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Vincristine, oxaliplatin, and cisplatin are commonly prescribed chemotherapeutic agents for the treatment of many tumors. However, a main side-effect is chemotherapy-induced peripheral neuropathy (CIPN), which may lead to changes in chemotherapeutic treatment. Although symptoms associated with CIPN are recapitulated by mouse models, there is limited knowledge of how these drugs affect the expression of genes in sensory neurons. The present study carried out a transcriptomic analysis of dorsal root ganglia (DRG) following vincristine, oxaliplatin, and cisplatin treatment with a view to gain insight into the comparative pathophysiological mechanisms of CIPN. RNA-Seq revealed 368, 295 and 256 differential expressed genes (DEGs) induced by treatment with vincristine, oxaliplatin and cisplatin, respectively and only five shared genes were dysregulated in all three groups. Cell type enrichment analysis and gene set enrichment analysis showed predominant effects on genes associated with the immune system after treatment with vincristine, while oxaliplatin treatment affected mainly neuronal genes. Treatment with cisplatin resulted in a mixed gene expression signature. Perspective: These results provide insight into the recruitment of immune responses to DRG and indicate enhanced neuro-inflammatory processes following administration of vincristine, oxaliplatin, and cisplatin. These gene expression signatures may provide insight into novel drug targets for treatment of CIPN.
Learn More >Patients with cancer, especially breast, prostate, and lung cancer, commonly experience bone metastases that are difficult to manage and are associated with bone cancer pain (BCP). Amitriptyline is often used to treat chronic pain, such as neuropathic pain. In the present study, the effects of amitriptyline on the mechanical withdrawal threshold (MWT) and its underlying mechanisms were evaluated in rat models of BCP. Walker 256 rat mammary gland carcinoma cells were injected into the bone marrow cavity of the right tibia of rats to provoke BCP. Then, amitriptyline was intraperitoneally administered twice daily from fifth day after the operation. Rats with bone cancer showed an apparent decline in the MWT at day 11 after Walker 256 cells inoculation. The levels of the glutamate transporter GLAST in the spinal cord dorsal horn decreased remarkably, and the concentration of the excitatory amino acid (EAA) glutamate (Glu) in the cerebrospinal fluid (CSF) increased substantially. Amitriptyline injection could prevent the decline of MWT in BCP rats. In addition, GLAST was upregulated on the glial cell surface, and Glu levels were reduced in the CSF. However, amitriptyline injection could not prevent the BCP-induced reduction in GLAST in the glial cell cytosol, it further downregulated cytosolic GLAST. Amitriptyline had no significant effect on GLAST mRNA expression, and BCP-invoked PKA/PKC upregulation was prevented. Taken together, these results suggest that the intraperitoneal injection of amitriptyline can prevent the decrease of MWT in BCP rats, the underlying mechanisms may be associated with the inhibition of PKA/PKC expression, thus promoting GLAST trafficking onto the glial cell surface and reducing EAA concentrations in the CSF.
Learn More >This study aims to (1) examine the temporal influence of peer victimization on mood, sleep quality, pain, and activity limitations in clinical and community samples of youth, and (2) test mood and sleep as mediators of peer victimization-pain pathways. One hundred fifty-six adolescents (n=74 chronic pain group) completed a week of online diary monitoring assessing their daily peer victimization experiences, negative mood, sleep quality, pain intensity, and pain-related activity limitations. In multilevel models controlling for group status, person-mean peer victimization (averaged across days) significantly predicted worse mood, pain, and activity limitations (all ps < .01) while daily victimization predicted worse mood (p < .05). Results from within-person mediation indicated a significant indirect effect of daily peer victimization on next-day activity limitations, through daily negative mood. Results from between-person mediation indicated that negative mood significantly mediated the relation between peer victimization and pain and the relation between peer victimization and activity limitations. Peer victimization is associated with negative health indicators in clinical and community samples of youth and may exert its influence on pain and pain-related activity limitations through negative mood. PERSPECTIVE: This article examines the temporal influence of peer victimization on pain in adolescents with and without chronic pain, and examines mood and sleep quality as mechanisms linking victimization to pain. This information may be useful for pain prevention researchers as well as providers who assess and treat pain in childhood.
