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FSC231 can alleviate paclitaxel-induced neuralgia by inhibiting PICK1 and affecting related factors.
To explore the inhibitory effect of FSC231, a PDZ domain inhibitor of protein interacting with C kinase 1 (PICK1), on paclitaxel induced neuralgia and its possible pathways.
Learn More >Meditation has been shown to improve outcomes for chronic pain by increasing patients' awareness of their own bodies. Some patients have an innate ability to leverage their mind-body connection, and this interoceptive awareness may aid them in garnering pain relief. We explored whether spinal cord stimulation (SCS) patients with greater innate awareness had better outcomes.
Learn More >Translation regulation in the context of aged-associated inflammation and behavioral impairments is not well characterized. Aged individuals experience lower life quality due to behavioral impairments. In this study, we used young and aged transgenic mice that are unable to activate the cap-binding protein, eukaryotic translation initiation factor 4E (eIF4E) to examine the role of protein translation control in aging, memory, depression, and anxiety. To determine how products of cap-dependent translation play a permissive role in aged-associated inflammation, we assessed levels of pro-inflammatory cytokines in various brain regions involved in the above-mentioned behaviors. We found that functional eIF4E is not necessary for age-related deficits in spatial and short-term memory but is important for depressive and anxiety-like behavior and this is correlated with pro-inflammatory cytokines in discrete brain regions. Thus, we have begun to elucidate a role for eIF4E phosphorylation in the context of aged-related behavioral impairments and chronic low-grade inflammation that may help identify novel immune modulators for therapeutic targets and decrease the burden of self-care among the geriatric population.
Learn More >Chronic pain (CP) and cognitive decline (CD) are costly, challenging to treat, highly prevalent among older adults, and worsen each other over time. We are iteratively developing Active-Brains-Fitbit (AB-F), a live video program for older adults with CP and CD that teaches mind-body skills and gradual increases in step count aided by a Fitbit. AB-F has demonstrated feasibility, acceptability, and signals of improvement in emotional, physical, and cognitive function when delivered in-person to this population.
Learn More >Chronic pain is a significant comorbid condition among individuals with opioid use disorder (OUD). However, due to conflicting perceptions of responsibility, structural barriers, and a lack of widely applied standards of care, it is unclear what the landscape of chronic pain management looks like in addiction medicine. Using a national opioid surveillance system, we analyzed survey data from new entrants (n=14,449) to 225 OUD treatment centers from 2013 to 2018, as well as an online survey among a subset of respondents (n=309). While chronic pain was reported by 33.4% of the sample, two-thirds of the chronic pain group (66.0%) reported their pain was not managed through their OUD treatment program, with 47% reporting worsening pain. Pain that was managed was primarily done so through pharmaceuticals (75.2%), notably as a secondary effect of medication-assisted treatment. In addition, 43.2% reported chronic pain as a primary factor in their opioid relapse. These data suggest that chronic pain is commonly reported, yet not managed by many OUD treatment programs, increasing the likelihood of opioid relapse. In order to improve poor outcomes among OUD patients, interdisciplinary collaboration/care, along with evidence-based policies or processes for quality pain management in addiction care need to be prioritized. Perspective: This article suggests chronic pain is commonly reported, yet not managed by many OUD treatment programs, increasing the likelihood of opioid relapse. In order to improve low retention and success rates among OUD patients, interdisciplinary collaboration, evidence-based policies or processes (e.g., referral) for quality pain management in addiction care need to be prioritized.
Learn More >Chronic low back pain is a common condition, with high societal costs and often ineffectual treatments. Communication between macrophages/monocytes (MØ) and sensory neurons has been implicated in various preclinical pain models. However, few studies have examined specific MØ subsets, although distinct subtypes may play opposing roles. This study used a model of low back pain/radiculopathy involving direct local inflammation of the dorsal root ganglia (DRG). Reporter mice were employed that had distinct fluorescent labels for two key MØ subsets: CCR2-expressing (infiltrating pro-inflammatory) MØ, and CX3CR1-expressing (resident) macrophages. We observed that local DRG inflammation induced pain behaviors in mice, including guarding behavior and mechanical hypersensitivity, similar to the previously described rat model. The increase in MØ in the inflamed DRG was dominated by increases in CCR2 MØ, which persisted for at least 14 days. The primary endogenous ligand for CCR2, CCL2, was upregulated in inflamed DRG. Three different experimental manipulations that reduced the CCR2 MØ influx also reduced pain behaviors: global CCR2 knockout; systemic injection of INCB3344 (specific CCR2 blocker); and intravenous injection of liposomal clodronate. The latter two treatments when applied around the time of DRG inflammation reduced CCR2 but not CX3CR1 MØ in the DRG. Together these experiments suggest a key role for the CCR2/CCL2 system in establishing the pain state in this model of inflammatory low back pain and radiculopathy. Intravenous clodronate given after pain was established had the opposite effect on pain behaviors, suggesting the role of macrophages or their susceptibility to clodronate may change with time.
