Pharmacology Lecture 9 PDF: Opioids, Pain, and Reward Pathways

9.1 Opioids and Pain Opioid Receptors -​ The body has multiple opioid receptors -​ Receptors named after the substance that was discovered to activate them -​ Common for old school naming of receptors -​ These receptors regulate a wide range of processes: -​ Paid p...

9.1 Opioids and Pain Opioid Receptors -​ The body has multiple opioid receptors -​ Receptors named after the substance that was discovered to activate them -​ Common for old school naming of receptors -​ These receptors regulate a wide range of processes: -​ Paid perception -​ Reward Seeking Behaviors -​ Hedonic Pleasure -​ Respiration -​ More -​ Activated by NTs called endogenous opioids -​ Aka endorphins Opioids/Opiates -​ Opiates are natural occurring substances produced by the opium poppy -​ Active agent of a broad range of clinically used medications and illegal recreational drugs -​ Opioids are the general term for the naturally produced opiates from opium poppies and synthetic substances with same mechanism of action -​ Examples -​ Morphine -​ Heroin -​ Fentanyl -​ Codeine  -​ Oxycodone -​ Etc. -​ Opioids are agonists for opioid receptors -​ When opioids bind to the receptors, the receptor activates Pain -​ Subdivision of sensory neurons in the PNS encodes for pain -​ Axons carry pain information from the body to the CNS -​ Useful tool for: -​ Avoiding harmful stimuli -​ Being aware of possible damage to the body -​ Learning Endogenous Opioid Pain Suppression -​ Suppressing pain perception is important for certain survival situations -​ Ex. Running from danger -​ Some neurons with opioid receptors inhibit the signaling of pain receptors -​ When endogenous opioids activate these receptors, pain sensory neurons are inhibited -​ Temporarily reducing or eliminating pain perception Opioids and Pain -​ Primary clinical use of opioid drugs is for pain management -​ Takes advantage of the pain suppression signaling of endogenous opioids -​ Opioid drugs bind to opioid receptors -​ Effectively and efficiently inhibiting the pain sensory neurons  -​ Blocking the pain from reaching the brain -​ Will never perceive the pain Opioids - Pain Management -​ Unbelievably important tool to help people mitigate pain due to: -​ Injury -​ Disease -​ Medical procedure recovery -​ Etc. Double-Edged Sword -​ Opioid drugs do not act on only pain receptors -​ Opioid drugs will activate all the opioid receptors across the body -​ Leading to other side effects 9.2 Tolerance Endogenous Opioids in the Brain -​ Opioid receptors in the brain are important for modulating multiple cognitive processes: -​ Hedonic Pleasure -​ Reward-Seeking Behavior -​ Play Behaviors -​ More ! -​ Endogenous opioids are released in small quantities -​ True for most NT signaling -​ A little bit goes a long way Opioid Drugs in the Brain -​ Opioid drugs will interact with all opioid receptors in the brain and body -​ Influencing psychological and physiological processes -​ Concentration of opioid drugs is significantly larger than naturally released endogenous opioids Acute Effect of Opioids -​ Opioid drugs will oversaturate synapses -​ Greatly activating opioid receptors -​ Changing behavior and perception -​ Pain -​ Euphoria -​ Reward seeking behaviors -​ Short-term behavioral and perceptual changes are typically the desired outcome for opioid users -​ Clinical -​ Pain suppression -​ Recreational -​ Euphoria Homeostasis -​ This extreme activation of opioid receptors is a deviation from the normal -​ Body wants to maintain at homeostasis -​ Seesaw -​ Will modify neural structures to adapt to abnormal stimuli Long-Term Effects of Opioids -​ The synapse will want to return to normal activation levels -​ Neurons will detect the over activation of opioid receptors -​ Opioid receptors are removed from the membrane -​ Will have weaker response to the same amount of ligand Tolerance -​ The drug dose must be increased to obtain the same effect -​ Higher dose will cause an over activation of the synapse again -​ Resulting in more synaptic changes -​ Decrease of receptors will influence the response to both: -​ Opioid Drugs -​ Endogenous Opioids -​ Opioid receptor mediates behaviors that will be suppressed following tolerance -​ Increased pain sensitivity -​ Decreased hedonic pleasure -​ Increased reward seeking behaviors Recovery -​ It is unclear if the synapses return to how they were before tolerance -​ Possible recovery could take years to return to normal endogenous opioids -​ Major drive for relapsing for people with substance use disorder 9.3 Reward Pathway Opioids and the Reward Pathway -​ Neural adaptations due to opioid drugs will change synaptic communication in the brain’s reward pathway -​ Changes in the reward pathway will significantly influence behavior Reward Pathway -​ Series of brain areas important for the regulation