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Peripheral nerve function is metabolically demanding and nerve energy failure has been implicated in the onset and development of diabetic peripheral neuropathy and neuropathic pain conditions. Distal peripheral nerve oxygen supply relies on the distribution of red blood cells (RBCs) in just a few, nearby capillary-sized vessels and is therefore technically challenging to characterize. We developed an approach to characterize distal sural nerve hemodynamics in anesthetized, adult male mice using two-photon laser scanning microscopy. Our results show that RBC velocities in mouse sural nerve vessels are higher than those previously measured in mouse brain, and are sensitive to hindlimb temperatures. Nerve blood flow, measured as RBC flux, however, was similar to that of mouse brain and unaffected by local temperature. Power spectral density analysis of fluctuations in RBC velocities over short time intervals suggest that the technique is sufficiently sensitive and robust to detect subtle flow oscillations over time scales from 0.1 to tens of seconds. We conclude that two-photon laser scanning microscopy provides a suitable approach to study peripheral nerve hemodynamics in mice, and that local temperature control is important during such measurements.
Learn More >Novel suggestions derived from the inhibitory learning model on how to optimize exposure therapy have been debated with enthusiasm in the last few years, particularly with respect to the focus on expectancy violations. However, little is known about how this new approach directly compares to the traditional habituation rationale of exposure therapy. In the present study, we examined these two competing therapeutic instructions among healthy female participants in an experimental heat pain paradigm.
Learn More >Inflammatory pain is the most common type of pain treated clinically. However, the currently available treatments for inflammatory pain have limited effects and can cause severe side effects. The aim of this study is to describe the effect of miRNA-485-5p on osteoarthritis-related inflammatory pain.
Learn More >Fibromyalgia (FM) is a frequent comorbidity in patients with chronic migraine (CM). PREEMPT trials, which demonstrated the efficacy of OnabotulinumtoxinA (OnabotA) on CM, excluded patients with FM. Our aim was to evaluate the effectiveness of OnabotA in a series of patients with CM and FM. We analyzed patients with a previous diagnosis of CM and FM who had received sessions of OnabotA quarterly between January 2014 and January 2020 in a specialized Headache Clinic. Primary endpoint was the reduction in moderate to severe headache days at 3, 6, 9, and 12 months. Data were collected from 31 patients with CM and FM that received OnabotA (100% females). Mean age at first procedure was 50.2 ± 11.3 years. Depression (93.5%), other central sensitization syndromes (irritable bowel syndrome, interstitial cystitis, multiple chemical sensitivity, endometriosis, and chronic fatigue syndrome) (48.4%), and medication overuse headache (90.3%) were frequent comorbidities. 48.4% of patients had failed ≥3 preventives previously. The percentage of patients who achieved ≥30 and ≥50% moderate-severe headache reduction on the third month was 65.4 and 48.2%, respectively. Twenty-three patients completed four cycles of treatment, with 13.4 fewer headache days per month than at baseline ( < 0.001). By 1 year, 69.5% had ≥50% reduction of headache frequency and 39.1% had a ≥75% reduction. In 4 cases (21%), OnabotA was interrupted due to a lack of response. Only mild adverse effects were recorded. OnabotA is an effective treatment for CM in patients with FM.
Learn More >Sensory abnormalities generated by nerve injury, peripheral neuropathy or disease are often expressed as neuropathic pain. This type of pain is frequently resistant to therapeutic intervention and may be intractable. Numerous studies have revealed the importance of enduring increases in primary afferent excitability and persistent spontaneous activity in the onset and maintenance of peripherally induced neuropathic pain. Some of this activity results from modulation, increased activity and /or expression of voltage-gated Na channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. K channels expressed in dorsal root ganglia (DRG) include delayed rectifiers (K1.1, 1.2), A-channels (K1.4, 3.3, 3.4, 4.1, 4.2, and 4.3), KCNQ or M-channels (K7.2, 7.3, 7.4, and 7.5), ATP-sensitive channels (K6.2), Ca-activated K channels (K1.1, 2.1, 2.2, 2.3, and 3.1), Na-activated K channels (K4.1 and 4.2) and two pore domain leak channels (K; TWIK related channels). Function of all K channel types is reduced via a multiplicity of processes leading to altered expression and/or post-translational modification. This also increases excitability of DRG cell bodies and nociceptive free nerve endings, alters axonal conduction and increases neurotransmitter release from primary afferent terminals in the spinal dorsal horn. Correlation of these cellular changes with behavioral studies provides almost indisputable evidence for K channel dysfunction in the onset and maintenance of neuropathic pain. This idea is underlined by the observation that selective impairment of just one subtype of DRG K channel can produce signs of pain Whilst it is established that various mediators, including cytokines and growth factors bring about injury-induced changes in DRG function and excitability, evidence presently available points to a seminal role for interleukin 1β (IL-1β) in control of K channel function. Despite the current state of knowledge, attempts to target K channels for therapeutic pain management have met with limited success. This situation may change with the advent of personalized medicine. Identification of specific sensory abnormalities and genetic profiling of individual patients may predict therapeutic benefit of K channel activators.
