1 - Central Pain Modulation

Question 1

Analgesia

Answer 1

Increased threshold for pain

Question 2

Secondary Hyperalgesia

Answer 2

Decreased threshold for pain

Secondary = occurs in CNS (usually spinal level, dorsal horn)

Question 3

Mechanisms of Analgesia: Gate Control

Definition?

Theory?

Answer 3

Non-painful stimulus can produce analgesia (reduces sensation of pain)

“When you rub your body after hitting it”

Mechanoreceptors and nociceptors converge on common set of interneuron and projection neurons

Question 4

Mechanisms of Analgesia: Gate Control

Functional Organization?

Interneuron role?

Answer 4

Pain signals are relayed by disinhibition and excitation of projection neurons

Interneurons prevent non-noxious stimuli from causing pain on a day to day basis

Question 5

Mechanisms of Analgesia: Gate Control

Nociceptor inhibition target?

Answer 5

Inhibitory Interneuron acts as gatekeeper

Nociceptor fibers inhibit it to allow transmission of pain signals

Question 6

Mechanisms of Analgesia: Descending Pain Contol System

Components?

Type of effect–which is greater?

Answer 6

Neurons in Brain and Spinal cord

5-HT (serotonin) / NE (noepinephrine) neurons inhibit transmission from nociceptor afferents to spinal projection neurons

Inhibition is both direct and indirect

Indirect (via enkephalin-GABA interneurons) is likely greater effect)

Question 7

Mechanisms of Analgesia: Descending Pain Control System

PAG Activation

PAG Input

Answer 7

Spinothalamic Tract Collaterals activated by ascending secondary pain sensors to produce analgesia (Feedback triggered)

Hypothalamus gives input to PAG; stress and emotion can effect perception of pain

Question 8

Mechanisms of Analgesia: Descening Pain Control Systems

Opiods?

Effect?

Pre Synaptic vs Post Synaptc Inhibitio

Answer 8

Endogenous option NT’s function at Midbrain (PAG) / Spinal Cord (Dorsal Horn)

Opiods exert powerful pre- and post- inhibition at synapses between nociceptor afferentcs and projection neurons

Post = hyperpolarize by opening of Ca2+ channels

Pre = Inhibit neurotransmitter release

Question 9

Presynaptic Inhibition by Opiods

Answer 9

Open Potassium Channels

Inhibit opening of Calcium Channels

Question 10

Mechanisms of Analgesia: Descending Pain Control System

Midbrain role?

What normally supresses excitatory output from PAH to serotonin and NE neurons?

Answer 10

Endogenous opioid neurotransmitters (enkephalin) function at Midbrain (PAG) and Spinal Cord (dorsal horn)

- - -

GABA interneurons keep it under tonic inhibition; Opiods can block this GABA inhibition (Turning ON system)

Question 11

What is primary opiod and receptor in dorsal horn?

What does the PAG contain?

Morphine?

Answer 11

Enkephalin

Mu (u)

PAG cont many “u” receptors, enkephalin and dynophin producing neurons

Morphine bind to and activate u receptors

Question 12

Opiate Drug-Induced Analgesia

Answer 12

Morphine (+related opiates) activate opiod receptors = analgesia

Substitute for ENKEPHALIN at two levels:

1. Midbrain (PAG) = Activate Descending (5-HT/NE) pathways
2. Spinal Cord (Dorsal Horn) = Inhibit tx of pain signals from nociceptors to dorsal horn projection neurons

Question 13

Wind-Up

C-Fibers release?

Answer 13

Repeated activation of C-fibers

“Temporal Summation of Pain”

C-fibers release:

1. glutamatel AMPA / NMDA receptors

2. CGRP / Substance P (Slow, long-lasting excitations)

Question 14

Wind-Up:

EPSPs?

Answer 14

Slow EPSPs Sum

NMDA receptrs are activated (depolarization + glutamate)

Question 15

Wind Up Pain

Answer 15

Can produce strong enhangement of tranmission of signal to 2^o neurons

Question 16

Long-Term Potentiation

Cause?

Network?

Duration?

Answer 16

Cause: Repeated activation of C-fibers

Network: Ca2+ influc through NMDA receptors, PLC activation of kinases

Cause greater excitation of second order neurons

- - -

Duration: Hours or longer

Question 17

(Normal) Synaptic Inhibition in Dorsal Horn

Answer 17

Gate control mechanism–prevents allodynia (activation of second-order neurons by non-painful stimulation)

Produces analgesia

Question 18

Altered Synaptic Inhibition: Microglia

Type of cell?

What is released?

Answer 18

Nerve injury activates microglia in dorsal horn

(immune cells of CNS)

Microglia release Brain-Derived Neurotophic Factor (BDNF)

Question 19

Altered Synaptic Inhibition: BDNF

Released by?

Target/Goal?

Answer 19

Released from activated microglia

Target: Second order neurons to alter Cl- distribution across membrane

KCC is downregulated

Question 20

Altered Synaptic Inhibition: End Result of Altered Cl- Distribution?

Answer 20

Weakened inhibition in dorsal horn–loss of gate control mechanism

= Hyperalgesia (sensitization), Allodynia

*Inflammatory mechanism*

Question 21

Non-Opiate Analgesic Drugs: Dangers of Opiates

Answer 21

• Opiate drugs less effective vs chronic pain than acute pain
• Repeated use leads to tolerance
• Opiate-induced hyperalgesia may occur
• Addictive

Question 22

Non-Opiate Analgesic Drugs

1. Antidepressants
2. NMDA Receptor Antagonists (Ketamine)

Answer 22

1. Antidepressants: Monoamine (5-HT/NE) reuptake inhibitors; enhance effects of descending pain control system
2. NMDA Receptor Antagonists (Ketamine): NMDA receptor important in excitatory neurotransmission, wind-up and LTP w/pain system–preventing has analgesic effect
3. Anticonvulsants: Reduce abnormal excitability in seizure disorders and pain systems