Analgesia and Addiction

Drug dependence and addiction is a serious, and sometimes fatal, risk of taking opioids. The "Opioid Crisis” took more than 42,000 lives within the United States alone during 2016. As reported by the US Department of Health and Human Services, approximately half of these deaths were overdoses from prescription opioids (HHS, 2019). When opioids are taken long-term, then a tolerance to the drug develops. Therefore, a higher dose of opioids is required to reach the same euphoric, analgesic and anxiolytic effects as before. In a SAMHSA survey: 63.4% of prescription opioid abusers reported that the reason for abusing their prescriptions was to “relieve physical pain” (Lipari et al., 2015). Even when medically necessary, opioids prescriptions still run a high risk of abuse due to the rapid development of a tolerance to them. Despite the risks of opioids, they are still regularly utilized in medicine for their analgesic properties. Unfortunately, there has yet to be a more effective analgesic on the market for the treatment of pain. For many people experiencing chronic pain, they have no alternative except to take opioids regularly. Understanding the mechanisms behind opioid activity in the brain is crucial for combatting the Opioid Crisis.

In a study by Steidl et al. (2017), the neural mechanisms of opioid activity were analyzed in a mouse model. Opioid administration in rodents elicit “conditioned place preference”, which is attributed to the release of DA in the forebrain (NAcc). This study utilized the conditioned place preference paradigm to further analyze the neural networks underlying opioid-induced behavior. They found that neurons in the LDTg/PPTg which innervate the VTA are important for conditioned place preference and opioid induced locomotion. LDTg/PPTg activity is sufficient to initiate opioid induced locomotion and conditioned place preference. More specifically, cholinergic and glutamatergic neurons from the LDTg/PPTg project to and excite the VTA. In response to excitatory input from the LTDg/PPTg neurons, the VTA will increase the release of DA into the NAcc. Cholinergic neurons were found to be responsible for prolonged and sustained excitation of the VTA. Glutamatergic neurons were found to be responsible for rapid and short-lasting excitation of the VTA. The combination of these effects is proposed to modulate the observed opioid-induced locomotion by increasing the DA levels release from VTA to the NAcc. In normal physiological conditions, LTDg/PPTg neurons are tonically inhibited by the VTA and opioid-induced locomotion is not observed. Opioids prevent the tonic inhibition of LTDg/PPTg neurons by binding to 𝛍-opioid receptors in VTA GABA-ergic neurons. Stopping the tonic inhibition of LTDg/PPTg neurons increases VTA excitation and NAcc DA levels which ultimately results in opioid-induced locomotion. They conclude that glutamatergic and cholinergic excitation of VTA is a critical component of opioid-induced reward.

A study conducted by Markos et al. (2018) also used to conditioned place preference paradigm to test if a drug of interest could modulate the effects of opioid-induced reward. Previous research demonstrated that cannabidiol, a plant-derived molecule, can inhibit opioid-induced reward processing in mice. Markos et al. tested if cannabidiol inhibits the development of conditioned place preference in mice when administered in conjunction with opioids. Mice administered opioids alone demonstrated robust conditioned place preference in response to opioid treatment, consistent with previous research. A second group of mice was administered cannabidiol alone and did not exhibit conditioned place preference after drug administration. A third group of mice was simultaneously administered both opioids and cannabidiol and did not display conditioned place preference despite opioid treatment. These results demonstrate that cannabidiol modulates the neural mechanisms involved with opioid reward since cannabidiol administered with opioids prevented the effects of opioids on reward-based conditioning. The coadministration of cannabidiol and opioids prevented mice from developing addictive behaviors, and this may show similar results in humans. Markos et al. postulate that understanding the mechanisms which allow cannabidiol to block opioid reward can allow for the development of safer pain medications. They conclude that future research into cannabidiol could be pharmacologically valuable for developing new analgesic drugs which do not run the risk of addiction. Treating pain with a combination of opioids and cannabidiol analogues may allow for opioids to be used more safely.

