the expression of neuron-type-specific and itch-related genes in somatosensory neurons, and this partially depends on the RNA binding protein MSI2. Our data reveal a cell-type-specific landscape of lincRNAs and a function for CLAP in somatosensory neurons in sensory transmission.

Cluster headache is considered a male-dominated disorder, but we have previously suggested that females may display a more severe phenotype. Studies on sex differences in cluster headache have been conflicting, therefore this study, with the largest validated cluster headache material at present, gives more insights into sex-specific characteristics of the disease. The objective with this study was to describe sex differences in patient demographics, clinical phenotype, chronobiology, triggers, treatment, and lifestyle in a Swedish cluster headache population.

Pain management for patients with dementia is challenging because many experience pain while being unable to communicate their pain. The aim of this study was to describe pain, pain management, and to perform a thorough clinical examination of chronic pain conditions among patients with dementia. Residents (n = 498) from 12 nursing homes were assessed for dementia (Clinical Dementia Rating scale [CDR]) and for pain with the Mobilization-Observation-Behavior-Intensity-Dementia-2 (MOBID-2) assessment form. Of all examined nursing home patients with dementia, 68% had moderate or severe chronic pain. The final study population (n = 262) with a CDR score of ≥1 and a MOBID-2 score of ≥3 were examined by pain expert physicians for chronic pain and categorized according to the International Classification of Disease (ICD-10/-11) classification systems. More than half (54.6%) had chronic pain conditions without underlying disease classified as chronic primary pain by ICD-11. Chronic widespread pain was the most prevalent (14.5%) followed by nonspecific pain from the back (13.4%), whereas the most prevalent chronic secondary pain conditions were chronic pain caused by osteoarthritis (15.4%) and stroke (8.0%). One-fourth received opioids, which was significantly associated with severe pain (P < 0.001) compared with moderate pain, although no significant association was found between opioid use and the type of pain condition. Although knowledge of the severity and specific types of pain conditions is recommended to direct the choice of treatment, these areas are not sufficiently explored in the nursing home populations with dementia and may hinder a better treatment of pain in this population.

Neuronal function relies on the maintenance of appropriate levels of various ion channels at the cell membrane, which is accomplished by balancing secretory, degradative, and recycling pathways. Neuronal function further depends on membrane specialization through polarized distribution of specific proteins to distinct neuronal compartments such as axons. Voltage-gated sodium channel Na1.7, a threshold channel for firing action potentials in nociceptors, plays a major role in human pain, and its abundance in the plasma membrane is tightly regulated. We have recently characterized the anterograde axonal trafficking of Na1.7 channels in Rab6A-positive vesicles, but the fate of internalized channels is not known. Membrane proteins which have undergone endocytosis can be directed into multiple pathways including those for degradation, recycling to the membrane, and transcytosis. Here we demonstrate Na1.7 endocytosis and dynein-dependent retrograde trafficking in Rab7-containing late endosomes together with other axonal membrane proteins using real-time imaging of live neurons. We show that some internalized Na1.7 channels are delivered to lysosomes within the cell body, and that there is no evidence for Na1.7 transcytosis. In addition, we show that Na1.7 is recycled specifically to the axonal membrane as opposed to the soma membrane, suggesting a novel mechanism for the development of neuronal polarity. Together, these results shed light on the mechanisms by which neurons maintain excitable membranes and may inform efforts to target ion channel trafficking for the treatment of disorders of excitability.

Chronic pain is a common and often debilitating problem that affects 100 million Americans. A better understanding of pain's molecular mechanisms is necessary for developing safe and effective therapeutics. Microglial activation has been implicated as a mediator of chronic pain in numerous preclinical studies; unfortunately, translational efforts using known glial modulators have largely failed, perhaps at least in part due to poor specificity of the compounds pursued, or an incomplete understanding of microglial reactivity. In order to achieve a more granular understanding of the role of microglia in chronic pain as a means of optimizing translational efforts, we utilized a clinically-informed mouse model of complex regional pain syndrome (CRPS), and monitored microglial activation throughout pain progression. We discovered that while both males and females exhibit spinal cord microglial activation as evidenced by increases in Iba1, activation is attenuated and delayed in females. We further evaluated the expression of the newly identified microglia-specific marker, TMEM119, and identified two distinct populations in the spinal cord parenchyma after peripheral injury: TMEM119+ microglia and TMEM119- infiltrating myeloid lineage cells, which are comprised of Ly6G + neutrophils and Ly6G- macrophages/monocytes. Neurons are sensitized by inflammatory mediators released in the CNS after injury; however, the cellular source of these cytokines remains somewhat unclear. Using multiplex hybridization in combination with immunohistochemistry, we demonstrate that spinal cord TMEM119+ microglia are the cellular source of cytokines IL6 and IL1β after peripheral injury. Taken together, these data have important implications for translational studies: 1) microglia remain a viable analgesic target for males and females, so long as duration after injury is considered; 2) the analgesic properties of microglial modulators are likely at least in part related to their suppression of microglial-released cytokines, and 3) a limited number of neutrophils and macrophages/monocytes infiltrate the spinal cord after peripheral injury but have unknown impact on pain persistence or resolution. Further studies to uncover glial-targeted therapeutic interventions will need to consider sex, timing after injury, and the exact target population of interest to have the specificity necessary for translation.

The voltage-gated sodium NaV1.7 channel sets the threshold for electrogenesis. Mutations in the gene encoding human NaV1.7 () cause painful neuropathies or pain insensitivity. In dorsal root ganglion (DRG) neurons, activity and trafficking of NaV1.7 are regulated by the auxiliary collapsin response mediator protein 2 (CRMP2). Specifically, preventing addition of a small ubiquitin-like modifier (SUMO), by the E2 SUMO-conjugating enzyme Ubc9, at lysine-374 (K374) of CRMP2 reduces NaV1.7 channel trafficking and activity. We previously identified a small molecule, designated , that prevented CRMP2 SUMOylation by Ubc9 to reduce NaV1.7 surface expression and currents, leading to a reduction in spinal nociceptive transmission, and culminating in normalization of mechanical allodynia in models of neuropathic pain. In this study, we investigated whether NaV1.7 control via CRMP2-SUMOylation is conserved in nodose ganglion (NG) neurons. This study was motivated by our desire to develop as a safe, non-opioid substitute for persistent pain, which led us to wonder how would impact NaV1.7 in NG neurons, which are responsible for driving the cough reflex. We found functioning NaV1.7 channels in NG neurons; however, they were resistant to downregulation via either CRMP2 knockdown or pharmacological inhibition of CRMP2 SUMOylation by CRMP2 SUMOylation and interaction with NaV1.7 was consered in NG neurons but the endocytic machinery was deficient in the endocytic adaptor protein Numb. Overexpression of Numb rescued CRMP2-dependent regulation on NaV1.7, rendering NG neurons sensitive to Altogether, these data point at the existence of cell-specific mechanisms regulating NaV1.7 trafficking.

Chronic headache disorders are a major cause of pain and disability. Education and supportive self-management approaches could reduce burden of headache disability. We tested the effectiveness of a group educational and supportive self-management programme for people living with chronic headaches.

Sleep deprivation can trigger migraine, and migraineurs often choose to sleep to relieve headaches during acute migraine. This study aimed to explore the effect of acute sleep deprivation on hyperalgesia induced by nitroglycerin in mice. In part one, after either 6-hour sleep deprivation or 6-hour normal sleep, mice were intraperitoneally injected with nitroglycerin or saline. The mechanical pain threshold and withdrawal latency of the hindpaw were measured every 30 minutes for 6 hours. Next, the same sleep deprivation and injection procedure was performed with new mice, and mice were sacrificed 4.5 hours after injection. The trigeminal nucleus caudalis and upper cervical spinal segments were taken for immunofluorescence Fos staining. In part two, after injection of saline or nitroglycerin, the mice were either deprived of sleep for 6 hours or allowed to sleep without interference. The mechanical and thermal pain threshold were measured after 6 hours. In part three, we compared the sleep time of mice after intraperitoneal injection of saline or nitroglycerin without interference. Sleep deprivation for 6 hours did not cause any changes in the baseline pain thresholds in mice. However, pretreatment with 6-hour sleep deprivation significantly prolonged the duration of hyperalgesia induced by nitroglycerin. Additionally, the expression of Fos at 4.5 hours was significantly higher in the 6-hour sleep deprivation and nitroglycerin group than in the other three groups. When intraperitoneal injection was given first, the mechanical pain threshold of the hind paw was significantly lower in the group that received nitroglycerin with 6-hour sleep deprivation than in the other groups. Compared to the saline injection, one-time nitroglycerin injection would result in a significant increase in sleep latency and decrease in sleep duration for the normal mice. Acute sleep deprivation significantly aggravated the hyperalgesia induced by nitroglycerin in mice, which highlights the importance of sleep disorders for migraine.

Irritable bowel syndrome (IBS) related chronic visceral pain affects 20% of people worldwide. The treatment options are very limited. Although the scholarly reviews have appraised the potential effects of the intestinal microbiota on intestinal motility and sensation, the exact mechanism of intestinal microbiota in IBS-like chronic visceral pain remains largely unclear. The purpose of this study is to investigate whether Folic Acid (FA) attenuated visceral pain and its possible mechanisms.

Retinoic acid receptors are important for homeostatic synaptic plasticity and have many beneficial effects within the brain. New work by Cao et al. uncovers a role for these receptors in driving neuropathic pain development, thus identifying a potential preventative therapeutic target.

Transcutaneous auricular vagus nerve stimulation (taVNS) has been investigated as a novel neuromodulation tool. Although taVNS is generally considered safe with only mild and transient adverse effects (AEs), those specifically caused by taVNS have not yet been investigated. This systematic review and meta-analysis on taVNS aimed to (1) systematically analyze study characteristics and AE assessment, (2) characterize and analyze possible AEs and their incidence, (3) search for predictable risk factors, (4) analyze the severity of AE, and (5) suggest an evidence-based taVNS adverse events questionnaire for safety monitoring. The articles searched were published through April 7, 2022, in Medline, Embase, Web of Science, Cochrane, and Lilacs databases. In general, we evaluated 177 studies that assessed 6322 subjects. From these, 55.37% of studies did not mention the presence or absence of any AEs; only 24.86% of the studies described that at least one adverse event occurred. In the 35 studies reporting the number of subjects with at least one adverse event, a meta-analytic approach to calculate the risk differences of developing an adverse event between active taVNS and controls was used. The meta-analytic overall adverse events incidence rate was calculated for the total number of adverse events reported on a 100,000 person-minutes-days scale. There were no differences in risk of developing an adverse event between active taVNS and controls. The incidence of AE, in general, was 12.84/100,000 person-minutes-days of stimulation, and the most frequently reported were ear pain, headache, and tingling. Almost half of the studies did not report the presence or absence of any AEs. We attribute this to the absence of AE in those studies. There was no causal relationship between taVNS and severe adverse events. This is the first systematic review and meta-analysis of transcutaneous auricular stimulation safety. Overall, taVNS is a safe and feasible option for clinical intervention.

