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To evaluate the use of low-dose naltrexone (LDN) as a broad-spectrum analgesic. Retrospective cohort study from a single pain management practice using data from 2014 to 2020. Thirty-six patients using LDN for ≥2 months were matched to 42 controls. Pain scores were assessed at initial visit and at most recent/final documented visit using a 10-point scale. Cases reported significantly greater pain reduction (-37.8%) than controls (-4.3%; p < 0.001). Whole sample multivariate modeling predicts 33% pain reduction with LDN, with number needed to treat (for 50% pain reduction) of 3.2. Patients with neuropathic pain appeared to benefit even more than those with 'nociceptive'/inflammatory pain. LDN is effective in a variety of chronic pain states, likely mediated by TLR-4 antagonism.
Learn More >To examine postpartum opioid prescribing practices. Obstetricians were interviewed about opioids: choice of opioid, clinical factors considered when prescribing, thoughts/beliefs about prescribing, and typical counseling provided. Inductive thematic analyses were used to identify themes. A total of 38 interviews were analyzed. Several key points emerged. The choice of opioid, dosing and number of pills prescribed varied widely. The mode of delivery is the primary consideration for prescribing opioids. All providers would prescribe opioids to breastfeeding women. Some providers offered counseling on nonopioid treatment of pain. At two large tertiary centers in Pennsylvania, the 38 physicians interviewed wrote 38 unique opioid prescriptions. Patient counseling addressed short-term pain management, but not the chronic overuse of opioids.
Learn More >Brain activity is reported to be associated with individual pain susceptibility and inflammatory status, possibly contributing to disease activity assessment in inflammatory arthritis (IA) including rheumatoid arthritis (RA) and spondyloarthritis (SpA). However, what alteration of brain function associated with disease activity and therapeutic effectiveness in IA remains unclear. We aimed to identify the alterations of brain functional connectivity (FC) shared in both RA and SpA, and evaluate its relationship to anti-rheumatic treatment response using functional magnetic resonance imaging (MRI).
Learn More >Background Mutations in gene encoding the Na,K-ATPase α isoform are associated with familial hemiplegic migraine type 2. Migraine with aura is a known risk factor for heart disease. The Na,K-ATPase is important for cardiac function, but its role for heart disease remains unknown. We hypothesized that is a susceptibility gene for heart disease and aimed to assess the underlying disease mechanism. Methods and Results Mice heterozygous for the familial hemiplegic migraine type 2-associated G301R mutation in the gene (α mice) and matching wild-type controls were compared. Reduced expression of the Na,K-ATPase α isoform and increased expression of the α isoform were observed in hearts from α mice (Western blot). Left ventricular dilation and reduced ejection fraction were shown in hearts from 8-month-old α mice (cardiac magnetic resonance imaging), and this was associated with reduced nocturnal blood pressure (radiotelemetry). Cardiac function and blood pressure of 3-month-old α mice were similar to wild-type mice. Amplified Na,K-ATPase-dependent Src kinase/Ras/Erk1/2 (p44/42 mitogen-activated protein kinase) signaling was observed in hearts from 8-month-old α mice, and this was associated with mitochondrial uncoupling (respirometry), increased oxidative stress (malondialdehyde measurements), and a heart failure-associated metabolic shift (hyperpolarized magnetic resonance). Mitochondrial membrane potential (5,5´,6,6´-tetrachloro-1,1´,3,3´-tetraethylbenzimidazolocarbocyanine iodide dye assay) and mitochondrial ultrastructure (transmission electron microscopy) were similar between the groups. Proteomics of heart tissue further suggested amplified Src/Ras/Erk1/2 signaling and increased oxidative stress and provided the molecular basis for systolic dysfunction in 8-month-old α mice. Conclusions Our findings suggest that mutation leads to disturbed cardiac metabolism and reduced cardiac function mediated via Na,K-ATPase-dependent reactive oxygen species signaling through the Src/Ras/Erk1/2 pathway.
Learn More >Chronic low back pain (CLBP) is the leading cause of years lived with disability. Recently, it has been reported that CLBP is associated with alterations in the central nervous system. The present study aimed to investigate the association between CLBP and regional brain atrophy in an older Japanese population. A total of 1106 community-dwelling participants aged ≥65 years underwent brain magnetic resonance imaging scans and a health examination in 2017 to 2018. We used the FreeSurfer software for the analysis of brain magnetic resonance imaging. Chronic pain was defined as subjective pain for ≥3 months. Participants were divided into 3 groups according to the presence or absence of chronic pain and the body part that mainly suffered from pain: a "no chronic pain (NCP)" group (n = 541), "CLBP" group (n = 189), and "chronic pain in body parts other than the lower back (OCP)" group (n = 376). The brain volumes of the ventrolateral and dorsolateral prefrontal cortex, the posterior cingulate gyrus, and the amygdala were significantly lower in the CLBP group than in the NCP group after adjustment for sociodemographic, physical, and lifestyle factors and depressive symptoms. In addition, the left superior frontal gyrus was identified as a significant cluster by the Query, Design, Estimate, Contrast interface. There were no significant differences in the brain volumes of pain-related regions between the NCP and the OCP groups. The present study suggests that CLBP is associated with lower brain volumes of pain-related regions in a general older population of Japanese.