While the Markos et al. study does not elaborate on the mechanisms of cannabidiol activity at the cellular level, we can still pose some intriguing questions in relation to the both studies. Perhaps cannabidiol inhibits the VTA? Or perhaps cannabidiol strengthens the tonic inhibition on the LTDg/PPTg neurons? Or perhaps this system is even more complex than our current model? These studies pose interesting questions to explore in the future. Hopefully, future research will develop drugs which provide analgesia without the risk of addiction.


Works Cited:

• Lipari, R., et al. (2017). Why Do Adults Misuse Prescription Drugs?. Retrieved from https://www.samhsa.gov/data/sites/default/files/report_3210/ShortReport-3210.html
• Markos et al., (2018). Effects of Cannabidiol on Morphine Conditioned Place Preference in Mice. Planta Med, 84 (04), 221-224. DOI:10.1055/s-0043-117838
• Steidl, S., et al., (2017). Opioid-induced rewards, locomotion, and dopamine activation: a proposed model for control by mesopontine and rostromedial tegmental neurons. Neuroscience and Biobehavioral Reviews, 83, 72-82. http://dx.doi.org/10.1016/j.neubiorev.2017.09.022
• U.S. Department of Health and Human Services (2019). What is the U.S. Opioid Epidemic? [PDF file]. Retrieved from https://www.hhs.gov/opioids/about-the-epidemic/index.html

Vincristine Shortage and the FDA

An incredibly important drug to treat a lot of childhood cancers, vincristine, is facing massive shortages in the United States. Vincristine is used as the backbone of many treatments for childhood cancer for leukemias, lymphomas, and brain tumors. This is particularly problematic as there is no appropriate substitute.

There used to be two main suppliers for vincristine: Teva Pharmaceutical Industries and Pfizer. Unfortunately, in July, Teva stopped manufacturing vincristine for “business decisions”. Pfizer is now the sole manufacturer of vincristine and has had some manufacturing problems which has only exasperated the vincristine shortage. Oftentimes, these shortages happen to older, generic drugs which are difficult to manufacture, but have a low price. This causes manufactures to lose money and not manufacture the drug anymore.

The Children’s Oncology Group (COG), who specializes in pediatric cancer clinical trials in the U.S., issued a statement on October 16^th saying that any “situation that requires rationing of drug is unacceptable,” but it “welcome[s] the news that drug distribution should resume soon.” Peter C. Adamson, the Chair of the COG proposed an action plan to ensure that this kind of drug shortage would not happen again. His plan includes the establishment and maintenance of a national stockpile of key cancer drugs used in childhood cancer treatment, and the U.S. government purchasing contracts that provide a guaranteed buyer and help stabilize the volatile drug market.

A drug shortages task force was established in 2018 by former F.D.A. Commissioner Scott Gottlieb and they plan on submitting a report with findings and recommendations to Congress by the end of the year.

However, there are some who question the responsibility of the government in dictating which drugs manufacturers should produce. Sharona Hoffman, professor of law and bioethics at Case Western Reserve University School of Law, says “you can’t force a manufacturer to produce a particular drug against its other drugs, so this is a big problem.” In a free market, the government does not have the jurisdiction to tell manufacturers which drugs they should or should not produce.

Drug shortages are not a new issue in the U.S., however the vincristine shortage has brought more light to this incredibly important issue. The F.D.A. has a lot of room to improve in ensuring that the drugs needed to save lives are readily available.

https://www.nytimes.com/2019/10/14/health/cancer-drug-shortage.html#

https://www.forbes.com/sites/victoriaforster/2019/10/16/fda-deliveries-of-scarce-childhood-cancer-drug-due-to-resume-but-not-until-late-october/#1196439a56d9