Itching and skin pain are bothersome symptoms of psoriasis, but evidence is limited regarding the treatment effectiveness on these symptoms in daily clinical settings. We assessed the changes in the levels of itching and skin pain after brodalumab treatment in Japanese patients with psoriasis using patient-reported outcomes (PROs). Patients with psoriasis who have inadequate response to existing treatments were enrolled in the single-arm, open-label, multicenter, prospective ProLOGUE study and received brodalumab 210 mg subcutaneously in daily clinical practice. Psoriasis Area and Severity Index (PASI) and PRO assessments were performed at baseline and weeks 12 and 48. Seventy-three patients (men, 82.2%; median age, 54.0 years) were enrolled. The Itch Numeric Rating Scale (NRS; p < 0.0001 at weeks 12 and 48) and Skin Pain NRS (week 12, p = 0.0004; week 48, p < 0.0001) scores significantly decreased from baseline. The Itch NRS score was significantly higher in patients with a Dermatology Life Quality Index (DLQI) score of ≥2 (vs. 0/1; p < 0.0001 at weeks 12 and 48) and in patients with a Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) global satisfaction domain score of ≤70% (vs. >70%; week 12, p = 0.0120; week 48, p = 0.0348). The Itch NRS score cutoff value for achieving a PASI score of ≤2, DLQI score of 0/1, and TSQM-9 global satisfaction domain score of >70% was 1 at week 12 and 0 at week 48. Brodalumab treatment was associated with improvement in itching and skin pain in Japanese patients with psoriasis. An Itch NRS score of 0 can be a long-term treatment goal for psoriasis (Japan Registry of Clinical Trials identifier: jRCTs031180037).

The aim of the present study was to assess erenumab efficacy in migraine disability and intensity throughout the first treatment cycle, discontinuation, and the first 6 months of re-treatment in patients with high-frequency episodic migraine. The study design was retrospective and observational. Inclusion criteria were the following: diagnosis of high-frequency episodic migraine and ongoing treatment with erenumab 140 mg currently at their second treatment cycle. Data regarding migraine frequency, disability (MIDAS score), and severity of attacks (NRS score) were collected quarterly. Twenty-five patients were enrolled. At the end of the first treatment cycle, compared to baseline, a significant improvement of MIDAS scores was found (13.5 ± 11.1 vs. 72.5 ± 32.1; p = 0.005), with a subsequent worsening during treatment suspension (30.1 ± 26.9; p = 0.03). Pain intensity remained unmodified during the first treatment cycle (NRS score baseline: 7.6 ± 0.9 vs. 12 months: 7.5 ± 0.7; p = 0.13). During re-treatment, MIDAS scores documented a new significant improvement, reaching the same level at 6 months of re-treatment as at the end of the first cycle (30.1 ± 26.9 vs. 12.9 ± 5.4; p = 0.03). A significant improvement, compared to baseline, was observed for pain intensity during re-treatment (6.8 ± 2.2 vs. 5.6 ± 0.9 at RT3 vs. 5.2 ± 1.4 at RT6; p = 0.05). In conclusion, during re-treatment with erenumab 140 mg, migraine pain intensity and disability documented a significant and progressive improvement. Our data confirm the long-term efficacy, although in a very limited case series, of monoclonal antibodies targeting CGRP beyond headache frequency reduction.

A functional nerve growth factor (NGF)-TrkA system is an essential requisite for the generation and maintenance of long-lasting thermal and mechanical hyperalgesia in adult mammals. Indeed, mutations in the gene encoding for TrkA are responsible for a rare condition, named Hereditary Sensory and Autonomic Neuropathy type IV (HSAN IV), characterized by the loss of response to noxious stimuli, anhidrosis and cognitive impairment. However, to date, there is no available mouse model to properly understand how the NGF-TrkA system can lead to pathological phenotypes that are distinctive of HSAN IV. Here, we report the generation of a knock-in mouse line carrying the HSAN IV TrkAR649W mutation. First, by in vitro biochemical and biophysical analyses, we show that the pathological R649W mutation leads to kinase-inactive TrkA also affecting its membrane dynamics and trafficking. In agreement with the HSAN IV human phenotype, TrkAR649W/m mice display a lower response to thermal and chemical noxious stimuli, correlating with reduced skin innervation, in addition to decreased sweating in comparison to TrkAh/m controls. Moreover, the R649W mutation decreases anxiety-like behavior and compromises cognitive abilities, by impairing spatial-working and social memory. Our results further uncover unexplored roles of TrkA in thermoregulation and sociability. In addition to accurately recapitulating the clinical manifestations of HSAN IV patients, our findings contribute to clarify the involvement of the NGF-TrkA system in pain sensation.

This review summarizes major findings and recent advances in magnetic resonance spectroscopy (MRS) of migraine. A multi database search of PubMed, EMBASE, and Web of Science was performed with variations of magnetic resonance spectroscopy and headache until 20th September 2021. The search generated 2897 studies, 676 which were duplicates and 1836 were not related to headache. Of the remaining 385 studies examined, further exclusions for not migraine (n = 114), and not MRS of human brain (n = 128), and non-original contributions (n = 51) or conferences (n = 24) or case studies (n = 11) or non-English (n = 3), were applied. The manuscripts of all resulting reports were reviewed for their possible inclusion in this manuscript (n = 54). The reference lists of all included reports were carefully reviewed and articles relevant to this review were added (n = 2).Included are 56 studies of migraine with and without aura that involve magnetic resonance spectroscopy of the human brain. The topics are presented in the form of a narrative review. This review aims to provide a summary of the metabolic changes measured by MRS in patients with migraine. Despite the variability reported between studies, common findings focused on regions functionally relevant to migraine such as occipital cortices, thalamic nuclei, cerebellum and cingulate. The most reproducible results were decreased -acetyl-aspartate (NAA) in cerebellum in patients with hemiplegic migraine and in the thalamus of chronic migraine patients. Increased lactate (Lac) in the occipital cortex was found for migraine with aura but not in subjects without aura. MRS studies support the hypothesis of impaired energetics and mitochondrial dysfunction in migraine. Although results regarding GABA and Glu were less consistent, studies suggest there might be an imbalance of these important inhibitory and excitatory neurotransmitters in the migraine brain. Multinuclear imaging studies in migraine with and without aura, predominantly investigating phosphorous, report alterations of PCr in occipital, parietal, and posterior brain regions. There have been too few studies to assess the diagnostic relevance of sodium imaging in migraine.

Management of pain post-surgery is crucial for tissue healing in both veterinary and human medicine. Overuse of some analgesics such as opioids may lead to addictions and worsen pain syndromes (opioid-induced hyperalgesia), while underuse of it may affect the welfare of the patient. Therefore, the importance of using surgery models in laboratory animals is increasing, with the goal of improving our understanding of pain neurobiology and developing safer analgesics.

There is growing literature supporting cannabinoids as a potential therapeutic for pain conditions. The development of chronic pain has been associated with reduced concentrations of the endogenous cannabinoid anandamide (AEA) in the midbrain dorsal periaqueductal gray (dPAG), and microinjections of synthetic cannabinoids into the dPAG are antinociceptive. Therefore, the goal of this study was to examine the role of the dPAG in cannabinoid-mediated sensory inhibition. Given that cannabinoids in the dPAG also elicit sympathoexcitation, a secondary goal was to assess coordination between sympathetic and antinociceptive responses. AEA was microinjected into the dPAG while recording single unit activity of wide dynamic range (WDR) dorsal horn neurons (DHNs) evoked by high intensity mechanical stimulation of the hindpaw, concurrently with renal sympathetic nerve activity (RSNA), in anesthetized male rats. AEA microinjected into the dPAG decreased evoked DHN activity (n = 24 units), for half of which AEA also elicited sympathoexcitation. AEA actions were mediated by cannabinoid 1 receptors as confirmed by local pretreatment with the cannabinoid receptor antagonist AM281. dPAG microinjection of the synaptic excitant DL-homocysteic acid (DLH) also decreased evoked DHN activity (n = 27 units), but in all cases this was accompanied by sympathoexcitation. Thus, sensory inhibition elicited from the dPAG is not exclusively linked with sympathoexcitation, suggesting discrete neuronal circuits. The rostrocaudal location of sites may affect evoked responses as AEA produced sensory inhibition without sympathetic effects at 86 % of caudal compared to 25 % of rostral sites, supporting anatomically distinct neurocircuits. These data indicate that spatially selective manipulation of cannabinoid signaling could provide analgesia without potentially harmful autonomic activation.

Our study aimed to identify differentially methylated regions (i.e., genomic region where multiple adjacent CpG sites show differential methylation) and their enriched genomic pathways associated with knee osteoarthritis pain (KOA). We recruited cognitively healthy middle to older aged (age 45-85) adults with (n = 182) and without (n = 31) self-reported KOA pain. We also extracted DNA from peripheral blood that was analyzed using MethylationEPIC arrays. The R package (Aryee et al., 2014) was used to perform methylation data preprocessing and quality control. To investigate biological pathways impacted by differential methylation, we performed pathway enrichment analysis using Ingenuity Pathway Analysis (IPA) to identify canonical pathways and upstream regulators. Annotated genes within ± 5 kb of the putative differentially methylated regions (DMRs, p < 0.05) were subjected to the IPA analysis. There was no significant difference in age, sex, study site between no pain and pain group (p > 0.05). Non-Hispanic black individuals were overrepresented in the pain group (p = 0.003). At raw p < 0.05 cutoff, we identified a total of 19,710 CpG probes, including 13,951 hypermethylated CpG probes, for which DNA methylation level was higher in the groups with highest pain grades. We also identified 5,759 hypomethylated CpG probes for which DNA methylation level was lower in the pain groups with higher pain grades. IPA revealed that pain-related DMRs were enriched across multiple pathways and upstream regulators. The top 10 canonical pathways were linked to cellular signaling processes related to immune responses (i.e., antigen presentation, PD-1, PD-L1 cancer immunotherapy, B cell development, IL-4 signaling, Th1 and Th2 activation pathway, and phagosome maturation). Moreover, in terms of upstream regulators, NDUFAF3 was the most significant (p = 8.6E-04) upstream regulator. Our findings support previous preliminary work suggesting the importance of epigenetic regulation of the immune system in knee pain and the need for future work to understand the epigenetic contributions to chronic pain.

Neuropathic pain is a refractory pain state, and its mechanism is still not clear. Previous studies have shown that the purine receptor P2X4R expressed on hyperactive microglia in the spinal cord is essential for the occurrence and development of neuropathic pain. The cerebrospinal fluid-contacting nucleus (CSF-contacting nucleus) in the midbrain has been found to play an important role in the descending inhibition system of modulation. However, there have been no studies on P2X4R in the CSF-contacting nucleus involved in neuropathic pain. To investigate whether P2X4R is expressed in the CSF-contacting nucleus and whether its expression in the CSF-contacting nucleus is involved in the regulation of neuropathic pain, we used a model of chronic sciatic nerve ligation injury (CCI) to simulate neuropathic pain conditions. Immunohistochemistry experiments were conducted to identify the expression of P2X4R in the CSF-contacting nuclei in CCI rats, and western blot analysis showed a significant increase in P2X4R levels 7 days after modeling. Then, we packaged a P2rx4 gene-targeting shRNA in scAAV9 to knock down the P2X4R level in the CSF-contacting nucleus, and we found that CCI-induced mechanical hyperalgesia was reversed. In conclusion, P2X4R expressed in the CSF-contacting nucleus is involved in the process of neuropathic pain, and downregulating P2X4R protein in the CSF-contacting nucleus can reverse the occurrence and development of hyperalgesia, which could represent a potent therapeutic strategy for neuropathic pain.

