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Spinal cord stimulation (SCS) is used clinically to limit chronic pain but questions remain on the identity of axonal populations recruited. We developed an adult mouse spinal cord preparation to assess recruitment following delivery of clinically-analogous stimuli determined by downscaling a finite element model of clinical SCS. Analogous electric field distributions were generated with 300 µm x 300 µm electrodes positioned 200 µm above the dorsal column (DC) with stimulation between 50-200 µA. We compared axonal recruitment using electrodes of comparable size and stimulus amplitudes – when contacting the caudal thoracic DC, and at 200 or 600 mm above. Antidromic responses recorded from the DC, the adjacent Lissauer tract (LT), and in dorsal roots (DRs) were found to be amplitude and site-dependent. Responses in the DC included a unique component not seen in DRs, having the lowest SCS recruitment amplitude and fastest conduction velocity. At 200 mm above, mean cathodic SCS recruitment threshold for axons in DRs and LT were 2.6 and 4.4 times higher, respectively, than DC threshold. SCS recruited primary afferents in all (up to 9) caudal segments sampled. While A and C fibers could be recruited at nearby segments, only A fiber recruitment and synaptically-mediated dorsal root reflexes were observed in more distant segments. In sum, clinically-analogous SCS led to multisegmental recruitment of several somatosensory-encoding axonal populations. Most striking is the possibility that the lowest threshold recruitment of a non-primary afferent population in the DC are postsynaptic dorsal column tract cells (PSDCs) projecting to gracile nuclei.
Learn More >Central sensitization induces pain augmentation in chronic pain states. An analogous mechanism is speculated for chronic pruritus. This study compared patients with chronic pruritus (n = 79) of different origins (atopic dermatitis, chronic pruritus on non-lesional skin, chronic prurigo) and healthy controls (HC, n = 54) with regard to itch intensity and qualities of sensory symptoms after selective peripheral nerve fibre activation by electrical stimulation at 5 Hz (surrogate for C-fibre function) and 2,000 Hz (surrogate for Aβ-fibre function) using a Neurometer®. Electrically-induced itch was more intense in patients with chronic pruritus than in HC, but patients with chronic pruritus did not report "itch" more often than HC at 5 Hz. Stimulation at 2,000 Hz induced more pricking and tingling, but less throbbing in patients with chronic pruritus compared with HC. Treatment with cooling compound reduced clinical and experimental itch, but did not alter the distribution of sensory symptoms. These data show hyperknesis in chronic pruritus of various origins, arguing for common central sensitization mechanisms.
Learn More >Conditions with chronic widespread non-inflammatory muscle pain, such as fibromyalgia, have complex etiologies with numerous proposed mechanisms for their pathophysiology of underlying chronic pain. Advancements in neuroimaging have allowed for the study of brain function and connectivity in humans with these conditions, while development of animal models have allowed for the study of both peripheral and central factors that lead to chronic pain. This article reviews the current literature surrounding the pathophysiology of chronic widespread non-inflammatory muscle pain focusing on both peripheral and central nervous system, as well as immune system, contributions to the development and maintenance of pain. A better understanding of the mechanisms underlying these conditions can allow for improvements in patient education, treatment and outcomes.
Learn More >Over 70% of older adults report chronic or acute pain, and pain threatens affective wellbeing. The strategies older adults use to maintain affective wellbeing following acute pain remain unknown. Specific strategies that can be used to manage pain include recalling, recognizing, and responding to positive stimuli and prioritizing close over knowledgeable social partners. The study tested whether older adults used positivity-enhancing strategies and maintained affective wellbeing following acute pain better than younger adults. Fifty older (ages 65-85) and 50 younger (ages 18-30) pain-free adults experienced a control and a pain condition and were given the chance to employ positivity-enhancing strategies. Older and younger adults similarly used positivity-enhancing strategies following pain. Younger adults demonstrated reduced preference for knowledgeable social partners after experiencing pain. Pain-related affective changes were similar between age groups. Older and younger adults may cope with acute pain similarly, highlighting future directions for exploring age differences in pain coping.
Learn More >Experimental models of pain in humans are crucial for understanding pain mechanisms. The most often used muscle pain models involve the injection of algesic substances, such as hypertonic saline solution or nerve growth factor, or the induction of delayed onset muscle soreness (DOMS) by an unaccustomed exercise routine. However, these models are either invasive or take substantial time to develop, and the elicited level of pain/soreness is difficult to control. To overcome these shortcomings, we propose to elicit muscle pain by a localized application of short-wave diathermy (SWD).
Learn More >Mounting evidence suggests that the spinal dorsal horn (SDH) contains multiple subpopulations of inhibitory interneurons that play distinct roles in somatosensory processing, as exemplified by the importance of spinal dynorphin-expressing neurons for the suppression of mechanical pain and chemical itch. While it is clear that GABAergic transmission in the SDH undergoes significant alterations during early postnatal development, little is known about the maturation of discrete inhibitory "microcircuits" within the region. As a result, the goal of the present study was to elucidate the gene expression profile of spinal dynorphin (pDyn)-lineage neurons throughout life. We isolated nuclear RNA specifically from pDyn-lineage SDH interneurons at postnatal days 7, 21, and 80 using the Isolation of Nuclei Tagged in Specific Cell Types (INTACT) technique, followed by RNA-seq analysis. Over 650 genes were ≥2-fold enriched in adult pDyn nuclei compared to non-pDyn spinal cord nuclei, including targets with known relevance to pain such as galanin (Gal), prepronociceptin (Pnoc), and nitric oxide synthase 1 (Nos1). In addition, the gene encoding a membrane-bound guanylate cyclase, Gucy2d, was identified as a novel and highly selective marker of the pDyn population within the SDH. Differential gene expression analysis comparing pDyn nuclei across the three ages revealed sets of genes that were significantly upregulated (such as Cartpt, encoding cocaine- and amphetamine-regulated transcript peptide) or downregulated (including Npbwr1, encoding the receptor for neuropeptides B/W) during postnatal development. Collectively, these results provide new insight into the potential molecular mechanisms underlying the known age-dependent changes in spinal nociceptive processing and pain sensitivity.
