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To summarize the current literature on disparities in the treatment of chronic pain.
Learn More >Haematopoietic stem cells (HSCs) reside in specialized microenvironments in the bone marrow-often referred to as 'niches'-that represent complex regulatory milieux influenced by multiple cellular constituents, including nerves. Although sympathetic nerves are known to regulate the HSC niche, the contribution of nociceptive neurons in the bone marrow remains unclear. Here we show that nociceptive nerves are required for enforced HSC mobilization and that they collaborate with sympathetic nerves to maintain HSCs in the bone marrow. Nociceptor neurons drive granulocyte colony-stimulating factor (G-CSF)-induced HSC mobilization via the secretion of calcitonin gene-related peptide (CGRP). Unlike sympathetic nerves, which regulate HSCs indirectly via the niche, CGRP acts directly on HSCs via receptor activity modifying protein 1 (RAMP1) and the calcitonin receptor-like receptor (CALCRL) to promote egress by activating the Gα/adenylyl cyclase/cAMP pathway. The ingestion of food containing capsaicin-a natural component of chili peppers that can trigger the activation of nociceptive neurons-significantly enhanced HSC mobilization in mice. Targeting the nociceptive nervous system could therefore represent a strategy to improve the yield of HSCs for stem cell-based therapeutic agents.
Learn More >Provoked vestibulodynia (PVD) is a common chronic pain condition characterized by pain at the vulvar vestibule elicited by touch. Both PVD and sexual abuse lead to negative psychosocial and sexual consequences. However, little is known about the wellbeing of women with PVD and a history of sexual abuse. The aim of this study was to characterize a sample of women seeking treatment for PVD who have experienced sexual abuse.
Learn More >Reliable outcome measurement providing information both on early and late postoperative pain outcomes are still lacking. The purpose of this study was: 1) to characterise postoperative pain trajectories according to an innovative pragmatic concept: ideal pain trajectory (rapid and sustained pain relief) vs non-ideal pain trajectories (late, transient, or no pain relief); and 2) to assess the incidence of persistent post-surgical pain (PPSP) and the potential association between non-ideal pain trajectories and PPSP.
Learn More >Evidence suggests altered pronociceptive and antinociceptive mechanisms in many chronic pain conditions. Knowledge about these mechanisms in nonspecific chronic neck pain (NSNP) would improve understanding of the causes and the design of more effective treatments. Pressure pain threshold (PPT) is often used to assess presence of altered nociceptive processing in NSNP; however, its usefulness to detect this is yet to be established. The purpose of this study was to determine the functional status of temporal summation of second pain (TSSP) and conditioned pain modulation (CPM) in NSNP and to characterize the association of both measures with PPT and clinical features of NSNP.
Learn More >There is an ongoing established need to develop engaging pain assessment strategies to provide more effective individualized care to pediatric patients with serious illnesses. This study explores the acceptability of wireless devices as one option. To evaluate the ability of wrist-wearable technology to collect physiological data from children with serious illnesses. Single-site prospective observational study conducted between September 2017 and September 2018 at Rady Children's Hospital, San Diego, California, inpatient wards. Pediatric patients with diagnoses of cancer and sickle cell disease admitted to the hospital for acute-on-chronic pain and taking opioid pain medications were asked to complete two 24-hour continuous monitoring periods with the Empatica E4 wristband. Data collected from the device correlated with manually obtained vital signs. Children responded favorably to wearing the device. Participants with reported subjective pain versus no pain had average heart rate increased by 16.4 bpm, skin temperature decreased by 3.5°C, and electrodermal activity decreased by 0.27. This study shows the possibility of collecting continuous biophysical data in a nonobtrusive manner in seriously ill children experiencing acute-on-chronic pain using wearable devices. It provides the framework for larger studies to explore the utility of such data in relation to metrics of pain and suffering in this patient population.
Learn More >Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory system. Neuropathic pain represents a broad category of pain conditions, common complications of peripheral neuropathies, which are characterized by a combination of positive symptoms, including paresthesia and/or dysesthesia and sensory deficits in the painful area. In the present paper, we aimed to assess neuropathic pain frequency and clinical characteristics of peripheral neuropathies due to different aetiologies according to grading system criteria of the International Association for the Study of Pain for a definitive diagnosis of neuropathic pain. Epidemiological studies applying these criteria have been conducted in patients with diabetes, brachial plexus injury, and other traumatic nerve injuries. Neuropathic pain was diagnosed in 37-42% of patients with diabetic peripheral neuropathy, 56% of patients with brachial plexus injury, and 22% of patients with intercostobrachial neuropathy. The most frequent neuropathic pain type was ongoing pain (described as burning or pressing), followed by paroxysmal pain (electric shock-like sensations) and allodynia (pain evoked by brushing and pressure). By providing information on the frequency, clinical signs, and variables associated with neuropathic pain due to different aetiologies, these studies contribute to improving the clinical management of this condition.
