4/15/2018 Opioid Analgesics Pain Addiction LO “Well, I guess that explains the abdominal pains.” “Pain is a component of virtually all clinical strategies, and management of pain is a primary clinical imperative. Opioids are a mainstay of pain treatment.” Goodman & Gilman, 12 th edition Opioid Analgesics Opioid Analgesics Addiction Addiction The Dividend, 1916 January 26, 2013 New York Times New York Times, March 2016 1
4/15/2018 Opioid Analgesics Opioid Analgesics Addiction Addiction New York Times, January 2017 New York Times, January 2017 Opioid Analgesics Opioid Analgesics Addiction Addiction 2
4/15/2018 Opioid Analgesics Opioid Analgesics Addiction Addiction New York Times, January 2017 Neurons & Activity Neurons & Activity A. Neuronal Communication synapse receptor for transmitter transmitter - opiods B. Plug into Your Favorite Body Part B RAIN I ntestines 3
4/15/2018 “Opioid” Analgesics Pain pain: perception of aversive/unpleasant sensation. 1 nociception: transmission of signals to CNS that provide info about tissue damage. ouch spinal cord OUCH! DRG Papaver somniferum “opiate”: compounds structurally related to products found nociceptor ascending pathways in opium. A d fibers spinothalamic natural plant alkaloids C fibers spinoreticular semi-synthetic derivatives spinomesencephalic endogenous peptides (e.g. endorphins) pains “opioid”: any substance, regardless of structure that has acute nociception functional/pharmacological properties of an opiate. tissue injury factors released in injury site (e.g. prostaglandins, bradykinin,etc) activate “narcotic”: derived from Greek word narkotikos for benumbing A d fibers or stupor. Word now associated with opiates and often used in hyperalgesia (mildly warm water on a sunburn) nerve injury legal contexts. may involve low-threshold afferents (i.e. A b fibers) Pain Opioids & Receptors pain: perception of aversive/unpleasant sensation. Endogenous Opioids 2 nociception: transmission of signals to CNS that provide info 3 primary families: about tissue damage. endorphins major peptide: b -endorphin ouch spinal cord OUCH! precursor: prepro-opiomelanocortin (POMC) DRG enkephalins major peptides: met-enkephalin & leu-enkephalin precursor: proenkephalin dynorphins major peptides: dynorphin A, dynorphin B & neoendorphin precursor: prodynorphin nociceptor ascending pathways A d fibers spinothalamic Receptors C fibers spinoreticular 3 spinomesencephalic 3 receptor types (all GPCRs): m (MOR) pains acute nociception d (DOR) k (KOR) tissue injury factors released in injury site (e.g. prostaglandins, bradykinin,etc) activate A d fibers Widely distributed in the CNS hyperalgesia (mildly warm water on a sunburn) Not surprising considering profound effects opioids have on CNS nerve injury function may involve low-threshold afferents (i.e. A b fibers) 4
4/15/2018 Receptor Distribution Receptor Distribution Forebrain Midbrain Receptors Receptors m k d m k d Peckys & Landwehrmeyer, 1999 4 4 Peckys & Landwehrmeyer, 1999 Receptor Distribution Opioids & Receptors Spinal Cord Endogenous Opioids 2 3 primary families: endorphins major peptide: b -endorphin precursor: pro-opiomelanocortin (POMC) enkephalins Receptors major peptides: met-enkephalin & leu-enkephalin m k d precursor: proenkephalin dynorphins major peptides: dynorphin A, dynorphin B & neoendorphin precursor: prodynorphin Receptors Peckys & Landwehrmeyer, 1999 3 3 receptor types (all GPCRs): m (MOR) d (DOR) k (KOR) Widely distributed in the CNS Not surprising considering profound effects opioids have on CNS 4 function 5
4/15/2018 Opioids & Receptors Opioids & Receptors Endogenous Opioids Common Opioid Analgesics Endogenous Opioids 2 3 primary families: endorphins major peptide: b -endorphin precursor: pro-opiomelanocortin (POMC) Opioid Receptor enkephalins m d k major peptides: met-enkephalin & leu-enkephalin precursor: proenkephalin b -endorphin +++ +++ dynorphins met-enkephalin ++ +++ major peptides: dynorphin A, dynorphin B & neoendorphin precursor: prodynorphin leu-enkephalin ++ +++ Receptors dynorphin A ++ +++ 3 3 receptor types (all GPCRs): dynorphin B + +++ m (MOR) Opens potassium channels Closes calcium channels Inhibits cAMP Widely distributed in the CNS Not surprising considering profound effects opioids have on CNS function Opioids & Receptors Morphine 6 Common Opioid Analgesics Opioid Receptor m d k morphine heroin Morphine +++ + Hydromorphone +++ Oxymorphone +++ Methadone +++ Meperidine +++ Fentanyl +++ codeine naltrexone Sufentanil +++ + + Alfentanil +++ Summary Remifentanil +++ Decreases pain but highly addictive Levorphanol +++ (addiction potential similar to that of heroin) Codeine +/- Hydrocodone +/- m (MOR) – target of most opiate analgesics Oxycodone ++ MORs expressed in the periaqueductal gray (PAG) Pentazocine +/- + Nalbuphine MORs expressed in the spinal cord -- ++ Buprenorphine +/- -- -- 5 “The analgesic actions of opiates after systemic delivery are Butorphanol +/- +++ believed to represent actions in the brain, spinal cord, & in some instances in the periphery.” Lange, 12 th Edition - Goodman & Gilman 6
4/15/2018 Periaqueductal Gray (PAG) Mechanisms of Opiate Analgesia mesencephalic structure projects to rostral 7 ventromedial medulla constitutes essential neural circuit for opioid- based analgesia high density of MORs administration of opioids directly into PAG blocks nociceptive responses in all animals (rodents to primates) naloxone blocks response wikipedia direct electrical stimulation of PAG produces analgesia Mechanisms of Opiate Analgesia Mechanisms of Opiate Analgesia But What’s the Point? But What’s the Point? Sometimes You’re Already to Go, but Something’s Stopping You Sometimes You’re Already to Go, but Something’s Stopping You 7
4/15/2018 Mechanisms of Opiate Analgesia Mechanisms of Opiate Analgesia Scenario #1 Scenario #2 Activity Activity Action Potentials Action Potentials “Tonically Active” “Tonically Active” + X Activity When Inhibited? Activity When Inhibited Inhibitory Inhibitory Neuron Neuron “Inhibited” “Dis-inhibited” Bruce Bean Mechanisms of Opiate Analgesia Mechanisms of Opiate Analgesia Scenario #2 Scenario #2 Activity But what’s the point? Action Potentials “Tonically Active” “Tonically Active” Neurons Do Not Require Synaptic Excitation to Turn On X Removal of Inhibition (Dis-inhibition) Activity When Inhibited Can Also Turn Neurons On Inhibitory Inhibitory Neuron Neuron “Dis-inhibited” “Dis-inhibited” 8
4/15/2018 Periaqueductal Gray (PAG) Mechanisms of Opiate Analgesia PAG mesencephalic structure projects to rostral 7 ventromedial medulla Medulla constitutes essential (nuclei raphe magnus) neural circuit for opioid- based analgesia high density of MORs excitation administration of opioids directly into PAG blocks nociceptive spinal cord responses in all animals serotonin (rodents to primates) norepinephrine naloxone blocks response wikipedia direct electrical stimulation dorsal horn excitability of PAG produces analgesia Mechanisms of Opiate Analgesia PAG Medulla (nuclei raphe magnus) Neuroscience Online: UT Health Center excitation spinal cord serotonin norepinephrine dorsal horn excitability 9
4/15/2018 Neurons & Activity Mechanisms of Opiate Analgesia A. Neuronal Communication PAG synapse receptor for transmitter transmitter - Medulla (nuclei raphe magnus) opiods excitation B. Plug into Your Favorite Body Part spinal cord serotonin norepinephrine dorsal horn excitability B RAIN I ntestines Mechanisms of Opiate Analgesia Mechanisms of Opiate Analgesia PAG PAG excitatory projection neuron excitatory projection neuron inhibitory neuron inhibitory neuron Medulla Medulla (nuclei raphe magnus) (nuclei raphe magnus) excitation excitation spinal cord spinal cord serotonin serotonin norepinephrine norepinephrine dorsal horn excitability dorsal horn excitability 10
4/15/2018 Mechanisms of Opiate Analgesia Mechanisms of Opiate Analgesia PAG PAG excitatory projection neuron excitatory projection neuron inhibitory neuron inhibitory neuron Medulla Medulla (nuclei raphe magnus) (nuclei raphe magnus) excitation excitation spinal cord spinal cord serotonin serotonin GABA Vesicle norepinephrine norepinephrine axon axon terminal terminal GABA GABA dorsal horn excitability dorsal horn excitability Receptors Receptors Mechanisms of Opiate Analgesia Mechanisms of Opiate Analgesia PAG PAG excitatory projection neuron excitatory projection neuron inhibitory neuron inhibitory neuron Medulla Medulla (nuclei raphe magnus) (nuclei raphe magnus) excitation excitation Calcium Potassium Calcium Channel Channel Channel spinal cord spinal cord serotonin serotonin GABA Vesicle axon norepinephrine axon norepinephrine terminal terminal GABA GABA Receptors dorsal horn excitability Receptors dorsal horn excitability 11
Recommend
More recommend
