Inside Neuroscience: Understanding the Effects of Opioid Abuse

The opioid epidemic continues to exact a steep toll on people around the globe, but most of all in the United States, which accounts for more than a quarter of the estimated number of drug-related deaths worldwide, according to the United Nations. Approximately 2.1 million Americans have an opioid use disorder related to prescription pain relievers, according to NIDA, and the CDC states that more than 90 die of an opioid overdose every day.

“The societal consequences of that, when we talk about individual human lives and when we talk about the impact it has on our communities, is devastating,” said Edward Bilsky, provost and chief academic officer at Pacific Northwest University of Health Sciences and moderater of a press conference on opioids at Neuroscience 2017.

In light of such widespread opioid use, researchers are working to better understand the effects of opioids on the brain. By seeking ways to minimize the risks posed to infants exposed to opioids before and after birth, examining interactions between opioids and factors such as trauma and diet, and trying novel approaches to treating opioid use disorder, researchers hope to minimize the prevalence and consequences of opioid use. The studies discussed in this article were presented at a Neuroscience 2017 press conference and are unpublished preliminary work.

With the rise in the number of people who are dependent on opioids, more babies have been exposed to opioids in utero, which can lead to neonatal abstinence syndrome (NAS), symptoms of which include incessant crying, gastrointestinal distress, and in severe cases, seizures.

Shivon Robinson, a postdoctoral fellow, and her colleagues in the lab of Julie Blendy at the University of Pennsylvania conducted a study in mice that showed a genetic variant that affects the mu opioid receptor, which is activated by commonly prescribed opioids including morphine, may help protect some infants from the harmful effects of in utero exposure to these drugs. The genetic variant is most common in people of Asian and Caucasian ethnicity and has been assosicated with shorter NAS-related hospital stays.

The researchers exposed newborn mice with and without the variant to morphine throughout the first two weeks of their lives — a period equivalent to the third trimester of a human pregnancy. The researchers tested the mice pups’ response to being separated from their mother and siblings by observing how much they cried or vocalized. Morphine exposure significantly reduced vocalization in mice without the genetic variant but had no effect in mice with the variant. These results suggest that the variant may have protected against negative behavioral effects related to social attachment following prenatal opiate exposure; however, the genetic variant didn’t protect against developmental delays related to surface righting and grasping.

Since this study focused on morphine exposure during the third trimester of pregnancy, Robinson said that many questions remain unanswered about the effects of in utero morphine exposure throughout pregnancy.

“We would also like to identify some central nervous system mechanisms that might be underlying this, with the eventual goal of helping to find effective treatments,” she said.

Individuals with post-traumatic stress disorder (PTSD) are three to four times more likely to have a substance use disorder, and people who are dependent on opioids seem to have a particularly high risk of developing PTSD.

“The relationship between PTSD and substance use disorder has traditionally been thought to emerge as a consequence of an individual with PTSD self-medicating,” said Zachary Pennington, lead author on a study presented at the press conference. “Little is known about the opposite direction. How does drug use directly influence the likelihood of developing PTSD in the face of trauma?”

To examine this relationship between opioids and trauma, researchers at the University of California, Los Angeles developed a mouse model of PTSD and examined the effects of prior opiate exposure on fear responses

Some mice received escalating doses of morphine for eight days, after which they experienced a withdrawal period. Others did not receive any morphine. The mice then experienced a traumatic event — a series of mild shocks — and were put into a new environment, to which they were returned after exposure to a minor stressor. The mice that had received morphine showed exaggerated fear symptoms, which is consistent with the presentation of PTSD in humans. The researchers also found that mice that were given morphine after experiencing trauma showed a similar response.

“Opioid exposure both before or after trauma could alter fear learning,” Pennington said. “These findings are the first to show that opioid exposure may be able to produce lasting increases in fear learning, and this may be of relevance to individuals suffering from opioid use disorders as well as individuals prescribed with opioids in the case of common pain,” Pennington said.

Eating a diet rich in sugars, such as high fructose corn syrup (HFCS), may also influence how opioids affect people, according to recent research from the University of Guelph in Canada.

Substance use disorders and eating disorders sometimes present concurrently, co-lead author Meenu Minhas explained. For example, people with opioid use disorder who are undergoing treatment with methadone, a slow-acting opioid, sometimes experience intense cravings for sugary foods.

Based on the study’s preliminary findings, HFCS could be decreasing the amount of dopamine that the brain’s reward region produces in response to use of opioids such as oxycodone, Minhas said.

In the study, dopamine levels in the brains of rats whose diets included HFCS did not rise after they received oxycodone, while rats that did not consume HFCS did have increased amounts of dopamine in their brains after being given oxycodone. These findings suggest that high fructose corn syrup blunts the brain’s response to oxycodone — which could encourage greater consumption of the drug.

“It suggests that a diet that's rich in high fructose corn syrup ... might influence responses to oxycodone, which may increase the abuse potential for those utilizing that opioid,” Minhas said.

Scientists in Beijing are researching a novel way to help prevent relapse in people who depend on opioids by “erasing” their drug memories, with the goal of reducing their cravings for the drug.

“The major problem in the treatment of addiction is how to prevent drug cravings even after long-term abstinence,” said Ping Wu, a researcher at Peking University in China and the study’s lead author.

Wu and her colleagues had previously developed a procedure called memory retrieval-extinction that allows for reactivation, modification, and even elimination of subjects’ memories associated with drug use.

The subjects of this study had been undergoing methadone maintenance treatment, whereby methadone is administered to dampen the symptoms of opioids withdrawal as people wean themselves off of heroin. After methadone was administered, the researchers used the retrieval-extinction procedure to successfully inhibit drug cravings and reduce relapse when the procedure was used 10 minutes after patients took methadone. The procedure also reduced heroin cravings when used six hours after patients took methadone, although its effects did not last as long.

The addictive potential of opioids is becoming increasingly evident, and more steps should be taken to protect people from the harm they can cause, noted Bilsky, who has cofounded two biotechnology companies that work toward this goal — one that is developing analgesic pain relievers with less abuse potential  and one that seeks to use opioid antagonists to manage the side effects of opioids including abuse deterrence.

Quoting Drs. Louis S. Goodman and Alfred Gilman from their first edition of The Pharmacological Basis of Therapeutics, printed in 1941, Bilsky reminded the audience of their cautionary advice for using opioids: “Great care should be exercised not to prescribe narcotics for a longer period of time than is absolutely necessary.”