Learn More >Cyclooxygenase-2 (COX-2) is known to be involved in the pathogenesis of migraine, and some polymorphisms are known to affect the expression of COX-2. This retrospective case-control study aimed to explore the associations between the -765 G>C (rs20417), -1759 G>A (rs3218625), and -8473 C>T (rs5275) COX-2 polymorphisms and migraine in Chinese Han individuals. One hundred and ten unrelated Han Chinese patients with migraine and 108 healthy controls were recruited between 03/2014 and 08/2016 at the First Affiliated Hospital of Nanjing Medical University and the First People's Hospital of Lianyungang City. The genotypes of all polymorphisms in controls followed the Hardy-Weinberg equilibrium (P = 0.215, P = 0.884, and P = 0.689). There were differences in the genotype and allele distributions of the COX-2-1759G>A (Gly587Arg) polymorphism between the migraine and control groups (P = 0.038 and P = 0.040, respectively). Compared with the COX-2-1759AG genotype, GG genotype carriers had an increased risk of migraine (odds ratio (OR) = 8.720, 95% confidence interval (CI): 1.072-70.960, P = 0.038). The frequency of the COX-2-1759A allele in patients with migraine was significantly lower than the controls (OR = 0.119, 95%CI: 0.015-0.957, P = 0.040). Adjusted age and sex, a statistical difference was found in the dominant model of COX-2-1759 G>A (OR = 0.118, 95% CI 0.014 to 0.962, P = 0.046). No significant difference was detected regarding the -765G>C and -8473T>C polymorphisms between the two groups. The COX-2 1759A allele might be involved in the development of migraine in Chinese Han individuals, but this will have to be confirmed in large-scale studies.
Learn More >In this review, we will explore the use of biomarkers in chronic pain, using the examples of two prototypical facial pain conditions: trigeminal neuralgia and temporomandibular disorder. We will discuss the main categories of biomarkers and identify various genetic/genomic, molecular, neuroradiological, and psychophysical biomarkers in both facial pain conditions, using them to compare and contrast features of neuropathic, non-neuropathic, and mixed pain. By using two distinct model facial pain conditions to explore pain biomarkers, we aim to familiarize readers with different types of biomarkers currently being studied in chronic pain, and explore how these biomarkers may be used to develop new precision medicine approaches to pain diagnosis, prognosis, and management.
Learn More >Many diseases display unequal prevalence between sexes. The sex-specific immune response to both injury and persistent pain remains underexplored and would inform treatment paradigms. We utilized high-dimensional mass cytometry to perform a comprehensive analysis of phenotypic and functional immune system differences between male and female mice after orthopedic injury. Multivariate modeling of innate and adaptive immune cell responses after injury using an elastic net algorithm, a regularized regression method, revealed sex-specific divergence at 12 h and 7 days after injury with a stronger immune response to injury in females. At 12 h, females upregulated STAT3 signaling in neutrophils but downregulated STAT1 and STAT6 signals in T regulatory cells, suggesting a lack of engagement of immune suppression pathways by females. Furthermore, at 7 days females upregulated MAPK pathways (p38, ERK, NFkB) in CD4T memory cells, setting up a possible heightened immune memory of painful injury. Taken together, our findings provide the first comprehensive and functional analysis of sex-differences in the immune response to painful injury.
Learn More >A relationship between chronic pain and frailty has been reported. The early detection and prevention of frailty are recommended, in part because community-dwelling older adults in a pre-frailty state may return to a healthy state. The relationship between chronic pain and pre-frailty is not known. Toward the goal of promoting a reversible return to health from pre-frailty, we investigated the relationship between chronic pain and pre-frailty among community-dwelling older adults. We assessed the frailty and chronic pain of 107 older adults who were participating in community health checks. The status of physical frailty was based on the five components described by Fried (2001): muscle weakness shown by handgrip strength, slowness of gait speed, weight loss, low physical activity, and exhaustion. Chronic pain was assessed based on pain intensity, the Pain Catastrophizing Scale (PCS), the Japanese version of the Geriatric Depression Scale-15 (GDS-15), and the Central Sensitization Inventory (CSI). The prevalence of chronic pain with pre-frailty was 40.2%. A hierarchical analysis revealed that PCS-measured helplessness (odds ratio [OR]: 0.88) and the CSI (OR: 0.87) were significant factors associated with the presence of chronic pain with pre-frailty. The prevalence of chronic pain with pre-frailty was high, and chronic pain and pre-frailty were strongly related. New intervention or prevention programs that take into account both chronic pain and pre-frailty must be created as soon as possible.
Learn More >To investigate the functional connectivity (FC) and its variability in the primary somatosensory cortex (S1) of patients with low-back-related leg pain (LBLP) in the context of the persistent stimuli of pain and numbness.
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