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 š¯›¨-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:
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 š¯›¨-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
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