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The mechanisms responsible for the persistence of chemotherapy-induced peripheral neuropathy (CIPN) in a significant proportion of cancer survivors are still unknown. Our previous findings show that CD8 T cells are necessary for the resolution of paclitaxel-induced mechanical allodynia in male mice. In the present study, we demonstrate that CD8 T cells are not only essential for resolving cisplatin-induced mechanical allodynia, but also to normalize spontaneous pain, numbness, and the reduction in intra-epidermal nerve fiber density in male and female mice. Resolution of CIPN was not observed in Rag2 mice that lack T and B cells. Reconstitution of Rag2 mice with CD8 T cells prior to cisplatin treatment normalized the resolution of CIPN. In vivo education of CD8 T cells by cisplatin was necessary to induce resolution of CIPN in Rag2 mice because adoptive transfer of CD8 T cells from naïve WT mice to Rag2 mice after completion of chemotherapy did not promote resolution of established CIPN. The CD8 T cell-dependent resolution of CIPN does not require epitope recognition by the T cell receptor (TCR). Moreover, adoptive transfer of cisplatin-educated CD8 T cells to Rag2 mice prevented CIPN development induced by either cisplatin or paclitaxel, indicating that the activity of the educated CD8 T is not cisplatin-specific.In conclusion, resolution of CIPN requires in vivo education of CD8 T cells by exposure to cisplatin. Future studies should examine whether ex vivo CD8 T cell education could be applied as a therapeutic strategy for treating or preventing CIPN in patients.
Learn More >There is uncertainty regarding the clinical significance of findings on MRI in patients with whiplash associated disorder (WAD) or nonspecific neck pain (NSNP).
Learn More >Diabetic neuropathy is an incapacitating complication in diabetic patients. The cellular and molecular mechanisms involved in this pathology are poorly understood. Previous studies have suggested that the loss of spinal GABAergic inhibition participate in painful diabetic neuropathy. However, the role of extrasynaptic α5 subunit-containing GABAA (α5GABAA) receptors in this process is not known. The purpose of this study was to investigate the role of α5GABAA receptors in diabetes-induced tactile allodynia, loss of rate-dependent depression (RDD) of the Hoffmann reflex (HR), and modulation of primary afferent excitability. Intraperitoneal administration of streptozotocin induced tactile allodynia. Intrathecal injection of α5GABAA receptor inverse agonist, L-655,708, produced tactile allodynia in naive rats, whereas it reduced allodynia in diabetic rats. In healthy rats, electrical stimulation of the tibial nerve at 5 Hz induced RDD of the HR, although intrathecal treatment with L-655,708 (15 nmol) abolished RDD of the HR. Streptozotocin induced the loss of RDD of the HR, while intrathecal L-655,708 (15 nmol) restored RDD of the HR. L-655,708 (15 nmol) increased tonic excitability of the primary afferents without affecting the phasic excitability produced by the primary afferent depolarization. α5GABAA receptors were immunolocalized in superficial laminae of the dorsal horn and L4 to L6 dorsal root ganglion. Streptozotocin increased mean fluorescence intensity and percentage of neurons expressing α5GABAA receptors in dorsal horn and L4 to L6 dorsal root ganglia in 10-week diabetic rats. Our results suggest that spinal α5GABAA receptors modulate the HR, play an antinociceptive and pronociceptive role in healthy and diabetic rats, respectively, and are tonically active in primary afferents.
Learn More >Children represent a patient demographic composed of multiple, unique subpopulations differentiated by rapidly changing age-related physiology, which includes the means of metabolizing opioids. Opioids are an important part of the pharmacological treatment of both acute and chronic pain. In both clinical medicine and clinical research, it is necessary to understand the differences in drug handling by age cohort in order to appropriately dose children to effect, and to avoid exacerbating deleterious adverse events with potentially grave sequelae.
Learn More >We examined the efficacy and safety of galcanezumab after treatment cessation in randomized double-blind, placebo-controlled, migraine prevention studies (EVOLVE-1; EVOLVE-2).
Learn More >Few investigations examine patterns of opioid and nonopioid analgesic prescribing and concurrent pain intensity ratings before and after institution of safer prescribing programs such as the October 2013 Veterans Health Administration system-wide Opioid Safety Initiative (OSI) implementation. We conducted a quasi-experimental pre-post observational study of all older U.S. veterans (≥50 years old) with osteoarthritis of the knee or hip. All associated outpatient analgesic prescriptions and outpatient pain intensity ratings from January 1, 2012 to December 31, 2016, were analyzed with segmented regression of interrupted time series. Standardized monthly rates for each analgesic class (total, opioid, nonsteroidal anti-inflammatory drug, acetaminophen, and other study analgesics) were analyzed with segmented negative binomial regression models with overall slope, step, and slope change. Similarly, segmented linear regression was used to analyze pain intensity ratings and percentage of those reporting pain. All models were additionally adjusted for age, sex, and race. Before OSI implementation, total analgesic prescriptions showed a steady rise, abruptly decreasing to a flat trajectory after OSI implementation. This trend was primarily due to a decrease in opioid prescribing after OSI. Total prescribing after OSI implementation was partially compensated by continuing increased prescribing of other study analgesics as well as a significant rise in acetaminophen prescriptions (post-OSI). No changes in nonsteroidal anti-inflammatory drug prescribing were seen. A small rise in the percentage of those reporting pain but not mean pain intensity ratings continued over the study period with no changes associated with OSI. Changes in analgesic prescribing trends were not paralleled by changes in reported pain intensity for older veterans with osteoarthritis.
Learn More >The purpose of this review is to summarize recent findings on conditioned pain modulation (CPM) in humans with a focus on methodology, factors modulating CPM, and the potential for CPM as a clinical marker for pain progression.
Learn More >Chronic pain patients are frequent and recurrent users of health services, which may have an impact on levels of health literacy (HL). Therefore, the aim of the present study was to investigate associations between healthcare utilization and varying levels of HL in individuals with and without chronic pain.
Learn More >Despite optimal medical management (OMM), low back pain (LBP) can be disabling, particularly after spinal surgery. Spinal cord stimulation (SCS) is effective in reducing neuropathic leg pain; however, evidence is limited for LBP.This prospective, open-label, parallel-group trial randomized (1:1) failed back surgery syndrome (FBSS) patients with predominant LBP to SCS plus OMM (SCS group) or OMM alone (OMM group) in 28 sites in Europe and the Americas. If trial stimulation was successful, a SCS system was implanted. Outcomes were assessed at baseline (pre-randomization) and 1, 3, 6, and 12 months post-randomization. Patients could change treatment groups at 6 months. The primary outcome was the proportion of patients with ≥50% reduction in LBP (responder) at 6 months. Secondary outcomes included change in pain intensity, functional disability and health-related quality of life (HRQoL). Results are posted at ClinicalTrials.gov registration number NCT01697358.In the intent-to-treat analysis, there were more responders in the SCS group than the OMM group (13.6%,15/110 versus 4.6%, 5/108, difference 9% with 95% CI 0.6-17.5%, P=0.036) at 6 months. The SCS group improved in all secondary outcomes compared to the OMM group. The OMM group only improved in HRQoL. In the SCS group, 17.6% (18/102) experienced SCS-related AEs through 6 months, with 11.8% (12/102) requiring surgical re-intervention.Adding multicolumn SCS to OMM improved pain relief, HRQoL and function in a traditionally difficult to treat population of FBSS patients with predominant LBP. Improvements were sustained at 12 months.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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