scholarly journals Opioids depress breathing through two small brainstem sites

2019 ◽  
Author(s):  
Iris Bachmutsky ◽  
Xin Paul Wei ◽  
Eszter Kish ◽  
Kevin Yackle
Keyword(s):  
Respiratory Depression ◽  
Cell Types ◽  
Opiate Receptor ◽  
The United States ◽  
Opioid Overdose ◽  
Brain Areas ◽  
Brain Site ◽  
Innovative Solutions ◽  
Μ Opiate Receptor

AbstractThe rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering the key brain areas and cell types mediating the cause of overdose—opioid respiratory depression. Here, we identify two primary changes to breathing after administering opioids. These changes implicate the brainstem’s breathing circuitry which we confirm by locally eliminating the μ-Opiate receptor. We find the critical brain site is the origin of the breathing rhythm, the preBötzinger Complex, and use genetic tools to reveal that just 70-140 neurons in this region are responsible for its sensitivity to opioids. Future characterization of these neurons may lead to novel therapies that prevent respiratory depression while sparing analgesia.

scholarly journals Opioids depress breathing through two small brainstem sites

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Iris Bachmutsky ◽  
Xin Paul Wei ◽  
Eszter Kish ◽  
Kevin Yackle
Keyword(s):  
United States ◽  
Respiratory Depression ◽  
Cell Types ◽  
The United States ◽  
Opioid Overdose ◽  
Novel Therapies ◽  
Brain Areas ◽  
Brain Site ◽  
Innovative Solutions

The rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering the key brain areas and cell types mediating the cause of overdose— opioid-induced respiratory depression. Here, we identify two primary changes to murine breathing after administering opioids. These changes implicate the brainstem’s breathing circuitry which we confirm by locally eliminating the µ-Opioid receptor. We find the critical brain site is the preBötzinger Complex, where the breathing rhythm originates, and use genetic tools to reveal that just 70–140 neurons in this region are responsible for its sensitivity to opioids. Future characterization of these neurons may lead to novel therapies that prevent respiratory depression while sparing analgesia.

scholarly journals Synthesis and pharmacological characterization of ethylenediamine synthetic opioids in human μ‐opiate receptor 1 (OPRM1) expressing cells

2019 ◽  
Vol 7 (5) ◽  
Author(s):  
Tom Hsu ◽  
Jayapal R. Mallareddy ◽  
Kayla Yoshida ◽  
Vincent Bustamante ◽  
Tim Lee ◽  
...  
Keyword(s):  
Opiate Receptor ◽  
Pharmacological Characterization ◽  
Synthetic Opioids ◽  
Μ Opiate Receptor

scholarly journals Pharmacologic and Clinical Considerations of Nalmefene, a Long Duration Opioid Antagonist, in Opioid Overdose

2021 ◽  
Vol 2 (4) ◽  
pp. 365-378
Author(s):  
Amber N. Edinoff ◽  
Catherine A. Nix ◽  
Tanner D. Reed ◽  
Elizabeth M. Bozner ◽  
Mark R. Alvarez ◽  
...  
Keyword(s):  
Respiratory Depression ◽  
The United States ◽  
Opioid Use Disorder ◽  
Opioid Antagonist ◽  
Opioid Overdose ◽  
Opioid Use ◽  
Physical Damage ◽  
Onset Of Action ◽  
Duration Of Action ◽  
Opioid Intoxication

Opioid use disorder is a well-established and growing problem in the United States. It is responsible for both psychosocial and physical damage to the affected individuals with a significant mortality rate. Given both the medical and non-medical consequences of this epidemic, it is important to understand the current treatments and approaches to opioid use disorder and acute opioid overdose. Naloxone is a competitive mu-opioid receptor antagonist that is used for the reversal of opioid intoxication. When given intravenously, naloxone has an onset of action of approximately 2 min with a duration of action of 60–90 min. Related to its empirical dosing and short duration of action, frequent monitoring of the patient is required so that the effects of opioid toxicity, namely respiratory depression, do not return to wreak havoc. Nalmefene is a pure opioid antagonist structurally similar to naltrexone that can serve as an alternative antidote for reversing respiratory depression associated with acute opioid overdose. Nalmefene is also known as 6-methylene naltrexone. Its main features of interest are its prolonged duration of action that surpasses most opioids and its ability to serve as an antidote for acute opioid overdose. This can be pivotal in reducing healthcare costs, increasing patient satisfaction, and redistributing the time that healthcare staff spend monitoring opioid overdose patients given naloxone.

