1. Conscious Arousal, Pain, & Analgesia Lesson 16

2. States of Consciousness/Arousal A. Classical Sensory Afferents u CSA B. Thalamus C. Ascending Reticular Arousal System u ARAS D. Cortical Feedback ~

3. Classical Sensory Afferents n Sensory information l external - from environment l internal - somatosensory n Most direct input to brain l Rapid l *point-to-point specificity n Also to reticular formation l slower, indirect input ~

4. Spinal Cord Touch R DRG Medulla S1 R Thalamus Brain stem Brain

5. ARAS n Ascending Reticular Arousal System l inputs from CSA n General cortical arousal l via basal forebrain l 2 pathways ~

6. CSA RF Thalamus BF ARAS n Ventral stream l via reticular formation n Dorsal stream l via thalamus ~

7. ARAS: Reticular Formation n ACh -  arousal l ventral reticular formation n NE -  arousal l locus coeruleus n 5HT -  arousal l raphe nucleus ~

8. ARAS: Basal Forebrain n ACh  arousal n Adenosine inhibits *ACh l Caffeine: adenosine inhibitor n Histamine stimulates *ACh l Antihistamines  drowsiness ~

9. ARAS Pharmacology: GABA GABA Modulated l Basal forebrain  GABA   decreased arousal  GABA  increased arousal n Agonists l Barbiturates, ETOH, benzodiazepines n Antagonists l picrotoxin, strychnine ~~

10. What four letter word might come to mind when you smash your hand in a car door?

11. n Pain = perception l subjective response... l to a noxious stimulus n Sensation = nociception l Nociceptors l free nerve endings ~ Pain

12. Spinothalamic Tract n Sensory neuron l Glutamate (fast) l Substance P (slow) n Projects to spinal cord l gray matter l 2d order neuron decussates ~

13. Pain Thalamus S1 DRG R Substance P & Glutamate Spinal Cord Brain stem Brain Periaqueductal Gray (PAG)

14. Behavioral Analgesia n Not always adaptive to attend to injury l fighting, fleeing, mating n Decreases... l nociception l subjective experience n Temporary effects n Opioid-mediated l aka Endorphins ~

15. Behavioral Analgesia n Naloxone sensitive: l Stress (e.g., Battlefield & Predation) l Acupuncture l Placebo Effects n NOT sensitive to naloxone l Hypnosis l Meditation ??? ~

16. Spinal Cord DRG R Periaqueductal Gray (PAG) - Opioid + GABA - Descending Analgesia Circuit Raphe System 5-HT +

17. Analgesia in Spinal Cord n Raphe serotonin neuron mediates l 1. 5-HT directly inhibits l 2. activates met-enkephalin u opioid l 3. activates GABA neuron ~~

18. Analgesia in Spinal Cord Substance P Postsynaptic inhibition Presynaptic inhibition - Opioid Neurons - - 5-HT +

19. Analgesia in Spinal Cord Substance P Postsynaptic inhibition GABA Neurons - 5-HT +

20. Nonopioid Analgesia n Naloxone bocks opioid-mediated analgesia l Induced by footshock u Tail flick test n Long intermittent (30 min) l naloxone  no analgesia n Brief continuous (3 min) l naloxone  still some analgesia n Suggests nonopioid analgesic systems ~

21. Nonopioid Analgesia n NMDA (N-methyl-D-aspartate) l Glutamate receptor l NMDA antagonist (MK-801) + naloxone u blocks analgesia in males rats u female rats: attenuated n Estrogen/progesterone analgesia l Ovariectomized female rats  nonopioid analgesia ~

22. Nonopioid Analgesia n Developed from frog skin toxin l epibetadine l 20x more potent than morphine l non-specific binding – too toxic for humans n Found ACh agonist with similar structure l Altered  ABT-594 ~

23. Cholinergic-mediated analgesia n ABT-594: cholinergic agonist l Comparable to opiate analgesia l nACh-R in raphe nucleus n Fewer side effects l no euphoria l no constipation l no respiratory depression n Conotoxins from cone snail l neuropathic pain ~