Visual Attention and Working Memory: An Advantageous Connection

Dr. Elizabeth Wakefield is part of the Psychology department at Loyola University Chicago. On September 24, she presented her research on her 2018 article titled Gesture help learners learn, but not merely by guiding their visual attention. Dr. Wakefield described how the main goal of the study was to provide insight as to how gesture plays a part in visual attention to aid learning. Visual patterns were studied in children who looked at instructional videos which included speech and gesture instruction, and only-speech instruction. Results demonstrated that children attending to speech and gesture instruction performed better when demonstrating what they learned after the video, than those who were presented with speech-alone instruction. This presents the claim that gesture regulates learning-related visual patterns. Furthermore, it suggests that when there is presence of gesturing, there is an increase in attention to speech, and thus, increase in attention efficacy.  

Dr. Wakefield’s talk and findings are of great importance to the science field, as attention is a complex and intriguing topic to study. This is demonstrated through the article The Relationship Between Visual Attention and Visual Working Memory Encoding: A Dissociation Between Covert and Overt Orienting (2016) published in the Journal of Experimental Psychology. This article presents a study regarding the relationship among visual attention and encoding of items in the visual working memory. The main findings depict that covert attention does not necessarily produce encoding of objects into the visual working memory, suggesting that attention and the working memory are separate system rather than one mechanism, as previously thought. Moreover, the results indicated that attention and the visual working memory depend how the orienting behavior is demanded. In other words, covert shifts of attention to objects does not interfere with working memory performance.

The results of the latter relate to Dr. Wakefield’s study in several ways. In Dr. Wakefield’s research, the focus is on visual patterns of the eye to record attention shifts between gesture and non-gesture instruction. It involves overt attention, and the results proved that more movement towards a target (the gesture), help children learn more efficiently. Thus, encoding is occurring effectively at the visual working memory level. The difference between the two studies is that Wakefield’s explicitly seeks for overt attention, while the other depicts how covert attention do not interfere with working memory performance. The 2016 study goes more in-depth regarding attention mechanisms, as they focus on how attention is processed in working memory, while Wakefield’s study seeks to prove benefits of gesture-related attention on working memory. Without a doubt, both studies are very insightful as to the existing connection between visual attention and working memory. They shed light to how cognitive processes function in our brain, and these should be further studied for us to comprehend and appreciate. 

Tas, A. C., Luck, S. J., & Hollingworth, A. (2016). The relationship between visual attention and visual working memory encoding: A dissociation between covert and overt orienting. Journal of Experimental Psychology: Human Perception and Performance. Retrieved from https://psycnet.apa.org/manuscript/2016-06216-001.pdf

Wakefield, E., Novack, M. A., Congdon, E. C., Franconeri, S., & Goldin-Meadow, S. (2018). Gesture helps learners learn, but not merely by guiding their visual attention. Wiley Developmental Science. Retrieved from http://visualthinking.psych.northwestern.edu/publications/WakefieldGesture2018.pdf

Emojis Are The New Gestures

Earlier in the semester our class heard the speaker Elizabeth Wakefield and as she described the importance of gestures in learning and teacher, I thought it very thought provoking that a small wake of the hand could communicate so much. She found that gestures in teaching material allowed for students to understand where to focus their attention at the appropriate time. By having these extra gestures in addition to speech, telling the student how to solve problems, these gestures helped children embed and understand the material quicker.

She explains that gestures aren’t just exploring with your hands but it’s the movement that enhances what you are saying or already doing, such as saying “he went up the staircase” but you draw a spiral with your hands. The onlooker can infer that the staircase is in fact spiral shaped.

While hand gestures can give context to meaning, there is a new form of gestures that is taking over our lives; emojis. Emojis give inflection where we cannot with typed words. They are able to signify how we feel, how mad we are about something, or to draw attention to the way something ‘should’ be said, aka how it was meant to come across. For example:

‘I’m sorry’

This small phrase can be construed in a variety of ways; mockingly, genuinely, regretfully, disingenuously… you get the point. With out emojis or really knowing the person there is no way to know what they are saying. With the range of emojis forever expanding to be more customization, there will be better and better ways to get our points and emotions across to others around us.

