• The Alpha Isoform of Heat Shock Protein 90 and the Co-chaperones p23 and Cdc37 Promote Opioid Anti-nociception in the Brain

      Lei, Wei; Duron, David I; Stine, Carrie; Mishra, Sanket; Blagg, Brian S J; Streicher, John M; Univ Arizona, Coll Med, Dept Pharmacol (FRONTIERS MEDIA SA, 2019-11-29)
      Opioid activation of the mu opioid receptor (MOR) promotes signaling cascades that evoke both analgesic responses to pain and side effects like addiction and dependence. Manipulation of these cascades, such as by biased agonism, has great promise to improve opioid therapy. However, the signaling cascades of the MOR are in general poorly understood, providing few targets for drug development. In our earlier work, we identified Heat shock protein 90 (Hsp90) as a novel and crucial regulator of opioid anti-nociception in the brain by promoting ERK MAPK activation. In this study, we sought to identify the molecular isoforms and co-chaperones by which Hsp90 carried out this role, which could provide specific targets for future clinical intervention. We used novel selective small molecule inhibitors as well as CRISPR/Cas9 gene editing constructs delivered by the intracerebroventricular (icv) route to the brains of adult CD-1 mice to target Hsp90 isoforms (Hsp90α/β, Grp94) and co-chaperones (p23, Cdc37, Aha1). We found that inhibition of the isoform Hsp90α fully blocked morphine anti-nociception in a model of post-surgical paw incision pain, while blocking ERK and JNK MAPK activation, suggesting Hsp90α as the main regulator of opioid response in the brain. We further found that inhibition of the co-chaperones p23 and Cdc37 blocked morphine anti-nociception, suggesting that these co-chaperones assist Hsp90α in promoting opioid anti-nociception. Lastly, we used cycloheximide treatment in the brain to demonstrate that rapid protein translation within 30 min of opioid treatment is required for Hsp90 regulation of opioid response. Together these studies provide insight into the molecular mechanisms by which Hsp90 promotes opioid anti-nociception. These findings thus both improve our basic science knowledge of MOR signal transduction and could provide future targets for clinical intervention to improve opioid therapy.
    • Nationally Representative Health Care Expenditures of Community-Based Older Adults with Pain in the United States Prescribed Opioids vs Those Not Prescribed Opioids

      Axon, David R; Slack, Marion; Barraza, Leila; Lee, Jeannie K; Warholak, Terri; Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona; Community, Environment, Policy Department, College of Public Health, University of Arizona (Oxford University Press, 2020-05-01)
      OBJECTIVE: To compare health care expenditures between older US adults (≥50 years) with pain who were prescribed opioid medications and those who were not. DESIGN: Cross-sectional. SETTING: Community-based adults in the 2015 Medical Expenditure Panel Survey (MEPS). SUBJECTS: Nationally representative sample of US adults alive for the calendar year, aged 50 years or older, who reported having pain in the past four weeks. METHODS: Older US adults (≥50 years) with pain in the 2015 MEPS data were identified. The key independent variable was opioid prescription status (prescribed opioid vs not prescribed opioid). Hierarchical linear regression models assessed health care expenditures (inpatient, outpatient, office-based, emergency room, prescription medications, other, and total) in US dollars for opioid prescription status from a community-dwelling US population perspective, adjusting for covariates. RESULTS: The 2015 study cohort provided a national estimate of 50,898,592 noninstitutionalized US adults aged ≥50 years with pain in the past four weeks (prescribed opioid N = 16,757,516 [32.9%], not prescribed opioid N = 34,141,076 [67.1%]). After adjusting for covariates, individuals prescribed an opioid had 61% greater outpatient (β = 0.477, P < 0.0001), 69% greater office-based (β = 0.524, P < 0.0001), 14% greater emergency room (β = 0.131, P = 0.0045), 63% greater prescription medication (β = 0.486, P < 0.0001), 29% greater other (β = 0.251, P = 0.0002), and 105% greater total (β = 0.718, P < 0.0001) health care expenditures. There was no difference in opioid prescription status for inpatient expenditures (P > 0.05). CONCLUSIONS: This study raises awareness of the economic impact associated with opioid use among US older adults with pain. Future research should investigate these variables in greater depth, over longer time periods, and in additional populations. © The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    • Use of continuous intercostal nerve blockade is associated with improved outcomes in patients with multiple rib fractures

      Uhlich, R.; Kerby, J.D.; Bosarge, P.; Hu, P.; Surgery, University of Arizona (BMJ Publishing Group, 2021)
      Background Rib fractures are common among trauma patients and may result in significant morbidity and mortality. There are numerous treatment options, but ideal management is unclear. Delivery of local anesthetic via an analgesia catheter for continuous intercostal nerve blockade offers an attractive potential option for management of patients with rib fractures. Methods We performed a single-center, retrospective case-control analysis of trauma patients with multiple rib fractures from 2016 to 2018, comparing patients managed with continuous intercostal nerve blockade with standard care. Matching was performed in a 2:1 ratio by Injury Severity Score, age, and gender. Respiratory morbidity potentially secondary to rib fractures, including unplanned intubation, failure of extubation, need for tracheostomy, pneumonia, or mortality, were all identified and included. Potential complications due to catheter insertion were identified to be recorded. The primary outcome of interest was 30-day hospital-free days. Results Nine hundred and thirty-three patients were eligible for analysis, with 48 managed using intercostal blockade compared with 96 matching controls. No complications of intercostal blockade were identified during the study period. Controls demonstrated fewer rib fractures (6.60±4.11 vs. 9.3±3.73, p=0.001) and fewer flail segments (0.8±1.76 vs. 2.0±2.94, p=0.02). Those managed with intercostal blockade demonstrated significantly more 30-day hospital-free days (15.9±6.43 vs. 13.2±9.94, p=0.048), less incidence of pneumonia (4.2% vs. 16.7%, p=0.03), and lower hospital mortality (2.1% vs. 13.5%, p=0.03). When adjusting for number of rib fractures and number of flail segments, use of continuous intercostal nerve blockade was significantly associated with lower hospital mortality (OR 0.10; 95% CI 0.01 to 0.91), pneumonia (OR 0.15; 95% CI 0.03 to 0.76), or need for tracheostomy (OR 0.23; 95% CI 0.06 to 0.83). Discussion The addition of continuous intercostal nerve blockade may help to improve outcomes in patients with multiple rib fractures compared with standard care alone. Level of evidence Therapeutic/care management; level IV. © BMJ Publishing Group Limited 2021.