of reward seeking behaviors -​ DA produced in ventral tegmental area (VTA) -​ One of the multiple DA producing regions in the midbrain -​ Axons from the VTA project to the nucellus accumbens (NA) and the cortex -​ Pathway most active during behaviors associated with motivation and reward seeking behaviors Dopamine Misconceptions -​ Pop culture often refers to dopamine (DA) as the “happiness” molecule -​ Drugs that result in experiencing euphoria activate DA neurons -​ Assuming that DA is the signal responsible for experiencing euphoria -​ Deeper inspection has shown that DA is not responsible for feeling “happy” -​ Might be an aspect, but not the major signaling molecule DA Reward Experiment -​ Recording from the DA producing cells of the VTA in mice -​ Fire APs when DA is released -​ Examine activity when: -​ Unexpectedly receive a reward  -​ Cue for upcoming reward and then receive it -​ Cue for upcoming reward and then don’t receive it DA Reward Experiment - Results -​ VTA cells are active when: -​ Receiving an unexpected reward -​ Cue associated with reward is presented -​ VTA cells are not active when receiving an expected reward -​ DA signaling is not crucial for “enjoying” a stimuli -​ DA is crucial for “wanting” and reward seeking behavior -​ Encodes for: -​ Learning about rewarding stimuli -​ Responding to information associated with a reward “Liking” Signaling -​ DA does not exclusively mediate “liking” or hedonic pleasure -​ Most likely a complex interaction amongst -​ Opioid receptors -​ Endocannabinoid receptors -​ DA receptors Reward Pathway Physiology -​ The NA has DA and opioid receptors to mediate reward seeking behaviors -​ Release of endogenous opioids will enhance the activity of DA axons -​ Opioid receptors inhibit an interneuron, reducing its inhibition of the DA axon -​ DA release is increased  -​ Activation of opioid receptors will enhance DA signaling, encoding rewarding stimuli Opioids in Reward Pathway -​ Opioids will oversaturate opioid receptors on interneurons -​ Greatly inhibiting interneurons -​ DA synaptic signaling is greatly enhanced -​ NA will encode opioid stimuli as an extremely rewarding experience -​ DA release will be significantly more salient than non-opioid stimuli -​ Increasing motivation to have repeated exposure to the opioid stimuli -​ Increasing the motivation to have repeated exposure to the opioid stimuli -​ Behaviors will prioritize experiencing more opioid stimuli over non-opioid stimuli -​ Ex. food, intercourse, social interactions, etc. Tolerance in the Reward Pathway -​ The NA will experience opioid tolerance with high and/or chronic doses of opioids -​ Fewer opioid receptors on the interneurons -​ Less sensitive to opioid drugs and endogenous opioids -​ Increased inhibition on DA cell -​ Non-opioid stimuli will be even less “rewarding” -​ Same number of endogenous opioids activating significantly fewer opioid receptors -​ Opioid stimuli will be more “rewarding” if opioid doses are increased -​ Increased number of opioids to activate the decreased number of opioid receptors Reward Pathway Changes -​ Brain structures responsible for reward seeking are re-wired -​ Behavior change to priorite experiencing opioid stimuli over non-opioid stimuli -​ As tolerance increases, drug seeking behaviors increases -​ Positive feedback loop Substance Use Disorder -​ Changes of neuroanatomy and behaviors result in physical and psychological dependence on opioid drugs -​ Resulting in substance use disorder -​ Aka, addition -​ Being recontextualized as a disease model, rather than personal choice -​ Acknowledging the physiological changes in the brain that influence behaviors -​ Neurological changes can occur due to: -​ Few large dose exposures -​ Chronic exposures -​ Motivation for: -​ Closely monitored clinical pain management -​ Illegalization of recreational use 9.4 Naloxone Opioids’ Effects on Respiration -​ Opioid receptors are also important for regulating respiration (aka breathing) -​ Activation of opioid receptors will suppress breathing -​ Important for parasympathetic responses Opioid ODs -​ Deaths due to opioid overdose (OD) are typically due to asphyxiation following over suppression of the respiratory system -​ Increased doses following tolerance increases likelihood of ODing Naloxone -​ Commercial name: Narcan -​ Opioid receptor antagonist -​ Counteracts immediate effects of opioids -​ Can be administered to revert respiratory arrest due to opioid OD -​ Will block the opioid receptors across the whole body -​ Naloxone will block the effect of opioids -​ Will not be able to undo the neurological changes that influence behaviors Opioid Research -​ Major field of research to better understand: -​ Mechanism and risk factors for substance use disorder -​ Development of non-addictive opioids for clinical use -​ Recovery from opioids mediated synaptic changes