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In the dorsal horn of the spinal cord, peripheral nerve injury induces structural and neurochemical alterations through which aberrant synaptic signals contribute to the formation of neuropathic pain. However, the role of injured primary afferent terminals in such plastic changes remain unclear. In this study, we investigated the effect of nerve injury on the morphology of cell adhesion molecule L1-CAM (total L1-CAM [tL1-CAM])-positive primary afferent terminals and on the synaptic contact pattern in the dorsal horn. In the confocal images, the tL1-CAM-positive terminals showed morphological changes leading to the formation of hypertrophic varicosities in the c-fiber terminal. These hypertrophic varicosities in the dorsal horn were co-labeled with phosphorylated (Ser1181) L1-CAM (pL1-CAM) and shown to store neurotransmitter peptides, but not when co-labeled with the pre-synaptic marker, synaptophysin. Quantitative analyses based on three-dimensional reconstructed confocal images revealed that peripheral nerve injury reduced dendritic synaptic contacts but promoted aberrant axo-axonic contacts on the tL1-CAM-positive hypertrophic varicosities. These tL1-CAM-positive varicosities co-expressed the injury-induced alpha2delta-1 (α2δ-1) subunit of the calcium channel in the dorsal horn. Administration of the anti-allodynic drug, pregabalin, inhibited accumulation of α2δ-1 and pL1-CAM associated with a reduction in hypertrophic changes of tL1-CAM-positive varicosities, and normalized injury-induced alterations in synaptic contacts in the dorsal horn. Our findings highlight the formation of aberrant spinal circuits that mediate the convergence of local neuronal signals onto injured c-fibers, suggesting that these hypertrophic varicosities may be important contributors to the pathological mechanisms underlying neuropathic pain. We describe, for the first time, morphological changes in L1-CAM-positive injured c-fiber terminals that lead to the formation of hypertrophic varicosities, in which we found phosphorylation of L1-CAM and increased expression of the calcium channel subunit α2δ-1. Moreover, we found alterations in synaptic contacts and discovered that peripheral nerve injury increased axo-axonic contacts onto L1-CAM-positive varicosities while decreasing axo-dendritic contacts. These plastic changes indicate the convergence of neuronal signals onto the pain pathway and may represent a pathological mechanism underlying neuropathic pain. Administration of the anti-allodynic drug pregabalin reversed the injury-induced synaptic alternations. These data highlight the unique role of injured c-fibers in peripheral nerve injury and their role as a possible therapeutic target for neuropathic pain.
Learn More >Despite empirical support for interdisciplinary pain rehabilitation programs improving functioning and quality of life, access to this treatment approach has decreased dramatically over the last 20 years within the United States but has grown significantly in the Department of Veterans Affairs (VA). Between 2009 and 2019, VA pain rehabilitation programs accredited by the Commission on Accreditation of Rehabilitation Facilities increased 10-fold in the VA, expanding from two to 20. The aim of this collaborative observational evaluation was to examine patient outcomes across a subset of six programs at five sites.
Learn More >Migraine is the second largest cause of years lost to disability globally among all diseases, with a worldwide prevalence over 1 billion. Despite the global burden of migraine, few classes of therapeutics have been specifically developed to combat migraine. After 30 years of translational research, calcitonin gene-related peptide (CGRP) inhibitors have emerged as a promising new tool in the prevention of migraine. Like all new therapeutics; however, we have limited real-world experience and CGRP has several known systemic actions that warrant consideration. This article provides a narrative review of the evidence for CGRP antagonists and summarises the known and potential side effects that should be considered.
Learn More >Spinal cord stimulation (SCS) is an effective method to treat neuropathic pain; however, it is challenging to compare different stimulation modalities in an individual patient, and thus, it is largely unknown which of the many available SCS modalities is most effective. Specifically, electrodes leading out through the skin would have to be consecutively connected to different, incompatible SCS devices and be tested over a time period of several weeks or even months. The risk of wound infections for such a study would be unacceptably high and blinding of the trial difficult. The PARS-trial seizes the capacity of a new type of wireless SCS device, which enables a blinded and systematic intra-patient comparison of different SCS modalities over extended time periods and without increasing wound infection rates.
Learn More >Children with amplified musculoskeletal pain (AMPS) experience significant functional disability, with impairment in their ability to participate in age-appropriate activities of daily living. Parental factors play an important role in a child's pain symptoms and treatment outcomes, with parental pain catastrophizing and protective behaviors linked to several maladaptive outcomes for children. Aims of the current study were to examine how parental pain catastrophizing, child pain catastrophizing, and parental protective behaviors longitudinally impacted functional disability for children with AMPS.
Learn More >Acutely, pain is protective. It promotes escape from, and future avoidance of, noxious stimuli through strong and often lifetime associative memories. However, with persistent acute pain or when pain becomes chronic, these memories can promote negative emotions and poor decisions often associated with deleterious behaviors. In this review, we discuss how preclinical studies can provide insights into the relationship between cognition and chronic pain. We also discuss the concept of pain as a cognitive disorder and new strategies for treating chronic pain that emphasize inhibiting the formation of pain memories or promoting 'forgetting' of established pain memories.
Learn More >The relationship between pain and cognition has primarily been investigated in patients with chronic pain and healthy participants undergoing experimental pain. Recently, there has been interest in understanding the disruptive effects of non-experimental pain in otherwise healthy individuals. Recent studies suggest that healthy individuals reporting pain also demonstrate decrements in working memory (WM) performance, however factors contributing to this relationship remain poorly understood. The present study examined the association between everyday pain and WM in a large community-based sample of healthy individuals and investigated whether self-reported affective distress and medial frontal cortex activity might help to explain this relationship. To address these research questions, a large publicly available dataset from the Human Connectome Project (N = 416) was sourced and structural equation modeling was utilized to examine relationships between pain intensity experienced over the past 7 days, self-reported affective distress (composite measure), performance on a WM (n-back) task, and task-related activation in the medial frontal cortex. Examining participants who reported non-zero pain intensity in the last 7 days (n = 228), we found a direct negative association between pain intensity and performance on the WM n-back task, consistent with prior findings. Self-reported affective distress was not associated with WM performance. Additionally, pain intensity was indirectly associated with WM performance via WM task-related activity in the ventromedial prefrontal cortex (vmPFC). Our findings suggest that everyday pain experienced outside of the laboratory by otherwise healthy individuals may directly impact WM performance. Furthermore, WM task-related increases in vmPFC activity may be a factor contributing to this relationship.
Learn More >Chronic pain has a significant impact on functioning and results in the disruption of one's assumed life trajectory, potentially altering their self-perceived identity. The present research is designed to determine whether identity-related issues are associated with common chronic pain cognitions and pain-related disability, which may help inform understanding of clinical chronic pain populations.
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