Pain science education is commonly integrated into treatments for childhood-onset chronic pain. A core component of pain science education is learning about, and often reconceptualizing, the biology of chronic pain. Yet, few interventions have been developed specifically for young adults and little is known about how young adults conceptualize the biology of pain. This study used a qualitative methodology to examine how young adults with childhood-onset chronic pain understand the biology of pain, and the language they use in this meaning-making process, which may inform future interventions tailored to this age group.

Sulfatide is a sulfated glycosphingolipid that is present abundantly in myelin sheaths of the brain and spinal cord. It is synthesized by a cerebroside sulfotransferase encoded by Gal3st1, which catalyzes the transfer of sulfate from 3'-phosphoadenylylsulfate to galactosylceramide. We previously reported that Gal3st1 gene expression in the spinal cord is upregulated 1 day after intraplantar injection of complete Freund's adjuvant (CFA), indicating that sulfatide is involved in inflammatory pain. In the present study, we found that intrathecal injection of sulfatide led to mechanical allodynia. Sulfatide caused levels of glial fibrillary acidic protein (GFAP) and nitric oxide in the spinal cord to increase. Mechanical allodynia induced by intrathecal injection of sulfatide was blocked by nitric oxide synthase inhibitors and by suppression of astrocyte activation by L-α-aminoadipate. These results suggest that sulfatide-induced mechanical allodynia involved glial activation and nitric oxide production. Blocking selectin, a sulfatide-binding protein, with bimosiamose attenuated sulfatide-induced allodynia and ameliorated CFA-induced mechanical allodynia during inflammatory pain. Finally, elevated levels of sulfatide concentration in the spinal cord was observed during CFA-induced inflammatory pain. The elevated sulfatide levels enhanced selectin activation in the spinal cord, resulting in mechanical allodynia. Our data suggest that sulfatide-selectin interaction plays a key role in inflammatory pain.

Sensory neuron hyperexcitability is a critical driver of pathological pain and can result from axon damage, inflammation, or neuronal stress. G-protein coupled receptor (GPCR) signaling can induce pain amplification by modulating the activation of Trp-family ionotropic receptors and voltage-gated ion channels. Here, we sought to use calcium imaging to identify novel inhibitors of the intracellular pathways that mediate sensory neuron sensitization and lead to hyperexcitability. We identified a novel stimulus cocktail consisting of L-054,264, a SST2R agonist, and CYM5541, a S1PR3 agonist, that elicits calcium responses in mouse primary sensory neurons in vitro as well as pain and thermal hypersensitivity in mice in vivo. We screened a library of 906 bioactive compounds and identified 24 hits that reduced calcium flux elicited by L-054,264/CYM5541. Among these hits, silymarin, a natural product derived from milk thistle, strongly reduced activation by the stimulation cocktail, as well as by a distinct inflammatory cocktail containing bradykinin and prostaglandin E2. Silymarin had no effect on sensory neuron excitability at baseline, but reduced calcium flux via Orai channels and downstream mediators of phospholipase C signaling. In vivo, silymarin pretreatment blocked development of adjuvant-mediated thermal hypersensitivity, indicating potential use as an anti-inflammatory analgesic.

The role of Aβ-afferents in somatosensory function is often oversimplified as low threshold mechanoreceptors (LTMRs) with large omission of Aβ-afferent involvement in nociception. Recently, we have characterized Aβ-afferent neurons which have large diameter somas in the trigeminal ganglion (TG) and classified them into non-nociceptive and nociceptive-like TG afferent neurons based on their electrophysiological properties. Here, we extend our previous observations to further characterize electrophysiological properties of trigeminal Aβ-afferent neurons and investigate their mechanical and chemical sensitivity by patch-clamp recordings from large-diameter TG neurons in ex vivo TG preparations of adult male and female rats. Based on cluster analysis of electrophysiological properties, trigeminal Aβ-afferent neurons can be classified into five discrete types (type I, IIa, IIb, IIIa, and IIIb), which responded differentially to mechanical stimulation and sensory mediators including serotonin (5-HT), acetylcholine (ACh) and adenosine triphosphate (ATP). Notably, type I neuron action potential (AP) was small in amplitude, width was narrow in duration, and peak dV/dt repolarization was great with no deflection observed, whereas discretely graded differences were observed for type IIa, IIb, IIIa, and IIIb, as AP increased in amplitude, width broadened in duration, and peak dV/dt repolarization reduced with the emergence of increasing deflection. Type I, IIa, and IIb neurons were mostly mechanically sensitive, displaying robust and rapidly adapting mechanically activated current (IMA) in response to membrane displacement, while IIIa and IIIb, conversely, were almost all mechanically insensitive. Interestingly, mechanical insensitivity coincided with increased sensitivity to 5-HT and ACh. Together, type I, IIa and IIb display features of LTMR Aβ-afferent neurons while type IIIa and type IIIb show properties of nociceptive Aβ-afferent neurons.

Cannabis has been proposed as a therapeutic with potential opioid-sparing properties in chronic pain, and its use could theoretically be associated with decreased amounts of opioids used and decreased risk of mortality among individuals prescribed opioids.

Fibromyalgia (FM) is a chronic and systemic condition that causes widespread chronic pain, asthenia, and muscle stiffness, as well as in some cases depression, anxiety, and disorders of the autonomic system. The exact causes that lead to the development of FM are still unknown today. In a percentage of individuals, the symptoms of FM are often triggered and/or exacerbated by proximity to electrical and electromagnetic devices. Plasma metabolomic profile of 54 patients with fibromyalgia and self-reported electromagnetic sensitivity (IEI-EMF) were compared to 23 healthy subjects using gas chromatography-mass spectrometry (GC-MS) coupled with multivariate statistical analysis techniques. Before the GC-MS analysis the plasma samples were extracted with a modified Folch method and then derivatized with methoxamine hydrochloride in pyridine solution and N-trimethylsilyltrifuoroacetamide. The combined analysis allowed to identify a metabolomic profile able of distinguishing IEI-EMF patients and healthy subjects. IEI-EMF patients were therefore characterized by the alteration of 19 metabolites involved in different metabolic pathways such as energy metabolism, muscle, and pathways related to oxidative stress defense and chronic pain. The results obtained in this study complete the metabolomic "picture" previously investigated on the same cohort of IEI-EMF patients with H-NMR spectroscopy, placing a further piece for better understanding the pathophysiological mechanisms in patients with IEI-EMF.

In low back pain (LBP), primary care and secondary prevention of recurrent and persistent LBP are not always successful. Enhanced understanding of neural mechanisms of sensorimotor processing and pain modulation in patients with acute LBP is mandatory. This explorative fMRI study investigated sensorimotor processing due to mechanosensory stimulation of the lumbar spine. We studied 19 adult patients with acute LBP (< 4 weeks of an acute episode) and 23 healthy controls. On a numeric rating scale, patients reported moderate mean pain intensity of 4.5 out of 10, while LBP-associated disability indicated mild mean disability. The event-related fMRI analysis yielded no between-group differences. However, the computation of functional connectivity resulted in adaptive changes in networks involved in sensorimotor processing in the patient group: Connectivity strength was decreased in the salience and cerebellar networks but increased in the limbic and parahippocampal networks. Timewise, these results indicate that early connectivity changes might reflect adaptive physiological processes in an episode of acute LBP. These findings raise intriguing questions regarding their role in pain persistence and recurrences of LBP, particularly concerning the multiple consequences of acute LBP pain. Advanced understanding of neural mechanisms of processing non-painful mechanosensations in LBP may also improve therapeutic approaches.

Cancer-induced bone pain (CIBP) is a moderate to severe pain and seriously affects patients' quality of life. Spinal cord plays critical roles in pain generation and maintenance. Identifying differentially expressed proteins (DEPs) in spinal cord is essential to elucidate the mechanisms of cancer pain.

Opioid use disorders (OUDs) constitute a major public health issue, and we urgently need alternative methods for characterizing risk for OUD. Electronic health records (EHRs) are useful tools for understanding complex medical phenotypes but have been underutilized for OUD because of challenges related to underdiagnosis, binary diagnostic frameworks, and minimally characterized reference groups. As a first step in addressing these challenges, a new paradigm is warranted that characterizes risk for opioid prescription misuse on a continuous scale of severity, i.e., as a continuum.

Discogenic low back pain (DLBP) is considered the most common type of chronic low back pain (CLBP). Sinuvertebral nerve block (SVNB) is a rapid and precise intervention performed under local anesthesia to treat DLBP induced CLBP. Thus, in this study, we aimed to explore the clinical efficacy of SVNB for DLBP.

Mild cognitive impairment (MCI) as a prestage of dementia shares the most risk factors with dementia. In the present study, we explored the effect of flurbiprofen axetil on reducing the response of the central nervous system to inflammatory factors and anti-inhibiting apoptosis with the aim of developing a formalin-induced inflammatory pain model using MCI rats.

The objective of the present study was to explore the diversity, quality, severity and distribution of symptoms in patients with radicular pain and a lumbar disc herniation.

In the absence of a gold-standard diagnostic test for different subtypes of dry eye disease (DED), we aimed to identify latent subtypes of DED within a well-characterized cohort.

Fatigue is a symptom that can negatively impact patients' quality of life. However, the relationship of AD with fatigue has not been fully studied, especially in children.

This study analyses the 2020 survey and reviews the 2009, 2014 surveys to ascertain which Behçet's symptoms, personal and family status, patients' lifestyle, and work-related outcomes impacted on Health-Related Quality of Life (HRQoL).

The purpose of this research was to assess the role of heparanase (HPSE)/syndecan1 (SDC1)/nerve growth factor (NGF) on cancer pain from melanoma.

The objective was to investigate the efficacy and safety of soticlestat as adjunctive therapy in participants with complex regional pain syndrome (CRPS).

Long-term use of opioids such as morphine has negative side effects, such as morphine analgesic tolerance and morphine-induced hyperalgesia (MIH). These side effects limit the clinical use and analgesic efficacy of morphine. Elucidation of the mechanisms and identification of feasible and effective methods or treatment targets to solve this clinical phenomenon are important. Here, we discovered that YTHDF1 and TNF receptor-associated factor 6 (TRAF6) are crucial for morphine analgesic tolerance and MIH. The m6A reader YTHDF1 positively regulated the translation of TRAF6 mRNA, and chronic morphine treatments enhanced the m6A modification of TRAF6 mRNA. TRAF6 protein expression was drastically reduced by YTHDF1 knockdown, although TRAF6 mRNA levels were unaffected. By reducing inflammatory markers such as IL-1β, IL-6, TNF-α and NF-κB, targeted reduction of YTHDF1 or suppression of TRAF6 activity in ventrolateral periaqueductal gray (vlPAG) slows the development of morphine analgesic tolerance and MIH. Our findings provide new insights into the mechanism of morphine analgesic tolerance and MIH indicating that YTHDF1 regulates inflammatory factors such as IL-1β, IL-6, TNF-α and NF-κB by enhancing TRAF6 protein expression.

