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Conscious Arousal, Pain, & Analgesia Lesson 17 States of Consciousness/Arousal A. Classical Sensory Afferents CSA B. Thalamus C. Ascending Reticular Arousal System ARAS D. Cortical Feedback ~ Classical Sensory Afferents Sensory information external - from environment internal - somatosensory Most direct input to brain Rapid *point-to-point specificity Also to reticular formation slower, indirect input ~ S1 Thalamus Brain stem Touch Brain Medulla DRG Spinal Cord R ARAS Ascending Reticular Arousal System inputs from CSA General cortical arousal via basal forebrain 2 pathways ~ ARAS BF Thalamus Ventral stream via reticular formation Dorsal stream via thalamus ~ RF CSA ARAS: Reticular Formation ACh - arousal ventral reticular formation NE - arousal locus coeruleus 5HT - arousal raphe nucleus ~ ARAS: Basal Forebrain ACh arousal Adenosine inhibits *ACh Caffeine: adenosine inhibitor Histamine stimulates *ACh Antihistamines drowsiness ~ ARAS Pharmacology: GABA GABA Modulated Basal forebrain GABA decreased arousal GABA increased arousal Agonists Barbiturates, ETOH, benzodiazepines Antagonists picrotoxin, strychnine ~~ What four letter word might come to mind when you smash your hand in a car door? Pain Pain = perception subjective response... to a noxious stimulus Sensation = nociception Nociceptors free nerve endings ~ Spinothalamic Tract Sensory neuron Glutamate (fast) Substance P (slow) Projects to spinal cord gray matter 2d order neuron decussates ~ S1 Thalamus Brain stem Pain Brain Periaqueductal Gray (PAG) DRG R Spinal Cord Substance P & Glutamate Behavioral Analgesia Not always adaptive to attend to injury fighting, fleeing, mating Decreases... nociception subjective experience Temporary effects Opioid-mediated aka Endorphins ~ Behavioral Analgesia Naloxone sensitive: Stress (e.g., Battlefield & Predation) Acupuncture Placebo Effects NOT sensitive to naloxone Hypnosis Meditation ??? ~ Periaqueductal Gray (PAG) Opioid GABA - + + Descending Analgesia Circuit Raphe System 5-HT DRG R Spinal Cord Analgesia in Spinal Cord Raphe serotonin neuron mediates 1. 5-HT directly inhibits 2. activates met-enkephalin opioid 3. activates GABA neuron ~~ Analgesia in Spinal Cord 5-HT + Opioid Neurons Presynaptic inhibition Postsynaptic inhibition Substance P Analgesia in Spinal Cord 5-HT + GABA Neurons Postsynaptic inhibition Substance P Nonopioid Analgesia Naloxone bocks opioid-mediated analgesia Induced by footshock Tail flick test Long intermittent (30 min) naloxone no analgesia Brief continuous (3 min) naloxone still some analgesia Suggests nonopioid analgesic systems ~ Nonopioid Analgesia NMDA (N-methyl-D-aspartate) Glutamate receptor NMDA antagonist (MK-801) + naloxone blocks analgesia in males rats female rats: attenuated Estrogen/progesterone analgesia Ovariectomized female rats nonopioid analgesia ~ Nonopioid Analgesia Developed from frog skin toxin epibetadine 20x more potent than morphine non-specific binding – too toxic for humans Found ACh agonist with similar structure Altered ABT-594 ~ Cholinergic-mediated analgesia ABT-594: cholinergic agonist Comparable to opiate analgesia nACh-R in raphe nucleus Fewer side effects no euphoria no constipation no respiratory depression Conotoxins from cone snail neuropathic pain ~