Maybe, sometime far in the future, even eliminating some types of gestures all together. 

link:
https://www.psychologytoday.com/us/blog/more-just-text/201705/emojis-tools-emotions

Genetic and Behavioral Factors that Impact Obesity

Jennifer Beshel began her lecture by mentioning the rising rate of obesity in the United States which marks obesity as a recognized disease/disorder that needs to be dealt with. She compared statistics from 1990 and it is important to note that levels of obesity in America and the world have skyrocketed. In regards to her research, she goes on to discuss the factors behind food cues and food behaviors in animals that results in an increase in consumption. In her article “"A Leptin Analog Locally Produced in the Brain Acts via a Conserved Neural Circuit to Modulate Obesity-Linked Behaviors in Drosophila” she and other researchers present how the manipulation of the leptin homolog upd1 (unpaired 1) can lead to subjects gaining weight. The upd1 when inhibited causes symptoms of increased food consumption, which is much similar to the way leptin impacts hunger. Subsequently, Beshel uses this research to further investigate the release of leptin and its regulation. Those subjects with inhibited upd1 also expressed higher sensitivity to food cues and much higher attraction to food. This also explains why upd1 knockout subjects gained almost 3x more weight than their wildtype counter parts. Furthermore, the researchers also noted that reduction of upd2 (unpaired 2) within adipose tissues leads to a reduction of bodyweight and size. When exposed to this new knowledge, it is easy to conclude that expression of leptin analogs is paramount to food-related behaviors.

On the other hand, genes are not the only impactors that affect body weight and size. Some of the issues regarding obesity can be attributed to improper food intake behaviors or other chronobiological factors. In the news article titled “Molecular Clocks Scattered throughout Your Body (Not Just in the Brain) Keep Your Tissues Humming” the authors compile research data from multiple studies and imply that the human body itself has multiple clocks spread through different regions of the body. These regions include the liver, pancreas, adipose tissues and many other organs in the human system. Scientists find that insufficient sleep, lack of exercise and poor diet (as seen in many shift workers in America) can affect the peripheral clocks in the body, which in turn leads to a diminished metabolic health which translates to physiological abnormalities such as obesity and other metabolic disorders. Another study mentioned in the article is Mitch Lazar’s manipulation of the clock gene called Re-Verba, which acts as a timer for the enzyme HDAC3. Inhibiting Re-verba lead to diminished amounts of HDAC3, which resulted in a fatty liver, or Hepatic Steatosis. This goes to show interruption of the biological clocks in the body can have negative effects, the same can be said for clock genes in the adipose tissues. Mice lacking intact clocks in adipose tissue cells changed their food intake behavior by eating more during the daytime (leading to obesity). All of this research in conjunction shows that internal body clocks impact feeding behaviors, and it is important to get proper sleep, exercise regularly and have a balanced diet in order to re-align these clocks and maintain proper metabolic health and protect from other disorders.

All in all, both these pieces of research highlight the prevalent issue of obesity in our community. This research should be further investigated in order to combat obesity through proper maintenance of health (sleeping, eating, and exercising appropriately), and to create treatments for those with genetic dispositions. Hopefully we get to see more results from these studies.

Works Cited

Beshel, Jennifer, et al. “A Leptin Analog Locally Produced in the Brain Acts via a Conserved Neural Circuit to Modulate Obesity-Linked Behaviors in Drosophila.” Cell Metabolism, vol. 25, no. 1, 2017, pp. 208–217.

Summa, Keith C. “Molecular Clocks Scattered throughout Your Body (Not Just in the Brain) Keep Your Tissues Humming.” Scientific American, Scientific American , Feb. 2015, https://www.scientificamerican.com/article/molecular-clocks-scattered-throughout-your-body-not-just-in-the-brain-keep-your-tissues-humming/.