Opioid drugs are a well-known class of drug due to both their ability to kill pain and kill people. Watch part 1 of this two-part series to learn how opioid drugs can manipulate our brain and body into no longer feeling pain and discomfort. Special thanks to Geoffrey Brown for helping research background information for this video! Watch Part 2 here: https://youtu.be/vLFf6dlKrqU Additional information: *Diversity of Opioid Drugs* The variety of opioid drugs available differ in aspects such as duration, rate of onset, potency (strength), risk of side effects, and metabolism. The video already addressed lipid solubility as a determinant for rate of onset and duration. Potency is determined by how well an opioid can bind to and stimulate the opioid receptor. For example, fentanyl can bind to and activate the opioid receptor much better than morphine, which is why fentanyl is 100 times more potent than morphine. Essentially, this means that you would need to use 100 times more morphine than fentanyl to get the same painkilling effect (which is also why it is so easy to overdose on fentanyl!) This website has some nice tables describing classic opioids and a variety of their pharmacodynamic and pharmacokinetic properties: https://basicmedicalkey.com/opioids/#ch13tab1 *Vesicle Release* Vesicle release from calcium influx is quite a complex process and crucial to neurotransmitter release and neuron function. Calcium ions bind to a protein called synaptotagmin on the visicle, which cause a variety of structural changes in SNARE proteins on both the vesicle and the membrane. The SNARE proteins intertwine and pull the vesicle closer to the membrane, eventually fusing the two. I may make a video about this sometime in the future, but for now, here is a decent animation on the process: https://youtu.be/knzNnhENlxg?t=45s *G Protein-Coupled Receptors* GPCRs are a crucial target for many drugs. In fact, 34% of drugs work on GPCRs, and even more drugs are being developed to target this large diverse family of receptors. When an agonist binds to a GPCR, a structural change occurs that causes the Gα subunit to kick out GDP and bind GTP. This activates the G protein and the subunits separate to perform their respective roles. When GTP is eventually hydrolyzed back to GDP, the subunits reassemble and the receptor is no longer activated. The video hinted at multiple functions of G proteins – what makes the story more interesting and complex is that two or more GPCRs can combine (dimerize or oligomerize), meaning that they now have access to each others’ different G protein. This likely allows for different signalling pathways to cross-communicate and achieve an even more powerful mechanism of regulation. Here is a good paper from Nature discussing this important class of receptors: https://www.nature.com/scitable/topicpage/gpcr-14047471 *Ascending and Descending Pain Pathways* Within the brainstem, there are multiple neurons and synapses (unlike the single synapse displayed in the video). Two important brainstem areas to know about are the periaqueductal gray area and the raphe nucleus, which are activated as part of the descending pathway. These areas receive innervation from the cortex, hypothalamus, and amygdala, which allows pain to be modulated according to conscious thought, stress, and fear, respectively. Here is a good website with animations discussing the pain pathways in more detail: https://nba.uth.tmc.edu/neuroscience/s2/chapter08.html

• published: 28 Jun 2018
• views: 239312