Learn More >The G-protein-coupled μ-opioid receptor (μ-OR) mediates the majority of analgesia effects for morphine and other pain relievers. Despite extensive studies of its structure and activation mechanisms, the inherently low maturation efficiency of μ-OR represents a major hurdle to understanding its function. Here we computationally designed μ-OR mutants with altered stability to probe the relationship between cell-surface targeting, signal transduction, and agonist efficacy. The stabilizing mutation T315Y enhanced μ-OR trafficking to the plasma membrane and significantly promoted the morphine-mediated inhibition of downstream signaling. In contrast, the destabilizing mutation R165Y led to intracellular retention of μ-OR and reduced the response to morphine stimulation. These findings suggest that μ-OR stability is an important factor in regulating receptor signaling and provide a viable avenue to improve the efficacy of analgesics. This article is protected by copyright. All rights reserved.
Learn More >The clinical use of noninvasive cortical stimulation procedures is hampered by the limited duration of the analgesic effects and the need to perform stimulation in hospital settings. Here, we tested the feasibility and pilot efficacy of an internet-based system for at-home, long-duration, medically controlled transcranial motor cortex stimulation (H-tDCS), via a double-blinded, sham-controlled trial in patients with neuropathic pain refractory to standard-of-care drug therapy. Each patient was first trained at hospital, received a stimulation kit, allotted a password-protected Web space, and completed daily tDCS sessions during 5 weeks, via a Bluetooth connection between stimulator and a minilaptop. Each session was validated and internet-controlled by hospital personnel. Daily pain ratings were obtained during 11 consecutive weeks, and afterwards via iterative visits/phone contacts. Twenty full procedures were completed in 12 consecutive patients (500 daily tDCS sessions, including 20% sham). No serious adverse effects were recorded. Superficial burning at electrode position occurred in 2 patients, and nausea/headache in two others, all of whom wished to pursue stimulation. Six out of the 12 patients achieved satisfactory relief on a scale combining pain scores, drug intake, and quality of life. Daily pain reports correlated with such combined assessment, and differentiated responders from nonresponders without overlap. Clinical improvement in responders could last up to 6 months. Five patients asked to repeat the whole procedure when pain resumed again, with comparable results. At-home, long-duration tDCS proved safe and technically feasible, and provided long-lasting relief in 50% of a small sample of patients with drug-resistant neuropathic pain.
Learn More >Chronic pain is a potentially stigmatizing condition. However, stigma has received limited empirical investigation in people with chronic pain. Therefore, we examined the psychometric properties of a self-report questionnaire of stigma in people with chronic pain attending interdisciplinary treatment. Secondarily, we undertook an exploratory examination of the magnitude of change in stigma associated with interdisciplinary treatment in a prospective observational cohort. Participants attending interdisciplinary treatment based on Acceptance and Commitment Therapy completed the Stigma Scale for Chronic Illness eight-item version (SSCI-8; previously developed and validated in neurological samples), and measures of perceived injustice, pain acceptance, and standard pain outcomes before (n=300) and after treatment (n=247). A unidimensional factor structure and good internal consistency were found for the SSCI-8. Total SSCI-8 scores were correlated with pain intensity, indices of functioning, and depression in bivariate analyses. Stigma scores were uniquely associated with functioning and depression in multiple regression analyses controlling for demographic factors, pain intensity, pain acceptance, and perceived injustice at baseline. SSCI-8 total scores did not significantly improve following treatment, although an exploratory subscale analysis showed a small improvement on internalized stigma. In contrast, scores on perceived injustice, pain acceptance, and pain outcomes improved significantly. Taken together, these data support the reliability and validity of the SSCI-8 for use in samples with chronic pain. Further research is needed optimise interventions to target stigma at both the individual and societal levels. Perspective: This study supports the use of the SSCI-8 to measure stigma in chronic pain. Stigma is uniquely associated with worse depression and pain-related disability. Research is needed to identify how to best target pain-related stigma from individual and societal perspectives.
Learn More >Dysautonomia and headache are 2 common diagnoses within pediatric neurology; in the case of dysautonomia, a lack of consideration may lead to misdiagnosis. Despite being common conditions, there is a lot to learn about each individually as well as collectively. Many of the symptoms between headache and dysautonomia patients overlap making the diagnosis difficult. Migraine patients often exhibit symptoms of dysautonomia, namely postural orthostatic tachycardia syndrome (POTS); yet these symptoms are overlooked or lumped in as a part of their migraine diagnosis. The distinction or coexistence between dysautonomia and headache is identified through a thorough history, a full exam, and an open mind. This is crucial for the treatment and outcomes of these patients. Struggles arise when critical treatment differences are overlooked because dysautonomia is not considered. In this review, we will look at the epidemiology of dysautonomia and headache with focus on POTS and migraine. We will then compare the clinical features of both conditions as well as some hypothesized pathophysiology overlaps. We will conclude by summarizing the diagnostic approach and multitiered treatment options for POTS and migraine.
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