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 ~

Spinal Cord

Touch

R

DRG

Medulla

S1

R

Thalamus

Brain stem

Brain

ARAS

Ascending Reticular Arousal System inputs from CSA

General cortical arousal via basal forebrain 2 pathways ~

CSA

RF

ThalamusBF

ARAS

Ventral stream via reticular formation

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 = perception subjective response... to a noxious stimulus

Sensation = nociception Nociceptors free nerve endings ~

Pain

Spinothalamic Tract

Sensory neuron Glutamate (fast) Substance P (slow)

Projects to spinal cord gray matter 2d order neuron decussates ~

Pain

Thalamus

S1

DRG

RSubstance P& Glutamate

Spinal Cord

Brain stem

Brain

PeriaqueductalGray (PAG)

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 ??? ~

Spinal Cord

DRG

R

PeriaqueductalGray (PAG)

-Opioid

+

GABA

-DescendingAnalgesia

Circuit

Raphe System 5-HT

+

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

Substance P

Postsynaptic inhibition

Presynaptic inhibition

-

Opioid Neurons

--

5-HT

+

Analgesia in Spinal Cord

Substance P

Postsynaptic inhibition

GABA Neurons

-

5-HT

+

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 ~