Project Summary:
The opioid crisis in the United States has escalated to an alarming peak, claiming over 80,000 lives through overdoses in 2022 alone. This is greater than the number of fatalities from car accidents and homicides combined in the same year. Opioid misuse also wreaks collateral damage onto friends and families in many ways. A particularly tragic consequence of opioid misuse is the epidemic of neonatal opioid withdrawal syndrome (NOWS), sometimes referred to as neonatal abstinence syndrome.
Symptoms of NOWS include seizures, tremors, autonomic dysfunction, and breathing problems, and treatment often includes administration of morphine or methadone to the baby. Prenatal opioid use is associated with elevated risk of preterm birth and stillbirth, and long-term consequences of NOWS include learning, memory, social, and motor disabilities. The estimated rate of NOWS in the United States is 8 infants per 1,000 live births.
Wisconsin is disproportionately affected by opioid misuse compared to the national average. Age-adjusted opioid overdose death rates in Wisconsin have been higher than the national average in each of the last 12 years that the data has been available (2011-2022). Within Wisconsin, racial disparity in opioid overdose deaths is especially staggering. Data from 2004 to 2019 indicated that Black Wisconsinites were nearly two-times as likely to die from an opioid overdose as white Wisconsinites. More recent data shows even more grim disparities. State-wide data from 2022 reported that while White Wisconsinites had an opioid overdose rate of 20.5 per 100,000, Black Wisconsinites had a rate of 78.4 per 100,000, while American Indian/Alaska Native Wisconsinites had a rate of 97.8 per 100,000. Although the rate of NOWS in Wisconsin approximates the national average, six Wisconsin counties have more than double the national average, with Ashland and Vilas counties having 33 and 39.5 NOWS diagnoses per 1,000 live births, respectively. Ashland county is home to the Bad River Reservation, the largest Chippewa reservation in the country. Both Ashland and Vilas counties are enriched in tribal constituents, with 11.2% and 9.7% of the populations being American Indian/Alaska Native, compared to the overall Wisconsin rate of 1.2%.
Treating opioid misuse continues to pose significant challenges. Even among treatment seeking individuals, relapse to opioid misuse is extremely prevalent. In a multicenter study, Nunes et al. found that six months following treatment initiation, relapse rates ranged from 59-77%. These rates also fall within other reports of opioid relapse ranging from 40-90%. Clearly, there is a need to identify better strategies to reduce opioid misuse in Wisconsin and throughout the world.
This project will study mechanisms of opioid craving during abstinence using a rodent model of voluntary opioid self-administration and subsequent drug seeking behavior. The project team’s approach will be to identify neuron-specific transcriptional changes associated oxycodone self-administration that persist into abstinence. The researchers have chosen to focus on neurons from the dorsal medial prefrontal cortex (dmPFC) because neuronal activity in this this area is associated with drug craving and seeking in humans and rodents. They expect the impact of this work to be evidenced by identification of novel gene signatures and transcriptional networks associated with dmPFC neurons that are engaged during drug seeking (ensemble neurons). This information will be used as the basis for a collaborative NIH R01-level grant proposal that will perform genetic and pharmacological (if tools are available) modulation of key transcripts and networks identified in this AHW award.
By reducing craving and relapse, the researchers expect to reduce opioid overdose deaths and rates of NOWS: two outcomes that are disproportionately high in Black and Native American Wisconsinites.