Browse by Audience
Pain is one of the most common and distressing symptoms suffered by patients with progression of bone cancer; however, the mechanisms responsible for hyperalgesia are not well understood. The purpose of our current study was to determine contributions of the sensory signaling pathways of inflammatory tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and downstream transient receptor potential ankyrin 1 (TRPA1) to neuropathic pain induced by bone cancer. We further determined if influencing these pathways can improve bone cancer pain. Breast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats to induce mechanical and thermal hyperalgesia. ELISA and western blot analysis were used to examine 1) the levels of TNF-α and IL-6 in dorsal root ganglion (DRG); and 2) protein expression of TNF-α and IL-6 receptors (TNFR1 and IL-6R) and TRPA1 as well as intracellular signals (p38-MAPK and JNK). TNF-α and IL-6 were elevated in the DRG of bone cancer rats and expression of TNFR1, IL-6R and TRPA1 was upregulated. In addition, inhibition of TNFR1 and IL-6R alleviated mechanical and thermal hyperalgesia in bone cancer rats, accompanied with downregulated TRPA1 and p38-MAPK and JNK. We revealed specific signaling pathways leading to neuropathic pain during the development of bone cancer, including TNF-α-TRPA1 and IL-6-TRPA1 signal pathways. Overall, our data suggest that blocking these signals is beneficial to alleviate bone cancer pain.
Learn More >Chemotherapy-induced painful peripheral neuropathy (CIPN) is a significant clinical problem that is associated with widely used chemotherapeutics. Unfortunately, the molecular mechanisms by which CIPN develops has remained elusive. The proteasome inhibitor, bortezomib, has been shown to induce aerobic glycolysis in sensory neurons. This altered metabolic phenotype leads to the extrusion of metabolites which sensitize primary afferents and cause pain. Hypoxia-inducible factor alpha (HIF1A) is a transcription factor that is known to reprogram cellular metabolism. Furthermore, HIF1A protein is constantly synthesized and undergoes proteasomal degradation in normal conditions. However, metabolic stress or hypoxia stabilize the expression of HIF1A leading to the transcription of genes that reprogram cellular metabolism. This study demonstrates that treatment of mice with bortezomib stabilize the expression of HIF1A. Moreover, knockdown of HIF1A, inhibition of HIF1A binding to its response element or limiting its translation by using metformin prevent the development of bortezomib-induced neuropathic pain. Strikingly, the blockade of HIF1A expression does not attenuate mechanical allodynia in mice with existing bortezomib-induced neuropathic pain. These results establish the stabilization of HIF1A expression as the molecular mechanism by which bortezomib initiates CIPN. Crucially these findings reveal that the initiation and maintenance of bortezomib-induced neuropathic pain are regulated by distinct mechanisms.
Learn More >Cannabis is widely used for chronic pain. However, there is some evidence of an inverse dose-response relationship between cannabis effects and pain relief which may negatively affect analgesic outcomes. In this cross-sectional survey, we examined whether daily cannabis use frequency was associated with pain severity and interference, quality of life measures relevant to pain (e.g., anxiety and depressive symptoms), and cannabis use preferences (administration routes, cannabinoid ratio). Our analysis included 989 adults who used cannabis every day for chronic pain. Participant use was designated as light, moderate, and heavy (1-2, 3-4, and 5 or more cannabis uses per day, respectively). The sample was also sub-grouped by self-reported medical only use (designated MED, n=531, 54%) vs. medical use concomitant with a past-year history of recreational use (designated MEDREC, n=458, 46%). In the whole sample, increased frequency of use was significantly associated with worse pain intensity and interference, and worse negative affect, although high frequency users also reported improved positive affect. Subgroup analyses showed that these effects were driven by MED participants. Heavy MED participant consumption patterns showed greater preference for smoking, vaporizing, and high THC products. In contrast, light MED participants had greater preference for tinctures and high CBD products. Selection bias, our focus on chronic pain, and our cross-sectional design likely limit the generalizability our results. Our findings suggest that lower daily cannabis use frequency is associated with better clinical profile as well as lower risk cannabis use behaviors among MED participants. Future longitudinal studies are needed to examine how high frequency of cannabis use interacts with potential therapeutic benefits. PERSPECTIVE: Our findings suggest that lower daily cannabis use frequency is associated with better clinical profile as well as safer use behaviors (e.g., preference for CBD and non-inhalation administration routes). These trends highlight the need for developing cannabis use guidelines for clinicians to better protect patients using cannabis.
Learn More >Daily fluctuation in pain acceptance and its impact on the physical and psychosocial functioning of individuals living with spinal cord injury (SCI) and chronic pain has not been examined. We used end-of-day (EOD) diaries and multilevel mixed effects modeling (MLM) to examine the moderating effect of within- and between-person pain acceptance on associations between pain and physical and psychosocial functioning. Individuals with SCI and chronic pain (N = 124) completed seven days of EOD diaries, which included measures of pain acceptance, pain intensity, pain catastrophizing, pain interference, participation in social roles and activities (SRA), depressive symptoms, and positive affect and well-being (PAWB). We found within-person variability in pain acceptance (28% of the total variance) and a significant moderating effect of daily fluctuation in pain acceptance on the same-day pain intensity-SRA association. Within-person changes in pain acceptance were also associated with daily changes in pain interference, depressive symptoms, and PAWB, adjusting for pain intensity and catastrophizing. Findings highlight the potential for daily or momentary assessments of pain acceptance to enhance understanding of how psychological flexibility may contribute to pain-related outcomes. Future studies could further investigate stable and variable characteristics of pain acceptance and their individual contribution to physical and psychosocial functioning. PERSPECTIVE: Daily fluctuations in pain acceptance and their association with physical and psychosocial functioning were observed in the lives of individuals with spinal cord injury (SCI) and chronic pain. These findings may guide future studies to inform the development of effective, pain acceptance-focused individualized treatment approaches for chronic pain management in people with SCI.
Learn More >The size and modular structure of versican and its gene suggests the existence of multiple splice variants. We have identified, cloned and sequenced a previously unknown exon located within the non-coding gene sequence downstream of exon 8. This exon, which we have named exon 8 specifies two stop-codons. mRNAs of the versican gene with exon 8 are predicted to be constitutively degraded by nonsense mediated RNA decay. Here we tested the hypothesis that these transcripts become expressed in a model of neuropathic pain.
Learn More >