scholarly journals Design, synthesis, and preliminary evaluation of a potential synthetic opioid rescue agent

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Sidnee L. Hedrick ◽  
Dan Luo ◽  
Sophia Kaska ◽  
Kumar Kulldeep Niloy ◽  
Karen Jackson ◽  
...  
Keyword(s):  
Respiratory Depression ◽  
Plasma Concentrations ◽  
The United States ◽  
Opioid Overdose ◽  
Preliminary Evaluation ◽  
Hot Plate ◽  
Plate Assay ◽  
Rescue Agent

Abstract Background One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids. Methods A series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogue 29 was chosen to undergo further PK studies, followed by in vivo pharmacological analysis to determine its ability to antagonize opioid-induced antinociception in the hot plate assay. Results A series of potent MOR antagonists were identified, including the highly potent analogue 29 (IC50 = 2.06 nM). Follow-up PK studies revealed 29 to possess near 100% bioavailability following IP administration. Brain concentrations of 29 surpassed plasma concentrations, with an apparent terminal half-life of ~ 80 min in mice. In the hot plate assay, 29 dose-dependently (0.01–0.1 mg/kg; IP) and fully antagonized the antinociception induced by oxycodone (5.6 mg/kg; IP). Furthermore, the dose of 29 that is fully effective in preventing oxycodone-induced antinociception (0.1 mg/kg) was ineffective against locomotor deficits caused by the KOR agonist U50,488. Conclusions Methods have been developed that have utility to identify enhanced rescue agents for the treatment of OIRD. Analogue 29, possessing potent MOR antagonist activity in vitro and in vivo, provides a promising lead in our search for an enhanced synthetic opioid rescue agent.

Characterization of μ-Opiate Receptor in Human Epidermis and Keratinocytes

2006 ◽  
Vol 885 (1) ◽  
pp. 368-371 ◽  
Author(s):  
M. BIGLIARDI-QI ◽  
P. L. BIGLIARDI ◽  
S. BÜCHNER ◽  
T. RUFLI
Keyword(s):  
Opiate Receptor ◽  
Human Epidermis ◽  
Μ Opiate Receptor

scholarly journals ß2-Arrestin germline knockout does not attenuate opioid respiratory depression

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Iris Bachmutsky ◽  
Xin Paul Wei ◽  
Adelae Durand ◽  
Kevin Yackle
Keyword(s):  
United States ◽  
Adenylyl Cyclase ◽  
Respiratory Depression ◽  
Opioid Receptor ◽  
Side Effect ◽  
Opioid Analgesics ◽  
The United States ◽  
Opioid Overdose ◽  
Novel Therapeutics ◽  
Deficient Mice

Opioids are perhaps the most effective analgesics in medicine. However, between 1999 to 2018, over 400,000 people in the United States died from opioid overdose. Excessive opioids make breathing lethally slow and shallow, a side-effect called opioid induced respiratory depression. This doubled-edged sword has sparked the desire to develop novel therapeutics that provide opioid-like analgesia without depressing breathing. One such approach has been the design of so-called 'biased agonists' that signal through some, but not all pathways downstream of the µ-opioid receptor (MOR), the target of morphine and other opioid analgesics. This rationale stems from a study suggesting that MOR-induced ß2-arrestin dependent signaling is responsible for opioid respiratory depression, whereas adenylyl cyclase inhibition produces analgesia. To verify this important result that motivated the 'biased agonist' approach, we re-examined breathing in ß2-arrestin deficient mice and instead find no connection between ß2-arrestin and opioid respiratory depression. This result suggests that any attenuated effect of 'biased agonists' on breathing is through an as-yet defined mechanism.

scholarly journals Isolation and characterization of novel reassortant mammalian orthoreovirus from pigs in the United States

2021 ◽  
pp. 1-43
Author(s):  
Liping Wang ◽  
Yan Li ◽  
Timothy Walsh ◽  
Zhenyu Shen ◽  
Yonghai Li ◽  
...  
Keyword(s):  
United States ◽  
The United States ◽  
Isolation And Characterization ◽  
Mammalian Orthoreovirus