Learn More >Endometriosis is an estrogen-dependent gynecological disease, with an associated chronic inflammatory component, characterized by the presence of endometrial tissue outside the uterine cavity. Its predominant symptom is pain, a condition notably altering the quality of life of women with the disease. This review is intended to exhaustively gather current knowledge on purinergic signaling in endometriosis-associated pain. Altered extracellular ATP hydrolysis, due to changes in ectonucleotidase activity, has been reported in endometriosis; the resulting accumulation of ATP in the endometriotic microenvironment points to sustained activation of nucleotide receptors (P2 receptors) capable of generating a persistent pain message. P2X3 receptor, expressed in sensory neurons, mediates nociceptive, neuropathic, and inflammatory pain, and is enrolled in endometriosis-related pain. Pharmacological inhibition of P2X3 receptor is under evaluation as a pain relief treatment for women with endometriosis. The role of other ATP receptors is also discussed here, e.g., P2X4 and P2X7 receptors, which are involved in inflammatory cell-nerve and microglia-nerve crosstalk, and therefore in inflammatory and neuropathic pain. Adenosine receptors (P1 receptors), by contrast, mainly play antinociceptive and anti-inflammatory roles. Purinome-targeted drugs, including nucleotide receptors and metabolizing enzymes, are potential non-hormonal therapeutic tools for the pharmacological management of endometriosis-related pain.
Learn More >Peripheral denervation and pain are hallmarks of small fiber neuropathy (SFN). We investigated the contribution of skin cells on nociceptor degeneration and sensitization. We recruited 56 patients with SFN and 31 healthy controls, and collected skin punch biopsies for immunohistochemical and immunocytochemical analysis of netrin-1 (NTN1) and pro- and anti-inflammatory cytokine expression patterns. We further applied co-culture systems with murine dorsal root ganglion (DRG) neurons for skin cell-nerve interaction studies and patch-clamp analysis. Human keratinocytes attract murine DRG neuron neurites and the gene expression of the axon guidance cue NTN1 is higher in keratinocytes of SFN patients than in controls. NTN1 slows and reduces murine sensory neurite outgrowth in vitro, but does not alter keratinocyte cytokine expression. In the naïve state, keratinocytes of SFN patients show a higher expression of transforming growth factor-β1 (p<0.05), while fibroblasts display higher expression of the algesic cytokines interleukin (IL)-6 (p<0.01) and IL-8 (p<0.05). IL-6 incubation of murine DRG neurons leads to an increase in action potential firing rates compared to baseline (p<0.01). Our data provide evidence for a differential effect of keratinocytes and fibroblasts on nociceptor degeneration and sensitization in SFN compared to healthy controls and further supports the concept of cutaneous nociception.
Learn More >The present study was designed to investigate whether the antinociceptive effect of bone marrow-derived mesenchymal stem/stromal cells (MSC) during oxaliplatin (OXL)-induced sensory neuropathy is related to antioxidant properties.
Learn More >Interstitial cystitis/bladder pain syndrome (IC/BPS) is a type of chronic bladder inflammation characterized by increased voiding frequency, urgency and pelvic pain. The sensitization of bladder afferents is widely regarded as one of the pathophysiological changes in the development of IC/BPS. There is evidence that adenosine A receptors are involved in regulating the sensitization of sensory afferents. However, the effect of adenosine A receptors on cystitis remains unknown. In the present study, a rat model of chronic cystitis was established by intraperitoneal injection with cyclophosphamide (CYP). Cystometry and behavioral tests were performed to investigate bladder micturition function and nociceptive pain. The rats with chronic cystitis showed symptoms of bladder overactivity, characterized by an increase in bladder voiding frequency and voiding pressure. CYP treatment significantly increased the expression of the A receptor in bladder afferent fibers and dorsal root ganglion (DRG) neurons. The A receptor antagonist ZM241385 prevented bladder overactivity and hyperalgesia elicited by CYP-induced cystitis. In addition, the A receptor and TRPV1 were coexpressed on DRG neurons. The TRPV1 antagonist capsazepine blocked bladder overactivity induced by the A receptor agonist CGS21680. In contrast, ZM241385 significantly inhibited the capsaicin-induced increase in intracellular calcium concentration in DRG neurons. These results suggest that suppression of adenosine A receptors in bladder afferents alleviates bladder overactivity and hyperalgesia elicited by CYP-induced cystitis in rats by inhibiting TRPV1, indicating that the adenosine A receptor in bladder afferents is a potential therapeutic target for the treatment of IC/BPS.
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