Learn More >There is concern that state laws to curb opioid prescribing may adversely affect patients with chronic noncancer pain, but the laws' effects are unclear because of challenges in disentangling multiple laws implemented around the same time.
Learn More >Burn injury is a trauma resulting in tissue degradation and severe pain, which is processed first by neuronal circuits in the spinal dorsal horn. We have recently shown that in mice, excitatory dynorphinergic (Pdyn) neurons play a pivotal role in the response to burn-injury-associated tissue damage via histone H3.1 phosphorylation-dependent signaling. As Pdyn neurons were mostly associated with mechanical allodynia, their involvement in thermonociception had to be further elucidated. Using a custom-made AAV9_mutH3.1 virus combined with the CRISPR/cas9 system, here we provide evidence that blocking histone H3.1 phosphorylation at position serine 10 (S10) in spinal Pdyn neurons significantly increases the thermal nociceptive threshold in mice. In contrast, neither mechanosensation nor acute chemonociception was affected by the transgenic manipulation of histone H3.1. These results suggest that blocking rapid epigenetic tagging of S10H3 in spinal Pdyn neurons alters acute thermosensation and thus explains the involvement of Pdyn cells in the immediate response to burn-injury-associated tissue damage.
Learn More >The pathological mechanisms of fibromyalgia (FM) are largely unknown. Recently, a rat reserpine-induced pain model showing exaggerated pain-related behaviors to mechanical and thermal stimuli has been used in FM research. However, the model has not been fully characterized. Here, we investigated nociceptive hypersensitivity to chemical stimuli and its spinal mechanisms to further characterize the model. The rat model was induced by administering reserpine to the nervous system. Nociceptive behaviors to chemical stimuli were quantified using the formalin pain test, and neuronal activation of the stimuli was examined using spinal c-Fos immunohistochemistry and electrophysiological recordings of superficial dorsal horn (SDH) neurons. The duration of pain-related behaviors was prolonged in both phases I (0-5min) and II (10-60min) and the interphase; and the number of c-Fos-immunoreactive nuclei increased in laminae I-II, III-IV, and V-VI at the spinal segments L3-L5 on the side ipsilateral to the formalin injection, and these factors were significantly and positively correlated. The action potentials of SDH neurons induced by formalin injection were markedly increased in rats treated with reserpine. These results demonstrate that pain-related behaviors are facilitated by noxious chemical stimuli in a rat reserpine-induced FM model, and that the behavioral hypersensitivity is associated with hyperactivation of SDH neurons.
Learn More >Originally characterized as an oncoprotein overexpressed in many forms of cancer that participates in numerous cellular pathways, DEK has since been well described regarding the regulation of epigenetic markers and transcription factors in neurons. However, its role in neuropathic allodynia processes remain elusive and intriguingly complex. Here, we show that DEK, which is induced in spinal dorsal horn neurons after spinal nerve ligation (SNL), is regulated by miR-489-3p. Moreover, SNL-induced decrease in miR-489-3p expression increased the expression of DEK, which recruited TET1 to the promoter fragments of the Bdnf, Grm5, and Stat3 genes, thereby enhancing their transcription in the dorsal horn. Remarkably, these effects were also induced by intrathecally administering naïve animals with miR-489-3p inhibitor, which could be inhibited by knockdown of TET1 siRNA or DEK siRNA. Conversely, delivery of intrathecal miR-489-3p-mimic into SNL rats attenuated allodynia behavior and reversed protein expression coupled to the promoter segments in the dorsal horn. Thus, a spinal miR-489-3p/DEK/TET1 transcriptional axis may contribute to neuropathic allodynia. These results may provide a new target for treating neuropathic allodynia.
Learn More >The amygdala plays a critical role in the emotional-affective component of pain and pain modulation. The central nucleus of amygdala (CeA) serves major output functions and has been linked to pain-related behaviors. Corticotropin releasing factor (CRF) in the CeA has emerged as an important modulator of pain and affective disorders. Here we measured the effects of optogenetic manipulation of CeA-CRF neurons on pain-related behaviors in a rat neuropathic pain model and under control conditions. Emotional-affective behaviors (vocalizations), mechanosensitivity (electronic von Frey anesthesiometer and calibrated forceps), and anxiety-like behaviors (open field test and elevated plus maze) were assessed in adult rats 1 week and 4 weeks after spinal nerve ligation (SNL model) and sham surgery (control). For optogenetic silencing or activation of CRF neurons, a Cre-inducible viral vector encoding enhanced halorhodopsin (eNpHR) or channelrhodopsin 2 (ChR) was injected stereotaxically into the right CeA of transgenic Crh-Cre rats. Light of the appropriate wavelength (590 nm for eNpHR; 473 nm for ChR) was delivered into the CeA with an LED optic fiber. Optical silencing of CeA-CRF neurons decreased the emotional-affective responses in the acute and chronic phases of the neuropathic pain model but had anxiolytic effects only at the chronic stage and no effect on mechanosensitivity. Optogenetic activation of CeA-CRF neurons increased the emotional-affective responses and induced anxiety-like behaviors but had no effect on mechanosensitivity in control rats. The data show the critical contribution of CeA-CRF neurons to pain-related behaviors under normal conditions and beneficial effects of inhibiting CeA-CRF neurons in neuropathic pain.
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