Globally, spinal cord injury (SCI) results in a big burden, including 90% suffering permanent disability, and 60%-69% experiencing neuropathic pain. The main causes are oxidative stress, inflammation, and degeneration. The efficacy of the stem cell secretome is promising, but the role of human neural stem cell (HNSC)-secretome in neuropathic pain is unclear. This study evaluated how the mechanism of HNSC-secretome improves neuropathic pain and locomotor function in SCI rat models through antioxidant, anti-inflammatory, anti-matrix degradation, and neurotrophic activities.

To evaluate the effectiveness of physiotherapy interventions on peripheral neuropathic pain (pNeP) due to any underlying cause.

To assess the effectiveness of mind-body (MB) exercise interventions provided by physical therapists for reducing pain and disability in people with low back pain (LBP).

We assessed whether race or ethnicity was associated with the incidence of high-impact chronic pain (cLBP) among adults consulting a primary care provider for acute low back pain (aLBP).

College students who experience chronic pain are a frequently overlooked population. This research attempts to provide insight into the language that college students use to describe their experiences with chronic pain, challenges they face and coping strategies they use. Over the course of 4 consecutive days, participants responded to an expressive writing prompt asking them to reflect on their emotions and thoughts related to being a college student with chronic pain. Writing samples were then analysed to identify themes pertaining to words with a positive or negative emotional valence, terms used to characterise pain, metaphors used to describe pain, challenges faced, and positive and negative coping strategies used. Results showed that participants were more likely to use negatively valenced words than positively valenced words to describe their pain. Several common words and phrases were used to characterise pain, including metaphors. Finally, participants reported a number of challenges associated with their lived-experience of chronic pain, as well as positive and negative strategies used to cope with those challenges. These findings help to put into perspective the language used to understand, and attempt to cope with, the challenges faced by college students experiencing chronic pain. Research must continue to investigate the needs of this population so that they can be properly supported physically, emotionally, socially and academically.

Interstitial cystitis (=painful bladder syndrome) is a chronic bladder syndrome characterised by pelvic and bladder pain, urinary frequency and urgency, and nocturia. Transient receptor potential (TRP) channels are an attractive target in reducing the pain associated with interstitial cystitis. The current study aims to determine the efficacy of combination of TRP vanilloid 1 (TRPV1) and TRP melastatin 8 (TRPM8) channel inhibition in reducing the pain associated with experimental cystitis in guinea pigs.

Dementia is an urgent public health problem worldwide, and the determination of the contribution of pain to cognitive decline or dementia is significant for the prevention of dementia.

This systematic review and meta-analysis aimed to determine the level of evidence for the psychometric properties of Ecological Momentary Assessment (EMA) in populations with persistent pain.

To study the prevalence of small-fiber neuropathy (SFN) in a large cohort of patients with fibromyalgia (FM) and to better characterize the subset of patients with both FM and SFN.

: This review aims to analyze the last years' experience of applying spinal cord stimulation (SCS) in complex regional pain syndrome (CRPS) patients with persistent or refractory chronic pain. : This is a narrative review which was executed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and was carried out through the following databases: PUBMED and Cochrane Library. Also, a search for trials in the metaRegister of controlled trials (www.clinicaltrials.gov) was performed. : SCS provides pain reduction and improves sensory, vasomotor and sudomotor symptoms. It can reduce opioid using, offering better life quality for the patients. : SCS found to be an excellent therapeutic alternative for patients with CRPS. It offers immediate pain relief and allows patients to regain functionality and have a better quality of life.

Postoperative nausea and vomiting (PONV) is a still highly relevant problem and is known to be a distressing side effect in patients. The aim of this study was to develop a machine learning model to predict PONV up to 24 h with fentanyl-based intravenous patient-controlled analgesia (IV-PCA).

Systematic review.

To develop a patient-centered text message-based platform that promotes self-management of symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS).

The pharmacological management of nonspecific chronic low back pain (NCLBP) aims to restore daily activities and improve the quality of life. No magic bullet exists for NCLBP; interventions to reduce pain and disability are available, but long-term results are unpredictable. Education in this regard needs to improve. This is often hard to accept for clinicians and patients, and provides a fertile soil to quacks, faith healers, and gurus to promote miraculous non-evidence-based solutions. The management of NCLBP is not well codified and extremely heterogeneous, and residual symptoms are common. Depending on the individual severity of NCLPB, pharmacological management may range from nonopioid to opioid analgesics. It is important to identify patients with generalized sensory hypersensitivity, who may benefit from a dedicated therapy. In this editorial, we provide an evidenced-based overview of the principles of pharmacological management of NCLPB.

Diffuse peripheral neuropathy is a well-known complication of several conditions, whereas many patients have peripheral neuropathy of unknown etiology and pathophyisology. Increased knowledge of mechanisms may provide insight into enteric neuropathy with gastrointestinal dysmotility. The aim of the present systematic review was to identify mechanisms behind diffuse idiopathic peripheral neuropathies in humans. Searches were performed in PubMed, Embase, and Web of Science. Human original and review articles, written in English, describing mechanisms behind diffuse peripheral neuropathy verified by objective examinations were intended to be studied. Articles that described animal models, well-described hereditary diseases, drug-induced neuropathy, pain syndromes, malnutrition, and local neuropathy were excluded. In total, 4712 articles were identified. After scrutinizing titles and abstracts, 633 remained and were studied in full text. After the removal of articles not fulfilling inclusion or exclusion criteria, 52 were finally included in this review. The most frequently described neuropathy was diabetic neuropathy, with a wide range of mechanisms involving mitochondrial dysfunction such as oxidative stress and inflammation. Microvascular changes in diabetes and vasculitis lead to ischemia and secondary oxidative stress with inflammation. Structural changes in neurons and glial cells are observed, with abnormalities in different neurotrophic factors. Neuropathy induced by autoantibodies or immunological mechanisms is described in infectious and systemic inflammatory diseases. Several ion channels may be involved in painful neuropathy. No study identified why some patients mainly develop large fiber neuropathy and others small fiber neuropathy. Metabolic and immunological factors and channelopathy may be considered in diffuse idiopathic peripheral neuropathy.

Chronic musculoskeletal pain (CMP) is characterised by pain related to the muscles or the joints with a duration of three months or more and is associated with high symptomatic burden in patients in primary health care. CMP is commonly associated with impaired mental health, which may affect the rehabilitation process. The primary aim of this study was to compare symptoms of anxiety, depression, fatigue, and insomnia in patients in primary health care with and without CMP. The secondary aim was to assess difference in mental health symptoms related to number of pain sites and pain intensity.

Four posters about the novel, fixed-dose calcipotriol and betamethasone dipropionate cream (CAL/BDP cream) based on Poly-Aphron Dispersion (PAD) Technology were presented at the 30 European Academy of Dermatology and Venereology (EADV) Congress 2021 and are summarized here. CAL/BDP cream was compared in two randomized, phase 3 trials to vehicle and active comparator (CAL/BDP gel/topical suspension [TS]) in adults with plaque psoriasis (NCT03802344 and NCT03308799). Pooled data from both trials demonstrated significant greater efficacy in favour of CAL/BDP cream for all efficacy endpoints, including PGA treatment success, mPASI, and mPASI75 compared to CAL/BDP gel/TS. CAL/BDP cream was well tolerated and comparable to CAL/BDP gel/TS with no adverse drug reactions with a frequency >1%. In the NCT03308799 study, CAL/BDP cream demonstrated a substantial improvement in the proportion of participants achieving a minimum 4-point improvement on the peak pruritus numeric rating scale (NRS) score compared with vehicle at Weeks 1, 4 and 8. CAL/BDP cream also improved quality of life (QoL), as assessed through the Dermatology Life Quality Index (DLQI), and the EQ-VAS at Week 8 compared with active comparator. Treatment convenience of CAL/BDP cream, as measured by the Psoriasis Treatment Convenience Scale, was superior to CAL/BDP gel/TS at all studied timepoints, including questions addressing formulation's greasiness and overall treatment satisfaction. Finally, an indirect comparison following the Bucher's method of adjusted indirect comparison and the difference-in-differences method was conducted to compare CAL/BDP cream and CAL/BDP foam, as both therapies have been compared to CAL/BDP gel/TS. Indirect evidence showed that treatment with CAL/BDP cream was associated with a trend for greater QoL improvement than CAL/BDP foam when DLQI improvement was assessed at the recommended treatment duration of 8 weeks for CAL/BDP cream and 4 weeks for CAL/BDP foam. CAL/BDP cream was statistically superior versus CAL/BDP foam in four out of five treatment satisfaction domains.

Inflammatory bowel diseases (IBDs) are chronic, immune-mediated disorders that include Crohn's disease and ulcerative colitis. A pediatric onset of disease occurs in about 10% of all cases. Clinical presentation of IBD with rectal bleeding or perianal disease warrants direct referral for endoscopic evaluation. In the absence of red-flag symptoms, a combination of patient history and blood and fecal biomarkers can help to distinguish suspected IBD from other causes of abdominal pain or diarrhea. The therapeutic management of pediatric IBD has evolved by taking into account predictors of poor outcome, which justifies the upfront use of anti-tumor necrosis factor therapy for patients at high risk for complicated disease. In treating patients with IBD, biochemical or endoscopic remission, rather than clinical remission, is the therapeutic goal because intestinal inflammation often persists despite resolution of abdominal symptoms. Pediatric IBD comes with unique additional challenges, such as growth impairment, pubertal delay, the psychology of adolescence, and development of body image. Even after remission has been achieved, many patients with IBD continue to experience nonspecific symptoms like abdominal pain and fatigue. Transfer to adult care is a well-recognized risk for disease relapse, which highlights patient vulnerability and the need for a transition program that is continued by the adult-oriented IBD team. The general pediatrician is an invaluable link in integrating these challenges in the clinical care of patients with IBD and optimizing their outcomes. This state-of-the-art review aims to provide general pediatricians with an update on pediatric IBD to facilitate interactions with pediatric gastrointestinal specialists.

Cannabis and cannabinoids continue to gain popularity as adjuncts or alternatives to opioids in pain management, with evolving evidence of effectiveness. The relationship between cannabis and opioid use has previously been investigated in smaller cohorts or ecological samples, but not yet in a nationally representative sample.

The study aim was to describe migraine incidence over the ten-year periods, 2000-2009 and 2010-2019, in individuals aged 10-79 years in primary healthcare centre (PHCC) Sólvangur and Fjörður, Hafnarfirði. Another aim was to estimate migraine prevalence in primary care clinics in the capital area of Iceland over the period 2010-2019 and describe prescriptions for migraine specific drugs and other drugs used for migraine.

Rheumatoid arthritis is a chronic condition that is characterized by joint pain and inflammation. It is an autoimmune disorder in which the body tissues are erroneously attacked by the immune system of the host itself. It has been evident that rheumatoid arthritis symptoms follow a 24 h circadian rhythm and exhibit high thresholds of pain, functional disability, and stiffness predominantly early in the morning. Colon-specific drug delivery systems can be utilized in the formulations to be used in the treatment of rheumatoid arthritis. The colon-specific drug delivery system has shown promising results in the treatment of different diseases at the colonic site like Crohn's disease, ulcerative colitis, colon cancer, etc. The colon-specific drug delivery is capable of delivering the formulation at the predetermined location and predetermined time. The early morning symptoms of rheumatoid arthritis like pain and inflammation can be treated using the various approaches of the colon-specific drug delivery system because it will lead to patient compliance as the patient will not require administering the formulation immediately after waking up in the morning. This review also explains the immunological factors which may trigger rheumatoid arthritis in human beings. It further explores conventional approaches like pH-dependant, microorganisms-driven, pressure-controlled, and time-dependant formulations. By employing two or more conventional approaches given above the various novel approaches have been designed to eliminate the drawbacks of individual techniques.