Learn More >Mutations in voltage-gated sodium channels (Navs) can cause alterations in pain sensation, such as chronic pain diseases like inherited erythromelalgia (IEM). The IEM-causing mutation Nav1.7 p.I848T is known to induce a hyperpolarized shift in the voltage dependence of activation in Nav1.7. So far, however, the mechanism to explain this increase in voltage sensitivity remains unknown. In the present study, we show that phosphorylation of the newly introduced Thr residue explains the functional change. We expressed either wild type human Nav1.7, the I848T mutant, or other mutations in HEK293T cells and performed whole-cell patch-clamp electrophysiology. As the insertion of a Thr residue potentially creates a novel phosphorylation site for Ser/Thr kinases and because Nav1.7 had been shown in Xenopus oocytes to be affected by protein kinases C (PKC) and A (PKA), we used different non-selective and selective kinase inhibitors and activators to test the effect of phosphorylation on Nav1.7 in a human system. We identify PKC, but not PKA, to be responsible for the phosphorylation of T848 and thereby for the shift in voltage sensitivity. Introducing a negatively charged amino acid instead of the putative phosphorylation site mimics the effect on voltage gating to a lesser extent. 3D modelling using the published cryo-EM structure of human Nav1.7 showed that introduction of this negatively charged site seems to alter the interaction of this residue with surrounding amino acids and thus to influence channel function. These results could provide new opportunities for the development of novel treatment options for chronic pain patients.
Learn More >The VLPFC vs. the DLPFC in down-regulating social pain using reappraisal and distraction strategies.
The dorsolateral (DLPFC) and ventrolateral prefrontal cortices (VLPFC) are both crucial structures involved in voluntary emotional regulation. However, it remains unclear whether the functions of these two cortical regions that are involved in emotional regulation-which are usually active in non-social situations-could be generalized to the regulation of social pain as well. This study employed transcranial magnetic stimulation (TMS) to examine the causal relationship between the DLPFC/VLPFC and the emotional regulation of social pain via distraction and reappraisal. Ninety human participants (45 males and 45 females) initially underwent either active (DLPFC/VLPFC, n = 30/30) or sham (vertex, n = 30) TMS sessions. Participants were then instructed to use both distraction and reappraisal strategies to down-regulate any negative emotions evoked by social exclusion pictures. Convergent results of the subjective emotional rating and electrophysiological indices demonstrated that: 1) both the DLPFC and VLPFC highly facilitate the down-regulation of affective responses caused by social exclusion, revealing a causal role of these lateral prefrontal cortices in voluntary emotional regulation of both non-social and social pain; and 2) these two cortical regions showed relative functional specificity for distraction (DLPFC) and reappraisal (VLPFC) strategies, which helps to refine the cortical targeting of therapeutic protocols. In addition, the TMS effect was sustainable for at least one hour, showcasing the potential feasibility of using this method in clinical practice. Together, these findings provide cognitive and neural evidence for the targeting of the VLPFC and/or the DLPFC to improve emotional regulation abilities, especially in social contexts.This study aimed to examine the role of the dorsolateral and ventrolateral prefrontal cortices in emotional regulation, particularly in response to social pain through the use of distraction and reappraisal strategies, as this is a relatively underexplored area of inquiry. This study makes a significant contribution to the literature because our results provide novel empirical information on the role of these cortical structures in the processing of negative emotions elicited within certain social contexts. As such, our findings have potential clinical implications, paving the way for future clinicians to be able to accurately target specific brain regions among patients struggling with impaired social cognition abilities, including those diagnosed with post-traumatic stress disorder, autism spectrum disorder, social anxiety disorder, and depression.
Learn More >Neuropathic pain is a major symptom of multiple sclerosis (MS) with up to 92% of patients reporting bodily pain, and 85% reporting pain severe enough to cause functional disability. None of the available therapeutics target MS pain. Toll-like receptors 2 and 4 (TLR2/TLR4) have emerged as targets for treating a wide array of autoimmune disorders, including MS, as well as having demonstrated success at suppressing pain in diverse animal models. The current series of studies tested systemic TLR2/TLR4 antagonists in males and females in a low-dose myelin oligodendrocyte glycoprotein (MOG) experimental autoimmune encephalitis (EAE) model, with reduced motor dysfunction to allow unconfounded testing of allodynia through 50+ days post-MOG. The data demonstrated that blocking TLR2/TLR4 suppressed EAE-related pain, equally in males and females; upregulation of dorsal spinal cord proinflammatory gene expression for TLR2, TLR4, NLRP3, interleukin-1β, IkBα, TNF-α and interleukin-17; and upregulation of dorsal spinal cord expression of glial immunoreactivity markers. In support of these results, intrathecal interleukin-1 receptor antagonist reversed EAE-induced allodynia, both early and late after EAE induction. In contrast, blocking TLR2/TLR4 did not suppress EAE-induced motor disturbances induced by a higher MOG dose. These data suggest that blocking TLR2/TLR4 prevents the production of proinflammatory factors involved in low dose EAE pathology. Moreover, in this EAE model, TLR antagonists were highly effective in reducing pain, whereas motor impairment, as seen in high dose MOG EAE, is not affected.
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