Commercial Fishing as an Occupational Determinant of Opioid Overdoses and Deaths of Despair in Two Massachusetts Fishing Ports, 2000–2014

2021 ◽  
pp. 104829112110234
Author(s):  
Scott Fulmer ◽  
Shruti Jain ◽  
David Kriebel
Keyword(s):  
United States ◽  
Cause Of Death ◽  
Death Certificate ◽  
The United States ◽  
Opioid Overdose ◽  
Commercial Fishing ◽  
Opioid Epidemic ◽  
Death Certificate Data ◽  
Deaths Of Despair

The opioid epidemic has had disproportionate effects across various sectors of the population, differentially impacting various occupations. Commercial fishing has among the highest rates of occupational fatalities in the United States. This study used death certificate data from two Massachusetts fishing ports to calculate proportionate mortality ratios of fatal opioid overdose as a cause of death in commercial fishing. Statistically significant proportionate mortality ratios revealed that commercial fishermen were greater than four times more likely to die from opioid poisoning than nonfishermen living in the same fishing ports. These important quantitative findings suggest opioid overdoses, and deaths to diseases of despair in general, deserve further study in prevention, particularly among those employed in commercial fishing.

scholarly journals I’m Every Woman: Advancing the Intersectional Leadership of Black Women School Leaders as Anti-Racist Praxis

2021 ◽  
Vol 31 (1-2) ◽  
pp. 7-28
Author(s):  
April L. Peters ◽  
Angel Miles Nash
Keyword(s):  
Black Women ◽  
The United States ◽  
Women's Leadership ◽  
Three Dimensions ◽  
Race And Gender ◽  
Leadership Framework ◽  
And Gender ◽  
Resisting Oppression ◽  
Epistemological Basis

The rallying, clarion call to #SayHerName has prompted the United States to intentionally include the lives, voices, struggles, and contributions of Black women and countless others of her ilk who have suffered and strived in the midst of anti-Black racism. To advance a leadership framework that is rooted in the historicity of brilliance embodied in Black women’s educational leadership, and their proclivity for resisting oppression, we expand on intersectional leadership. We develop this expansion along three dimensions of research centering Black women’s leadership: the historical foundation of Black women’s leadership in schools and communities, the epistemological basis of Black women’s racialized and gendered experiences, and the ontological characterization of Black women’s expertise in resisting anti-Black racism in educational settings. We conclude with a four tenet articulation detailing how intersectional leadership: (a) is explicitly anti-racist; (b) is explicitly anti-sexist; (c) explicitly acknowledges the multiplicative influences of marginalization centering race and gender, and across planes of identity; and (d) explicitly leverages authority to serve and protect historically underserved communities.

scholarly journals Assessing the Relationships Between COVID-19 Stay-at-Home Orders and Opioid Overdoses in the State of Pennsylvania

2021 ◽  
pp. 002204262110063
Author(s):  
Brian King ◽  
Ruchi Patel ◽  
Andrea Rishworth
Keyword(s):  
Age Groups ◽  
The United States ◽  
Opioid Use Disorder ◽  
Opioid Overdose ◽  
Policy Recommendations ◽  
Opioid Use ◽  
Fentanyl Analogs ◽  
Measure Change ◽  
Using Data ◽  
At Home

COVID-19 is compounding opioid use disorder throughout the United States. While recent commentaries provide useful policy recommendations, few studies examine the intersection of COVID-19 policy responses and patterns of opioid overdose. We examine opioid overdoses prior to and following the Pennsylvania stay-at-home order implemented on April 1, 2020. Using data from the Pennsylvania Overdose Information Network, we measure change in monthly incidents of opioid-related overdose pre- versus post-April 1, and the significance of change by gender, age, race, drug class, and naloxone doses administered. Findings demonstrate statistically significant increases in overdose incidents among both men and women, White and Black groups, and several age groups, most notably the 30–39 and 40–49 ranges, following April 1. Significant increases were observed for overdoses involving heroin, fentanyl, fentanyl analogs or other synthetic opioids, pharmaceutical opioids, and carfentanil. The study emphasizes the need for opioid use to be addressed alongside efforts to mitigate and manage COVID-19 infection.

Sign in / Sign up

Export Citation Format

Share Document