Emotional Awareness and Expression Therapy (EAET) targets trauma and emotional conflict to reduce or eliminate chronic pain, but video telehealth administration is untested. This uncontrolled pilot assessed acceptability, feasibility, and preliminary efficacy of group-based video telehealth EAET (vEAET) for older veterans with chronic musculoskeletal pain.

An expanding array of image-guided spine interventions have the potential to provide immediate and effective pain relief. Innovations in spine intervention have proceeded rapidly, with clinical adoption of new techniques at times occurring before the development of bodies of evidence to establish efficacy. Although new spine interventions have been evaluated by clinical trials, acceptance of results has been hindered by controversies regarding trial methodology. This article explores controversial aspects of four categories of image-guided interventions for painful conditions: spine interventions for postdural puncture headache resulting from prior lumbar procedures; epidural steroid injections for cervical and lumbar radiculopathy; facet and sacroiliac joint pain interventions; and vertebral augmentations for compression fractures. For each intervention, we summarize the available literature with an emphasis on persistent controversies and discuss how current areas of disagreement and challenge may shape future research and innovation. Despite the ongoing areas of debate for various aspects of these procedures, effective treatments continue to emerge and show promise for aiding relief on a range of debilitating conditions.

Self-efficacy is one of the important factors affecting chronic diseases. In the current epidemiological context of low back pain (LBP), LBP self-efficacy has become a topic of great practical interest for researchers. However, no bibliometric analysis related to LBP self-efficacy has been performed to date. The purpose of this study was to conduct and explore the current state of research in LBP self-efficacy from 1980 to 2021, by using bibliometric analysis and scientific mapping.

Medical cannabis is commonly and increasingly used by Canadians to manage chronic pain. As of March 2021, Health Canada reported that approximately 300,000 Canadians who were authorized to access medical cannabis, which is more than a 1000% increase from the 24,000 registered in 2015. Physicians, however, receive limited information on therapeutic cannabis during their training, and their perceptions regarding this therapeutic option are uncertain. This study focused on exploring attitudes and beliefs of pain physicians regarding medical cannabis for the management of chronic noncancer pain.

Animal models have consistently indicated that central sensitization and the development of chronic neuropathic pain is linked to changes to inhibitory signalling in the dorsal horn of the spinal cord. However, replication of data investigating the cellular mechanisms that underly these changes remain a challenge and there is still a lack of understanding about what aspects of spinal inhibitory transmission most strongly contribute to the disease. Here, we compared the effect of two different sciatic nerve injuries commonly used to generate rodent models of neuropathic pain on spinal glycinergic signalling. Using whole-cell patch-clamp electrophysiology in spinal slices, we recorded from neurons in the lamina II of the dorsal horn and evoked inhibitory postsynaptic currents with a stimulator in lamina III, where glycinergic cell bodies are concentrated. We found that glycine inputs onto radial neurons were reduced following partial nerve ligation (PNL) of the sciatic nerve, consistent with a previous report. However, this finding was not replicated in animals that underwent chronic constriction injury (CCI) to the same nerve region. To limit the between-experiment variability, we kept the rat species, sex, and age consistent and had a single investigator carry out the surgeries. These data show that PNL and CCI cause divergent spinal signalling outcomes in the cord and add to the body of evidence suggesting that treatments for neuropathic pain should be triaged according to nerve injury or cellular dysfunction rather than the symptoms of the disease.

Chronic, abdominal pain remains a problem in a subset of patients after cholecystectomy. The cause is often obscure but central sensitization may be an important component and could theoretically be mediated by spinal PGE2, which is regulated by several cytokines. The aim of the study was to examine cerebrospinal fluid (CSF) of participants with post cholecystectomy syndrome and healthy volunteers for signs of PGE2 and cytokine mediated central sensitization.

To assess the receptors of TRPV1 and GABA receptors that were colocalized in cerebrospinal fluid contacting nucleus (CSF-contact nucleus) of chronic inflammatory pain (CIP) rats bringing inspiration for reducing chronic pain.

Chronic pain is one of the most critical health issues worldwide. Despite considerable efforts to find therapeutic alternatives, opioid drugs remain the gold standard for pain management. The administration of μ-opioid receptor (MOR) agonists is associated with detrimental and limiting adverse effects. Overall, these adverse effects strongly overshadow the effectiveness of opioid therapy. In this context, the development of neurotensin (NT) ligands has shown to be a promising approach for the management of chronic and acute pain. NT exerts its opioid-independent analgesic effects through the binding of two G protein-coupled receptors (GPCRs), NTS1 and NTS2. In the last decades, modified NT analogues have been proven to provide potent analgesia in vivo. However, selective NTS1 and non-selective NTS1/NTS2 ligands cause antinociception associated with hypothermia and hypotension, whereas selective NTS2 ligands induce analgesia without altering the body temperature and blood pressure. In light of this, various structure-activity relationship (SAR) studies provided for findings addressing the binding affinity of ligands towards NTS2. Herein, we comprehensively review peptide-based NTS2-selective ligands as a robust alternative for future pain management. Particular emphasis is placed on SAR studies governing the desired selectivity and associated in vivo results.

Osteoarthritis (OA) is the most common age-related chronic and disabling joint disease, frequently causing pain and disability in the adult population. Given that there are no proven disease-modifying drugs for OA, it is urgent to gain a deeper understanding of OA pathogenesis. This study intended to uncover the circFOXK2 regulation in OA.

Neuropathic pain (NP) is a chronic health condition that presents a significant burden on patients, society, and even healthcare systems. However, in recent years, an emerging field in the treatment of neuropathic pain – optogenetic technology has dawned, heralding a new era in the field of medicine, and which has brought with it unlimited possibilities for studying the mechanism of NP and the treatment of research. Optogenetics is a new and growing field that uses the combination of light and molecular genetics for the first time ever. This rare combination is used to control the activity of living cells by expressing photosensitive proteins to visualize signaling events and manipulate cell activity. The treatments for NP are limited and have hardly achieved the desirable efficacy. NP differs from other types of pain, such as nociceptive pain, in that the treatments for NP are far more complex and highly challenging for clinical practice. This review presents the background of optogenetics, current applications in various fields, and the findings of optogenetics in NP. It also elaborates on the basic concepts of neuropathy, therapeutic applications, and the potential of optogenetics from the bench to the bedside in the near future.

Rotator cuff-related shoulder pain (RCRSP) is a common musculoskeletal problem. The multi-factorial contributors to persistent pain are often overlooked during treatment. Pain neuroscience education (PNE) contributes to a holistic approach for patients with persistent pain but has not yet been researched for patients with RCRSP.

The thalamocortical (TC) circuit is closely associated with pain processing. The hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 channel is predominantly expressed in the ventral posterolateral thalamus (VPL) that has been shown to mediate neuropathic pain. However, the role of VPL HCN2 in modulating TC circuit activity is largely unknown. Here, by using optogenetics, neuronal tracing, electrophysiological recordings, and virus knockdown strategies, we showed that the activation of VPL TC neurons potentiates excitatory synaptic transmission to the hindlimb region of the primary somatosensory cortex (S1HL) as well as mechanical hypersensitivity following spared nerve injury (SNI)-induced neuropathic pain in mice. Either pharmacological blockade or virus knockdown of HCN2 (shRNA-Hcn2) in the VPL was sufficient to alleviate SNI-induced hyperalgesia. Moreover, shRNA-Hcn2 decreased the excitability of TC neurons and synaptic transmission of the VPL-S1HL circuit. Together, our studies provide a novel mechanism by which HCN2 enhances the excitability of the TC circuit to facilitate neuropathic pain.

Ruxolitinib cream 1.5% (OPZELURA™) is a topical formulation of ruxolitinib, a potent, selective inhibitor of Janus kinase (JAK)1 and JAK2. The targeting of these kinases is associated with therapeutic benefits in patients with atopic dermatitis (AD). In two identically designed, multinational, phase III studies in patients aged ≥ 12 years with mild to moderate AD, ruxolitinib cream 1.5% improved measures of disease severity, pruritus and sleep disturbance relative to vehicle cream when applied twice daily for 8 weeks. Disease severity was controlled for the next 44 weeks when applied as needed to active lesions. Ruxolitinib cream 1.5% was well tolerated in this patient population; its safety profile was similar to that of vehicle cream over the short term, with the types of treatment-emergent adverse events typical of those seen in the vehicle-controlled period over the longer term. Moreover, application site treatment-emergent adverse events indicative of skin tolerability issues (e.g. stinging/burning sensation) were infrequent and no safety findings suggestive of systemic JAK inhibition were identified. Although further longer-term data would be of use, ruxolitinib cream 1.5% provides an alternative to established topical agents (e.g. corticosteroids and calcineurin inhibitors) for the treatment of mild to moderate AD in adults and adolescents.

Diagnosis of hip osteoarthritis (OA) is based on clinical arguments, and medical imaging is obtained to confirm the diagnosis and rule out other possible sources of pain. Conventional radiographs are recommended as the first line imaging modality to investigate chronic hip pain. They should be obtained in a rigorous technique that includes an antero-posterior (AP) radiograph of the pelvis. The choice of the appropriate lateral view depends on the clinical indication, Lequesne's false profile being valuable in the assessment of OA. Magnetic resonance imaging (MRI) is more sensitive to detect joint effusion/synovitis, cartilage, labral, and bone marrow lesions. However, structural joint changes are frequent in asymptomatic population and neither radiographs nor MRI have shown a good correlation with pain and functional impairment. MRI seems to be more suitable than radiographs as a biomarker for clinical trials addressing early OA. The absence of a validated MR biomarker of early OA, together with issues related to machine availability and MRI protocol repeatability, prevent the widespread use of MRI in clinical trials.

Adenomyosis is an estrogen-dependent gynecological disease. The pathogenesis of chronic pain, the main clinical symptom of adenomyosis, remains undefined. As a combination lymphocyte with both T-cell and natural killer (NK)-cell properties, NK T (NKT) cells play a role in immune defense against numerous diseases and modulate cell differentiation.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-2 selective inhibitors are the most widely used drugs to treat pain. Conventional NSAIDs and COX-2 selective inhibitors, however, cause several side effects such as gastric damage, kidney damage, and cardiovascular problems. Our previous study showed that 2-acetoxy-5-(2-4-(trifluoromethyl)-phenethylamino)-benzoic acid ie, flusalazine (also known as ND-07), which exerts dual actions by serving both as an anti-inflammatory agent and a free radical scavenger, is an effective and safe treatment for severe inflammatory diseases in mice. The goal of the present study was to examine the potential analgesic action and safety of flusalazine in mice models of pain.