Learn More >The periaqueductal gray (PAG) is a significant modulator of both analgesic and fear behaviors in both humans and rodents, but the underlying circuitry responsible for these two phenotypes is incompletely understood. Importantly, it is not known if there is a way to produce analgesia without anxiety by targeting the PAG, as modulation of glutamate or GABA neurons in this area initiates both antinociceptive and anxiogenic behavior. While dopamine (DA) neurons in the ventrolateral PAG (vlPAG)/dorsal raphe display a supraspinal antinociceptive effect, their influence on anxiety and fear are unknown. Using DAT-cre and Vglut2-cre male mice, we introduced designer receptors exclusively activated by designer drugs (DREADD) to DA and glutamate neurons within the vlPAG using viral-mediated delivery and found that levels of analgesia were significant and quantitatively similar when DA and glutamate neurons were selectively stimulated. Activation of glutamatergic neurons, however, reliably produced higher indices of anxiety, with increased freezing time and more time spent in the safety of a dark enclosure. In contrast, animals in which PAG/dorsal raphe DA neurons were stimulated failed to show fear behaviors. DA-mediated antinociception was inhibitable by haloperidol and was sufficient to prevent persistent inflammatory pain induced by carrageenan. In summary, only activation of DA neurons in the PAG/dorsal raphe produced profound analgesia without signs of anxiety, indicating that PAG/dorsal raphe DA neurons are an important target involved in analgesia that may lead to new treatments for pain.
Learn More >Sickle cell disease (SCD) describes a group of disorders associated with a point mutation in the beta chain of hemoglobin. The mutation leads to the creation of sickle hemoglobin (HbS) and causes distortion of erythrocytes through polymerization under low oxygen, resulting in characteristic sickle red blood cells. Vaso-occlusion episodes caused by accumulation of sRBCs results in ischemia-reperfusion injury, reduced oxygen supply to organs, oxidative stress, organ damage and severe pain that often requires hospitalization and opioid treatment. Further, many patients suffer from chronic pain, including hypersensitivity to heat and cold stimuli. Progress towards the development of novel strategies for both acute and chronic pain in patients with SCD has been impeded by a lack of understanding the mechanisms underlying pain in SCD. The purpose of this review is to highlight evidence for the contribution of peripheral and central sensitization that leads to widespread, chronic pain and hyperalgesia. Targeting the mechanisms that initiate and maintain sensitization in SCD might offer effective approaches to manage the severe and debilitating pain associated with this condition.
Learn More >Excessive opioid prescribing after surgery has been recognised as a contributor to the current crisis of opioid addiction and overdose. Clinicians may potentially tackle this crisis by using opioid-free postoperative analgesia; however, the scientific literature addressing this approach is sparse and heterogeneous, thereby limiting robust conclusions. A scoping review was conducted to systematically map the extent, range, and nature of the literature addressing postoperative opioid-free analgesia.
Learn More >Non-restorative sleep is a key diagnostic feature of the musculoskeletal pain disorder fibromyalgia, and is robustly associated with poor physical functioning, including activity interference. However, the mechanisms through which non-restorative sleep elicits activity interference among individuals with fibromyalgia at the within-person level remain unclear. The present study tested the following three-path mediation model, using data gathered from a 21-day electronic daily diary in 220 individuals with fibromyalgia: previous night non-restorative sleep → morning pain catastrophizing → afternoon pain severity → end-of-day activity interference. Results of multilevel structural equation modeling supported the three-path mediation model. Previous night's non-restorative sleep and morning pain catastrophizing were also directly related to end-of-day activity interference. Previous night non-restorative sleep did not significantly predict afternoon pain severity while controlling for the effect of morning pain catastrophizing. Greater non-restorative sleep during the previous night and a higher level of morning pain catastrophizing appear to serve as risk factors for experiencing greater daily pain and activity interference later in the day. These findings point to the potential utility of targeted interventions that improve both sleep quality and pain catastrophizing to help individuals with chronic pain engage in important daily activities despite experiencing pain.
Learn More >To analyze cervical tenderness scores (CTS) in patients with various temporomandibular disorders (TMD) and in controls and to examine associations of CTS with demographic and clinical parameters.
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