Central Mechanisms of Pain

Question 1

What is the gate control theory of pain modulation?

Answer 1

Non-painful stimuli can produce analgesia

Question 2

What type of input do projection neurons (2nd order) receive?

Answer 2

Inhibitory from dorsal horn interneurons

Excitatory from axon terminals of both nociceptors and non-nociceptor mechanoreceptors

Question 3

What type of input do dorsal horn interneurons receive?

Answer 3

Excitatory from mechanoreceptors

Inhibitory from nociceptors

Question 4

How does the inhibitor interneuron act as a gate keeper?

Answer 4

Nociceptors inhibit the interneuron, allowing pain to be transmitted

Mechanoreceptors excite the interneuron, thereby inhibiting the projection neuron, suppressing AP firing

Question 5

What are the three classes of endogenous opioid peptide in the nervous system?

Answer 5

Enkephalins

Dynorphins

Endorphins

Question 6

What are the three classes of opioid receptors in the nervous system?

Answer 6

mu

delta

kappa

All metabotropic (G-protein coupled)

Question 7

What are the major opioid and receptor in the dorsal horn of the spinal cord?

Answer 7

Enkephalin

mu receptor

Question 8

How do opioid receptors cause postsynaptic inhibition?

Answer 8

Opening of K channels, hyperpolarizing the projection neurons

Question 9

What are the three ways opioid receptors cause presynaptic inhibition?

Answer 9

Opening of K channels in the presynaptic terminal, hyperpolarization

Inhibition of VG calcium channels, reducing transmitter release

Inhibit Adenylyl cyclase, reducing mobilization of vesicles from the reserve pool

Question 10

What is the role of opioids in the PAG?

Answer 10

Excite neurons in the PAG by disinhibition (inhibit GABA interneurons)

PAG controls pain transmission in the dorsal horn of the spinal cord

Question 11

What are two ways opioid drugs produce analgesia?

Answer 11

Excitation of PAG projection neurons

Inhibition of neurotransmisstion from nociceptors to dorsal horn projection neurons

Question 12

What is the role of the PAG system?

Answer 12

Receives pain sensory input, activating the descending pain control system to produce analgesia

Can also be affected by stress and emotion

Question 13

What is wind-up?

Answer 13

Increase in pain sensitivity due to repeated firing of C-fiber nociceptors

Question 14

How does wind-up occur?

Answer 14

Projection neurons contain AMPA and NMDA glutamate receptors and receptors for substance P and CGRP (NK1)

NK1 receptors are metabotropic, and close K channels, decreases K conductance

This produces EPSPs that easily undergo temporal summation

Question 15

What is a longer lasting consequence to repeated C-fiber firing?

Answer 15

Products of repeated phospholipase C and adenylyl cyclase activation lead to a persistent increase in the ability of C-fibers to trigger firing of the second order neuron

I.e. long-term potentiation of the pain pathway

Question 16

What can result from inflammation and nerve injury?

Answer 16

Reduced effectiveness of Cl-mediated synaptic inhibition in the dorsal horn (GABAa and glycine receptors)

I.e. reduced gate control process

Contributes to allodynia and hyperalgesia

Question 17

How does allodynia occur from the loss of the gate control process?

Answer 17

Without the inhibitory gate control mechanisms, mechanoreceptors can excite second order pain projection neurons

This leads to the upward flow of sensory information in the pain pathways that results from non-painful stimulation

Question 18

How does the activation of microglia due to inflammatory peripheral injury cause a loss of the gate control process?

Answer 18

Mircorglia activated by ATP release from nocicpetors, in turn, release brain-derived neurotrophic factor (BDNF)

BDNF inhibits the expression of K-Cl cotransporters (KCC)

The loss of KCC transporter results in the loss of the chloride equilibrium potential, and therefore the loss of gate control

Question 19

What are three classes of non-opiate analgesic drugs?

Answer 19

Antidepressants - act on descending pain control system

NMDA receptor antagonists - inhibits processes of wind-up and LTP

Anticonvulsants - reduce abnormal excitability in the pain system