Vertigo is very common in children, but the specific diagnosis and characteristics are not clear. The main objective of this study was to analyze the characteristics of caloric test (CT) and video head impulse test (vHIT) in vestibular migraine of childhood (VMC), probable vestibular migraine of childhood (PVMC), and recurrent vertigo of childhood (RVC), which can provide a reference value for their clinical diagnosis.

Nuclear factor kappa B (NF-κB) signaling is an important modulator in osteoarthritis (OA), and IκB kinase ε (IKKε) regulates the NF-κB pathway. This study was undertaken to identify the functional involvement of IKKε and the effectiveness of IKKε inhibition in OA pathogenesis.

Cluneal neuropathy is encompassed by three distinct clinical entities. Superior, middle and inferior cluneal neuralgia make up the constellation of symptoms associated with cluneal neuropathy. Each has its own variable anatomy. Adjusted incidence rates of superior cluneal neuropathy are 1.6-11.7%. Accurate diagnosis remains challenging due to lack of standardized criteria and the aforementioned variability. Treatment may include therapeutic nerve blocks, ablative techniques, neuromodulation and surgical decompression. Gaps including those related to true incidence and work up exist. Outcomes from interventional studies are limited and mixed due to significant population heterogeneity and non-standardized treatment approaches coupled with very small sample sizes.

Chronic pain is often accompanied by emotional dysfunction. Transcranial direct current stimulation (tDCS) has been used for reducing pain, depressive and anxiety symptoms in chronic pain patients, but its therapeutic effect remains unknown.

The hub-and-spoke telehealth model leverages centrally located providers who utilize telehealth technology to bring specialized care to medically underserved areas. This model has the potential to promote equitable access to healthcare. However, few studies address how to facilitate the adoption and implementation of hub-and-spoke telehealth. We examined spoke site providers' experiences with TelePain, a national hub-and-spoke model of interdisciplinary chronic pain care, with a focus on improving future implementation. We conducted semi-structured individual interviews (20-45 min) with 27 VA spoke site providers via teleconferencing between August 2020 and February 2021. Interview transcripts were coded in Atlas.ti 8.0 using deductive (identified a priori and used to build the interview guide) and inductive (emerging) codes. Our analysis identified the following themes stressed by the spoke sites: (1) spoke sites needed to envision how TelePain services would work at their site before deciding to adopt; (2) TelePain implementation needed to fit into local existing care processes; (3) hub sites needed to understand spoke sites' context (e.g., via needs assessment) to tailor the services accordingly, and (4) hub-and-spoke sites needed to establish bidirectional communication. Our findings provide a practical guide to improve future rollout of hub-and-spoke telehealth models. Recommendations focus on the role of the hub site in promoting program adoption by (1) developing a clear and detailed marketing plan and (2) considering how the program can be adapted to fit the local spoke site context. To improve implementation, hub-and-spoke sites must establish ongoing and consistent bidirectional communication; this is particularly critical in the everchanging post-peak pandemic healthcare system. An important next step is the development of recommendations and guidelines for implementing hub-and-spoke telehealth, as well as examining pain outcomes for patients touched by this program.

One of the common negative effects of a stroke that seriously lowers patients' quality of life is post-stroke pain (PSP). Thus, exercise in PSP management has become a hot research topic. The main advantages of exercise therapy are affordability and ease of acceptance by patients compared to other treatment methods. Therefore, this article reviews the effectiveness and possible mechanisms of exercise interventions for PSP. Exercise training for patients with PSP not only improves physical function but also effectively reduces pain intensity and attenuates the behavioral response to pain. In addition, exercise therapy can improve brain function and modulate levels of pro-inflammatory and neurotrophic factors to exert specific analgesic effects. Potential mechanisms for exercise intervention include modulation of synaptic plasticity in the anterior cingulate gyrus, modulation of endogenous opioids , reversal of brain-derived neurotrophic factor overexpression, inhibition of purinergic receptor (P2X4R, P2X7R) expression, and inhibition of microglia activation. However, current research on exercise for PSP remains limited, and the sustainable benefits of exercise interventions for PSP need to be further investigated.

The term 'opioids' refers to both the natural compounds ('opiates') which are extracted from the opium poppy plant () and their semi-synthetic and synthetic derivatives. They all possess relatively similar biochemical profiles and interact with the opioid receptors within the human body to produce a wide range of physiological effects. They have historically been used for medicinal purposes, their analgesic and sedative effects, and in the management of chronic and severe pain. They have also been used for non-medicinal and recreational purposes to produce feelings of relaxation, euphoria and well-being. Over the last decade, the emergence of an illegal market in new synthetic opioids has become a major global public health issue, associated with a substantial increase in unintentional overdoses and drug-related deaths. Synthetic opioids include fentanyl, its analogues and emerging non-fentanyl opioids. Their popularity relates to changes in criminal markets, pricing, potency, availability compared to classic opioids, ease of transport and use, rapid effect and lack of detection by conventional testing technologies. This article expands on our previous review on new psychoactive substances. We now provide a more in-depth review on synthetic opioids and explore the current challenges faced by people who use drugs, healthcare professionals, and global public health systems.

Inflammation could impact on the formation and persistence of interoceptive fear and hypervigilance, with relevance to psychiatric disorders and chronic pain. To systematically analyze effects of inflammation on fear learning and extinction, we performed two complementary randomized, double-blind, placebo-controlled functional magnetic resonance imaging (fMRI) studies combining experimental endotoxemia as a translational model of acute systemic inflammation with a two-day multiple-threat fear conditioning paradigm involving interoceptive and exteroceptive unconditioned stimuli (US). Healthy volunteers (N=95) were randomized to receive intravenous injections of either endotoxin (lipopolysaccharide, LPS; 0.4ng/kg) or placebo prior to fear acquisition (study 1) or extinction training (study2). Treatment effects on behavioral and neural responses to conditioned stimuli (CS) predicting interoceptive or exteroceptive threat were assessed during fear learning and extinction phases, along with US valence ratings. Despite robust inflammatory and emotional responses triggered by LPS, no direct effects of inflammation on US ratings or on the formation or extinction of conditioned fear, as assessed with CS valence ratings, were observed. However, in the group treated with LPS prior to acquisition (i.e., study 1), we found enhanced neural responses to the interoceptive but not the exteroceptive CS in key regions of the central fear circuitry during extinction learning. After extinction, this group further showed enhanced negative valence ratings selectively for the interoceptive US during unexpected US re-exposure when compared to the placebo group. Together, inflammation during fear acquisition may promote the establishment of a more robust neural signature of the interoceptive fear memory trace, which may contribute to altered interoceptive pain perception. The fear extinction circuitry engaged during interoceptive fear memory processing may be particularly vulnerable to inflammation, with transdiagnostic implications for gut-brain mechanisms underlying disturbed interoception in psychiatric conditions and chronic visceral pain.

Sciatica is a pain disorder often caused by the herniated disk compressing the lumbosacral nerve roots. Neuroimaging studies have identified functional abnormalities in patients with chronic sciatica (CS). However, few studies have investigated the neural marker of CS using brain structure and the classification value of multidimensional neuroimaging features in CS patients is unclear.

Kinins are endogenous peptides that belong to the kallikrein-kinin system, extensively studied for over a century. Their essential role in multiple physiological and pathological processes is demonstrated by activating two transmembrane G-protein-coupled receptors, the kinin B and B receptors. Attention is mainly given to the pathological role of kinins in pain transduction mechanisms. In the past years, a wide range of preclinical studies has amounted to the literature reinforcing the need for an updated review about the participation of kinins and their receptors in pain disorders. Here, we performed an extensive literature search since 2004, describing the historical progress and the current understanding of the kinin receptors' participation and its potential therapeutic in several acute and chronic painful conditions. These include inflammatory (mainly arthritis), neuropathic (caused by different aetiologies, such as cancer, multiple sclerosis, antineoplastic toxicity and diabetes) and nociplastic (mainly fibromyalgia) pain. Moreover, we highlighted the pharmacological actions and possible clinical applications of the kinin B and B receptor antagonists, kallikrein inhibitors or kallikrein-kinin system signalling pathways-target molecules in these different painful conditions. Notably, recent findings sought to elucidate mechanisms for guiding new and better drug design targeting kinin B and B receptors to treat a disease diversity. Since the kinin B receptor antagonist, Icatibant, is clinically used and well-tolerated by patients with hereditary angioedema gives us hope kinin receptors antagonists could be more robustly tested for a possible clinical application in the treatment of pathological pains, which present limited pharmacology management.

To i) identify and map the available evidence regarding effectiveness and harms of spinal manipulation and mobilisation for infants, children and adolescents with a broad range of conditions; ii) identify and synthesise policies, regulations, position statements and practice guidelines informing their clinical use.

The selection strategy of non-steroidal anti-inflammatory drugs (NSAIDs) for migraine is hard to judge whether it is effective, leading to unnecessary exposure to insufficient or lengthy treatment trials. The goal of the study was to investigate potential predictors of NSAIDs efficacy in migraine therapy and to explore their influence on efficacy. 610 migraine patients were recruited and assigned into responders and non-responders. Potential predictors among demographic and clinical characteristics for NSAIDs efficacy were extracted using multivariable logistic regression (LR) analysis, and were applied to construct prediction models machine learning (ML) algorithms. Finally, Cochran-Mantel-Haenszel tests were used to examine the impact of each predictor on drug efficacy. Multivariate LR analysis revealed migraine-related (disease duration, headache intensity and frequency) and psychiatric (anxiety, depression and sleep disorder) characteristics were predictive of NSAIDs efficacy. The accuracies of ML models using support vector machine, decision tree and multilayer perceptron were 0.712, 0.741, and 0.715, respectively. Cochran-Mantel-Haenszel test showed that, for variables with homogeneity of odds ratio, disease duration, frequency, anxiety, and depression and sleep disorder were associated with decreased likelihood of response to all NSAIDs. However, the variabilities in the efficacy of acetaminophen and celecoxib between patients with mild and severe headache intensity were not confirmed. Migraine-related and psychiatric parameters play a critical role in predicting the outcomes of acute migraine treatment. These models based on predictors could optimize drug selection and improve benefits from the start of treatment.

Exosomes bind to and are endocytosed by neurons of various brain regions. Methods for isolating and extracting exosomes from specific brain samples are critical. At present, the most important extractive methods for exosomes are Ultracentrifugation and exosome isolation kit extraction. Both of these extraction methods have applications in neuroscience. We compare these methods to reveal the differences METHODS: We sectioned the nucleus accumbens of mice, and isolated exosomes. A culture medium containing exosomes was extracted using ultracentrifugation (UC) and a total exosome isolation kit (TEI). The exosomes were examined using transmission electron microscopy (TEM), measurement regarding the diameter of the exosomes was done, and the thermal allodynia and western blotting analysis were also conducted, respectively.

