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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
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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 Medulla Touch Brain Brain stem DRG Spinal Cord R R
ARAS • Ascending Reticular Arousal System • inputs from CSA • General cortical arousal • via basal forebrain • 2 pathways ~
ARAS • Ventral stream • via reticular formation Thalamus BF RF CSA • Dorsal stream • via thalamus ~
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 ~
Pain S1 Thalamus Substance P & Glutamate Brain Brain stem Periaqueductal Gray (PAG) DRG Spinal Cord R
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 ??? ~
- + - DescendingAnalgesiaCircuit GABA Opioid Periaqueductal Gray (PAG) + 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 ~~
Opioid Neurons - - Analgesia in Spinal Cord 5-HT + Presynaptic inhibition Postsynaptic inhibition - Substance P
GABA Neurons - Analgesia in Spinal Cord 5-HT + 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 ~