Eric Devaney Lab - Research

Opioids

Opioid abuse and overdose deaths are a public health crisis that are at epidemic levels in the United States. With the goal of treating pain pharmacology, opioid prescriptions steadily increased in the latter half of the 20th century. Tragically, the addictive nature of opioids was incompletely understood. Consequently, there has been a steady increase in the misuse of prescription and nonprescription opioids over the last two decades.

Figure 1. The Opioid Epidemic by The Numbers. From the U.S. Department OF Health and Human Services website.

 
Both naturally occurring and synthetic opioids used to treat opioid dependence alter human physiology by binding inhibitory G protein coupled receptors with opioids as their ligand (OR). The three major opioid receptors are the µ, δ and κ. While most opioid related deaths can be attributed to overdose, recent data suggest a possible link between opioid use and increased risk of cardiovascular disease. It is unknown if this increased risk is because of a direct effect on the heart, or the result of systemic physiological changes. Some data suggest there is an increased risk of cardiovascular death in opioid users with an underlying cardiovascular disease while other data suggest it is sex dependent, with women being at a somewhat higher risk than men. Healthy adult hearts express the δ and κ ORs, but not the µOR .

Figure 2. Diagram of Opioid and Estrogen Receptor Signaling. AC: adenylyl cyclase Akt: protein kinase B CAMKII: calmodulin-dependent protein kinase II ERK: extracellular-signal-regulated kinases GRK: GPCR kinase JNK: Jun N-terminal kinase MAPK: mitogen-activated protein kinase PI3K: Phosphoinositide 3-kinase PKA: protein kinase A PKC: protein kinase C STAT3: signal transducer and activator of transcription 3
Figure 3. Sex Dependent Differences in Excitation-Contraction Coupling. A, B. Representative recordings of sarcomere length (SL) shortening and intracellular calcium transients in an electrically paced cardiac myocyte after 24 hours in culture C, D. Peak contraction and calcium recorded from cells cultured with either 1 µM DADLE, a delta agonist, and/or 20 µM U50, a kappa agonist, for 24 hours. n > 30 myocytes for each group.

 
Preliminary data from our lab found that female myocytes are mostly immune to the detrimental effects of δ and κ OR stimulation. Consequently, using whole animal and cellular models we are discovering how male and female cardiovascular systems respond differently to opioid abuse.

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