Despite the prevalence of opioid misuse, opioids remain the frontline treatment regimen for severe pain. However, opioid safety is hampered by side-effects such as analgesic tolerance, reduced analgesia to neuropathic pain, physical dependence, or reward. These side effects promote development of opioid use disorders and ultimately cause overdose deaths due to opioid-induced respiratory depression. The intertwined nature of signaling via μ-opioid receptors (MOR), the primary target of prescription opioids, with signaling pathways responsible for opioid side-effects presents important challenges. Therefore, a critical objective is to uncouple cellular and molecular mechanisms that selectively modulate analgesia from those that mediate side-effects. One such mechanism could be the transactivation of receptor tyrosine kinases (RTKs) via MOR. Notably, MOR-mediated side-effects can be uncoupled from analgesia signaling via targeting RTK family receptors, highlighting physiological relevance of MOR-RTKs crosstalk. This review focuses on the current state of knowledge surrounding the basic pharmacology of RTKs and bidirectional regulation of MOR signaling, as well as how MOR-RTK signaling may modulate undesirable effects of chronic opioid use, including opioid analgesic tolerance, reduced analgesia to neuropathic pain, physical dependence, and reward. Further research is needed to better understand RTK-MOR transactivation signaling pathways, and to determine if RTKs are a plausible therapeutic target for mitigating opioid side effects.

Itch is an unpleasant sensation that provokes the desire to scratch. While acute itch serves as a protective system to warn the body of external irritating agents, chronic itch is a debilitating but poorly-treated clinical disease leading to repetitive scratching and skin lesions. However, the neural mechanisms underlying the pathophysiology of chronic itch remain mysterious. Here, we identified a cell type-dependent role of the anterior cingulate cortex (ACC) in controlling chronic itch-related excessive scratching behaviors in mice. Moreover, we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area (VTA) that was critically involved in chronic itch. Furthermore, we demonstrate that the ACC→VTA circuit also selectively modulated histaminergic acute itch. Finally, the ACC neurons were shown to predominantly innervate the non-dopaminergic neurons of the VTA. Taken together, our findings uncover a cortex-midbrain circuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention.

This review synthesizes recent findings related to the biopsychosocial processes that underlie racial disparities in chronic pain, while highlighting opportunities for interventions to reduce disparities in pain treatment among BIPOC.

Recent studies have shown that the ephrin/Eph signaling pathway may contribute to the pathology of neuropathic pain. Drugs like progesterone may be used to counteract both thermal hyperalgesia and mechanical allodynia in different models of neuropathic pain. The present study was designed to determine progesterone's modulatory role on neuropathic pain and spinal expression of ephrin-B2 following chronic constriction nerve injury (CCI). Thirty-six adult male Wistar rats were used. The sciatic nerve was chronically constricted. Progesterone (5 mg/kg and 15 mg/kg) was administrated for 10 days (from day 1 up to day10) following sciatic constriction. Behavioral tests were performed before surgery (day 0) and on days 1, 3, 7, and 14 after CCI and before progesterone administration on the same days. Western blotting was performed on days 3, 7, and 14 post-surgery. The findings showed that after CCI, the expression of spinal cord ephrin-B2 increased significantly in parallel with mechanical allodynia and thermal hyperalgesia. Post-injury administration of progesterone (15 mg/kg but not 5) decreased mechanical allodynia, thermal hyperalgesia, and the expression of spinal ephrin-B2. It is concluded that post-injury repeated administration of progesterone could be an effective way of alleviating neuropathic pain by suppressing ephrin-B2 activation and helps to make the better design of steroid-based therapies to inhibit pain after peripheral injury.

Cognitive behavioral therapy for chronic pain (CBT-CP) is an evidence-based treatment for improving functioning and pain intensity for people with chronic pain with extensive evidence of effectiveness. However, there has been relatively little investigation of the factors associated with successful implementation and uptake of CBT-CP, particularly clinician and system level factors. This formative evaluation examined barriers and facilitators to the successful implementation and uptake of CBT-CP from the perspective of CBT-CP clinicians and referring primary care clinicians.

Neuropathic pain is a common health problem resulting in exacerbated response to noxious and non noxious stimuli, as well as impaired emotional and cognitive responses. Unfortunately, neuropathic pain is also one of the most difficult pain syndromes to manage, highlighting the importance of better understanding the brain regions and neuromodulatory mechanisms involved in its regulation. Among the many interconnected brain areas which process pain, the amygdala is known to play an important role in the integration of sensory and emotional pain signals. Here we questioned the ability of a recently identified neuromodulatory mechanism associated with the metabotropic glutamate receptors mGlu in the amygdala to modulate neuropathic pain. In a murine model of peripheral mononeuropathy, we demonstrate that pharmacological activation of amygdala mGlu efficiently alleviates sensory and depressive-like symptoms in both male and female mice. Moreover, we reveal a differential modulation of these symptoms. Activating mGlu in the contralateral amygdala relative to the side of the mononeuropathy, is necessary and sufficient to relieve both sensory and depressive-like symptoms, while ipsilateral activation solely reduces depressive-like symptoms. Furthermore, using photopharmacology, a recent strategy allowing precise photocontrol of endogenous proteins, we further demonstrate the dynamic alleviation of neuropathic pain through light-dependent facilitation of mGlu by a photoswitchable positive allosteric modulator. Finally, coupling photopharmacology and analgesic conditioned place preference, we show a significant pain-reducing effect of mGlu4 activation. Taken together, these data highlight the analgesic potential of enhancing amygdala mGlu activity to counteract neuropathy reinforcing its therapeutic interest for the treatment of pathological pain.

The nucleotide oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) in dorsal root ganglion (DRG) contributes to pain hypersensitivity in multiple neuropathic pain models, but the function of the NLRP3 in diabetic neuropathic pain (DNP) and the regulation mechanism are still largely unknown. Epigenetic regulation plays a vital role in the controlling of gene expression. Ten-eleven translocation methylcytosine dioxygenase 2 (TET2) is a DNA demethylase that contributes to transcriptional activation. TET2 is also involved in high glucose (HG)-induced pathology.

Psoriatic arthritis (PsA) is a chronic, immune-mediated, spondyloarthropathy characterised by musculoskeletal signs and symptoms with associated joint pain and tenderness. The average worldwide PsA prevalence is 133/100,000, while in the Italian population is 90-420/100,000. Traditionally, nonsteroidal anti-inflammatory drugs, glucocorticoid, and disease-modifying antirheumatic drugs have been used in the treatment of PsA. However, for those patients who are not adequately controlled with conventional therapies, the new biologics compounds represent a valid option. Biologic therapies have been shown to be more effective but also more expensive than conventional systemic treatments. Based on the CHRONOS study, the economic analyses presented in this paper aim to assess the annualised direct costs and the cost-per-responder of biologics in a real-world context assuming the Italian National Health System perspective.

As one of the most frequent extra-articular manifestations of rheumatoid arthritis (RA), interstitial lung disease (ILD) is still challenging due to unrevealed pathophysiological mechanism. To address this question, in the present study, we used the classical collagen-induced arthritis (CIA) mouse model to determine the related-immune mechanism of lung injury and possible pharmacological treatment for RA-ILD. At the peak of arthritis, we found CIA mice developed apparent lung injury, characterized by interstitial thickening, inflammatory cell infiltration, and lymphocyte follicle formation. Additionally, the endothelial injury occurred as the number of endothelial cells (ECs) and their CD31 expression decreased. Along with those, monocytes, predominantly Ly6C monocytes with pro-inflammatory phenotype, were also increased. While in the remission period of arthritis, ECs gradually increased with retrieved CD31 expression, leading to decreased infiltrating monocytes, but boosted Ly6C population. Ly6C monocytes were prone to locate around damaged ECs, promoted ECs proliferation and vascular tube formation, and lessened the expression of adhesion molecules. In addition, we evaluated angiotensin II type 2 receptor (Agtr2), which has been demonstrated to be protective against lung injury, could be beneficial in RA-ILD. We found elevated Agtr2 in CIA lung tissue, and activation of Agtr2, within its specific agonist C21, alleviated the pulmonary inflammation in vivo, reduced ECs injury, and promoted monocytes conversion from Ly6C to Ly6C monocytes in vitro. Our data reveal a potential pathological mechanism of RA-ILD that involves ECs damage and inflammatory monocytes infiltration and provide a potential drug target, Agtr2, for RA-ILD treatment.

Endometriosis is a pathophysiological condition characterized by glands and stroma outside the uterus in regions such as the bladder, ureter, fallopian tubes, peritoneum, ovaries, and even in extra pelvic sites. One of the main clinical problems of endometriosis is chronic pelvic pain (CPP), which considerably affects the patients' quality of life. Patients with endometriosis may, cyclically or non-cyclically (80% of cases) experience CPP. High levels of anxiety and depression have been described in patients with endometriosis related to CPP; however, this has not been evaluated in endometriosis women with different types of CPP. Therefore, the research question of this study was whether there is a difference in the emotional dysregulation due to the type of pain experienced by women with endometriosis?

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal tract (GI). Currently, the treatment options for IBD are limited. It has been reported that a novel bioactive mitochondrial-derived peptide (MOTS-c) encoded in the mitochondrial 12S rRNA, suppresses inflammatory response by enhancing the phagocytosis of macrophages. The aim of this study was to investigate the protective effects of MOTS-c against dextran sulfate sodium (DSS)-induced colitis. The results showed that intraperitoneal (i.p.) administration of MOTS-c significantly ameliorated the symptoms of DSS-induced experimental colitis, such as body weight loss, colon length shortening, diarrhea, and histological damage. MOTS-c down-regulated the expression of pro-inflammatory cytokines, decreased the plasma levels of myeloperoxidase, and inhibited the activation of macrophages and recruitment of neutrophils. Moreover, treatment with MOTS-c exhibited anti-apoptotic effects and significantly suppressed the phosphorylation of AMPKα1/2, ERK, and JNK. Notably, oral administration of MOTS-c did not result in any significant improvements. Screening of cell penetrating peptides was performed, (PRR)5 was linked to the C-terminus of MOTS-c through a linker to synthesize a new molecule (termed MP) with better penetration into the colon epithelium. In vitro experiments revealed the longer half-life of MP than MOTS-c, and in vivo experiments showed that oral administration of MP significantly ameliorated DSS-induced colitis. CONCLUSION: The present results demonstrate a protective role of MOTS-c in experimental IBD.

Nonpharmacological interventions such as hypnosis show promising evidence for the self-management of pain and pain-related sequelae among cancer survivors. The purpose of this study was to evaluate the efficacy of a 4-week recorded hypnosis intervention in reducing pain intensity compared to a recorded relaxation intervention in cancer survivors with chronic pain.

Gelsemiumelegans(Gardner. & Chapm.) Benth. has long been considered a traditional Chinese medicine effective against rheumatoid pain, cancer, cirrhosis, and skin diseases. Koumine (KM), the most abundant alkaloid in G.elegans Benth., demonstrates a variety of biological effects, including antitumor, analgesic, anxiolytic, anti-inflammatory, antidepressant, antioxidant, immunoregulatory, and hepatoprotective effects. Furthermore, the relatively low toxicity of KM makes it a promising drug candidate. This study aimed to investigate the protective effects of KM and its possible mechanisms using a concanavalin A (Con A)-induced autoimmune hepatitis (AIH) model in mice. Mice were orally administered different doses of KM for 14 d before Con A tail vein injections. The effects of KM on serum biochemical markers and liver histopathology were then evaluated 12 h after Con A exposure. The Nrf2 and NF-κB signaling pathways and alterations in gut microbiota were determined using western blotting, immunohistochemistry, and 16S rRNA sequencing to explore the underlying mechanisms of KM exposure. KM pretreatment dose-dependently decreased serum liver injury markers (Alanine aminotransferase, and aspartate aminotransferase) and cytokine levels (Tumor necrosis factor-α and interleukin-6), as well as the liver pathological damage triggered by Con A. Furthermore, the results of the multi-technique analysis indicated that KM activated the Nrf2 pathway, upregulated the expression of anti-oxidation factors HO-1 and Nrf2, and downregulated the expression of Keap1. Moreover, the NF-κB signaling pathway was inhibited. Interestingly, pre-treatment with KM also significantly improved the composition of the gut microbiota probably because it increases the richness of probiotics. Our findings suggest that KM pretreatment could attenuate Con A-induced AIH, the Nrf2 and NF-κB signaling pathways, and that gut microbiota are involved in the process of the hepatoprotective effect. This study provides a theoretical basis for the development of KM as an effective agent against AIH.

The ventrolateral periaqueductal gray (vlPAG) collaborates with the dorsal raphe (DR) in pain regulation and emotional response. However, the roles of vlPAG and DR γ-aminobutyric acid (GABA)-ergic neurons in regulating nociception and anxiety are contradictory and poorly understood. Here, we observed that pharmacogenetic co-activation of vlPAG and DR GABAergic (vlPAG-DR) neurons enhanced sensitivity to mechanical stimulation and promoted anxiety-like behavior in naïve mice. Simultaneous inhibition of vlPAG-DR neurons showed adaptive anti-nociception and anti-anxiety effects on mice with inflammatory pain. Notably, vlPAG and DR neurons exhibited opposing effects on the sensitivity to mechanical stimulation in both naïve state and inflammatory pain. In contrast to the role of vlPAG neurons in pain processing, chemogenetic inhibition and chronic ablation of DR neurons remarkably promoted nociception while selectively activating DR neurons ameliorated inflammatory pain. Additionally, utilizing optogenetic technology, we observed that the pronociceptive effect arising from DR neuronal inhibition was reversed by the systemic administration of morphine. Our results collectively provide new insights into the modulation of pain and anxiety by specific midbrain GABAergic subpopulations, which may provide a basis for cell type-targeted or subregion-targeted therapies for pain management.

The objective of the current research study was to formulate the PEGylated lipid polymer hybrid nanoparticles of ergotamine and caffeine for intranasal administration with higher entrapment efficiency, better permeability, desirable controlled release pattern, and significant brain uptake in animal studies. A single-step nanoprecipitation method was employed in the processing of self-assembled hybrid nanoparticles constituting polymer PLGA, lipids soya lecithin, and DPPC with PEGylation using polyethylene glycol (PEG-2000). The optimal lipid/polymer weight ratio of 15% w/w showed lower particle size of 239.46 ± 2.31 nm with good colloidal stability depicted by zeta potential (- 18.36 ± 6.59 mV), higher entrapment efficiency of 86.88 ± 1.67%, and controlled release profile when evaluated for in vitro and ex vivo studies as 97.12 ± 2.79% and 75.13 ± 5.62% release, respectively, for 48 h. The formulation showed long-term serum stability when incubated in bovine serum albumin and displayed high brain uptake (4.35-fold) offering significant permeability in the brain post-intranasal administration via olfactory route. Histopathological investigations and serotonin toxicity studies in animals confirmed the safe and non-toxic nature of the formulation while the acetic acid writhing test proved the anti-hyperalgesic activity. The PEGylated lipid polymer hybrid nanoparticles of ergotamine and caffeine showed synergistic activity with efficacious higher anti-migraine potential.

Peripheral nerve stimulation (PNS) is an effective neuromodulation therapy for chronic neuropathic and nociceptive pain. Although the total number of PNS implantations has increased over the last decade, no curriculum exists to guide training and learning of this therapy. The goal of the North American Neuromodulation Society (NANS) education committee is to develop a series of competency-based curriculums for neuromodulation therapies. The PNS curriculum is the latest part of such series, following the curriculums for spinal cord stimulation and intrathecal drug delivery system.

Spinal cord stimulator (SCS) placement has been gaining traction as an approach to modulate pain levels for several different chronic pain conditions. This procedure can be performed via a percutaneous or open approach. Data regarding SCS complications are relatively limited.

Central sensitization (CS) is defined as increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input. The CS phenomenon is caused by continuous, intense nociceptor inputs triggering a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in the central nociceptive pathway. Most patients undergoing surgery for lumbar spinal stenosis (LSS) experience symptoms for more than three months; therefore, it is possible that CS is associated with postoperative symptoms of LSS. The aim of this study was to clarify the influence of CS in patients who underwent surgery for LSS.

Arthritis is a common chronic disease, and is a major cause of disability and chronic pain in adults. Considering inflammatory responses is closely related with trace elements (TEs), the role of TEs in arthritis has attracted much attention. This study aimed to assess the association between TEs and arthritis.

The Biospecimen Collection and Processing Working Group of the NIH HEAL Initiative BACPAC Research Program was charged with identifying molecular biomarkers of interest to chronic low back pain (cLBP). Having identified biomarkers of interest, the Working Group worked with the New York University Grossman School of Medicine, Center for Biospecimen Research and Development-funded by the Early Phase Pain Investigation Clinical Network Data Coordinating Center-to harmonize consortium-wide and site-specific efforts for biospecimen collection and analysis. Biospecimen collected are saliva, blood (whole, plasma, serum), urine, stool, and spine tissue (paraspinal muscle, ligamentum flavum, vertebral bone, facet cartilage, disc endplate, annulus fibrosus, or nucleus pulposus). The omics data acquisition and analyses derived from the biospecimen include genomics and epigenetics from DNA, proteomics from protein, transcriptomics from RNA, and microbiomics from 16S rRNA. These analyses contribute to the overarching goal of BACPAC to phenotype cLBP and will guide future efforts for precision medicine treatment.

This systematic review and meta-analysis aimed to determine the association between changes in patients' pain knowledge after pain science education (PSE) with treatment outcomes in people with chronic pain.

Pediatric chronic pain represents heterogeneous diagnoses; often, primary pain location informs research classifications and treatment. In contrast, recent research has highlighted the role of widespread pain and this perspective has been adopted in assessments in specialty pediatric pain clinics. The lack of direct comparison between these 2 methods of categorizing pediatric chronic pain may hinder the adoption of evidence-based practices across the spectrum of care. Therefore, this study aimed to compare whether primary pain location or pain widespreadedness is more informative for pain-related symptoms in pediatric chronic pain.

Pain assessment and management are essential components of paediatric care. Developmentally appropriate pain assessment is an important first step in optimizing pain management. Self-reported pain should be prioritized. Alternatively, developmentally appropriate behavioural tools should be used. Acute pain management and prevention guidelines and strategies that combine physical, psychological, and pharmacological approaches should be accessible in all health care settings. Chronic pain is best managed using combined treatment modalities and counselling, with the primary goal of attaining functional improvement. The planning and implementation of pain management strategies for children should always be personalized and family-centred.

The POINT project aims to provide evidence to optimise chronic pain management, prevent adverse consequences of opioids, and improve chronic pain patients' pain relief, functional capacity, and quality of life. We describe the outline of the project and its work packages. More specifically, we describe a cohort of persons with chronic pain and a cohort of long-term opioid users identified from a national registry linkage.

Osteoarthritis (OA) is the most prevalent articular disease, especially in aged population. Caused by multi-factors (e.g., trauma, inflammation, and overloading), OA leads to pain and disability in affected joints, which decreases patients' quality of life and increases social burden. In pathophysiology, OA is mainly characterized by cartilage hypertrophy or defect, subchondral bone sclerosis, and synovitis. The homeostasis of cell-cell communication is disturbed as well in such pro-inflammatory microenvironment, which provides clues for the diagnosis and treatment of OA. MicoRNAs (miRNAs) are endogenous non-coding RNAs that regulate various processes post-transcriptional mechanisms. The miR-17-92 cluster is an miRNA polycistron encoded by the host gene called MIR17HG. Mature miRNAs generated from MIR17HG participate in biological activities such as oncogenesis, neurogenesis, and modulation of the immune system. Accumulating evidence also indicates that the expression level of miRNAs in the miR-17-92 cluster is tightly related to the pathological processes of OA, such as chondrocyte apoptosis, extracellular matrix degradation, bone remodeling, and synovitis. In this review, we aim to summarize the roles of the miR-17-92 cluster in the underlying molecular mechanism during the development and progression of OA and shed light on the new avenue of the diagnosis and treatment of OA.

Calcitonin gene-related peptide (CGRP) pathway-targeted treatments have been shown to be efficacious in the prevention of episodic and chronic migraine. Currently approved therapies include monoclonal antibodies (mAbs) that target CGRP (eptinezumab, fremanezumab, and galcanezumab) and the CGRP receptor (erenumab), and small molecule CGRP receptor antagonists (atogepant and rimegepant). While CGRP pathway-targeted treatments are generally well-tolerated, in a review article by Holzer and Holzer-Petsche published in the January 2022 issue of the authors discussed the role of the CGRP pathway in gastrointestinal physiology, with a specific focus on constipation associated with the use of CGRP pathway-targeted treatments. The authors state that real-world surveys have shown constipation to be a "major adverse event" reported in "more than 50% of patients treated with erenumab, fremanezumab or galcanezumab." As described in the current commentary, the limited data from the cited references in the review article by Holzer and Holzer-Petsche do not support that statement.

Endometriosis is a common gynecological disease, characterized by the presence of endometrial-like lesions outside the uterus. This debilitating disease causes chronic pelvic pain and infertility with limited therapeutics. Chemerin is a secretory protein that acts on CMKLR1 (Chemokine-Like Receptor 1) to execute functions vital for immunity, adiposity, and metabolism. Abnormal chemerin/CMKLR1 axis underlies the pathological mechanisms of certain diseases including cancer and inflammatory diseases, but its role in endometriosis remains unknown. Herein, our results showed that chemerin and CMKLR1 are up-regulated in endometriotic lesions by analyzing the human endometriosis database and murine model. Knockdown of chemerin or CMKLR1 by shRNA led to mesenchymal-epithelial transition (MET) along with compromised viability, migration, and invasion of hEM15A cells. Most importantly, 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA), a small molecule antagonist for CMKLR1, was evidenced to exhibit profound anti-endometriosis effects (anti-growth, anti-mesenchymal features, anti-angiogenesis, and anti-inflammation) and . Mechanistically, α-NETA exhibited a dual inhibition effect on PI3K/Akt and MAPK/ERK signaling pathways in hEM15A cells and murine endometriotic grafts. This study highlights that the chemerin/CMKLR1 signaling axis is critical for endometriosis progression, and targeting this axis by α-NETA may provide new options for therapeutic intervention.

More than one in five American adults experiences chronic pain, and numerous approaches can be used to treat chronic pain. Opioid analgesics are commonly used to treat pain though precise estimates of the prevalence of opi-oid analgesic use vary widely. This study sought to determine the prevalence of opioid use for pain among adults in the United States.

Quantitative sensory testing (QST) has been one of the neurophysiological tools used for follow-up and disease progression assessment in ATTRv amyloidosis. We aimed to detect the utility of QST in identifying subclinical neuropathic involvement in ATTRV30M amyloidosis carriers.