Nocioception - Ribera

Question 1

Discuss warm vs cool receptors. What temperatures do they detect? What type of fibers carry their information? Are there more cool or warm receptors on the body? What is the neutral point (degrees C) of the skin?

Answer 1

Both warm and cool receptors exist on free endings of nerves. There are 10x more cool receptors than warm receptors.

The skin temp is 33C, and this is the neutral point (both fire at the same speed).

Cool receptors are assx with Aδ fibers (10-37C)
Warm receptors are associated with C fibers. (30-48C)

Question 2

What would happen to the frequency of APs leaving a warm receptor in response to increasing warmth, which then becomes steady (temperature stabilizes)? What will happen when the temperature drops?

Answer 2

Frequency will increase, then stabilize at a given rate based on the temperature. When the temperature drops, the receptor won’t fire APs. (increased temp, increased firing rate)

(The cool receptor will fire APs, as it has the same function in the opposite direction. Decreased temp, decreased firing rate)

Question 3

Differentiate between first pain/second pain. What fibers carry each type? Which arrives first? What sensation accompanies each?

Which pain is more precisely localized?

Answer 3

In response to a painful stimulus, one senses 2 types of pain that are temporally separated.

First a tolerable, localized, “pricking” pain is detected (Aδ fiber first pain).

Then, a burning, intolerable, diffusely localized, “burning” pain is experienced (C fiber second pain).

Aδ = smaller receptive field
C = larger receptive field

Question 4

What type of stimuli can activate polymodal receptors? What type of afferent carries the information?

Answer 4

High intensity mechanical
High intensity chemical
High intensity thermal

Use C fibers as afferents.

Question 5

What compounds can act as chemical activators of nocioceptors? Sensitizers?

What causes release of the most important activator, and what pain fibers does it activate?

Answer 5

Activators: BRADYKININ, serotonin, K, acid
Sensitizers: Prostaglandins, serotonin, and SUBSTANCE P

Upon tissue damage, proteases are released that cleave kinogen to bradykinin, which acts on both Aδ and C fibers.

Activators get you to depolarization.
Sensitizers don’t get you to depolarization, just nudge in that direction.

Question 6

What stimuli activate the VR-1 receptor? Where is it located? What does activation of the receptor accomplish and how?

Answer 6

The VR-1 receptor is located on the polymodal receptors. It is activated by capsaicin (and weakly by acids and moderate heat). Activation depolarizes the cell by opening a non-selective cation channel.

Activation of the VR-1 receptor with capsaicin is used in treatment of chronic pain due to inappropriate activation of C fibers (which, remember, carry polymodal afferents) by depleting stores of Substance P.

Question 7

8. Discuss the type of pain information is carried by C fiber afferents.

Answer 7

Chemical (Capsaicin)
Heat (Charcoal)

C fibers carry C and C?

Question 8

Where is the first synapse in the pain pathway? What neurotransmitter is used?

Answer 8

The first synapse in the pain pathway is in the dorsal horn of the spinal column. The C fibers terminate in the substantia gelatinosa (aka Rexed’s Lamina II).

Glutamate is the neurotransmitter.

Question 9

What neurotransmitter do the AMPA and NMDA receptors use at the dorsal horn synapse? What differentiates these two receptor types?

Answer 9

AMPA and NMDA receptors are activated by glutamate.

NMDA receptors require simultaneous depolarization of the cell in addition to glutamate, and it gives rise to SLOWER synaptic responses.

AMPA receptor gives rise to FASTER synaptic responses.

Question 10

Describe the basis for peripheral sensitization.

Answer 10

Increased concentration of Nav channels (both TTX-R and TTX-S [R/S resistant/sensitive to lidocaine]) leads to spontaneous firing.

[Central mechanisms: GABA content and receptors, sprouting and rewiring, glia & immune system]

Question 11

Describe four mechanisms by which central sensitization occurs.

Answer 11

Central sensitization mediated by the NMDA receptor: Prolonged stimulation of C fibers causes AMPA, then NMDA activation, leading to larger post-synaptic responses over time. Repeated stimulation of the NMDA results in its phosphorylation by PKC, which removes the requirement of dual activation (glutamate + depolarization) to open.

In a separate mechanism, Substance P is released and closes K+ channels, leading to increased ease of depolarization.

In a separate mechanism, reduction in dorsal horn inhibitory neurons (GABAnergic) increases excitability in the dorsal horn.

In a separate mechanism, BDNF is secreted by glial cells which change the expression of KCC2 which reverses the polarity of the GABA receptor, making it excitatory.

Question 12

Describe the basis for the analgesic action of aspirin.

Answer 12

Prevents nocioceptor sensitization.

[Aspirin is a common, well-known analgesic agent. Aspirins inhibit the enzyme, cyclooxygenase, which converts arachidonic acid to prostaglandin. By preventing the synthesis of prostaglandins, aspirin prevents nociceptor sensitization.]

Question 13

What characterizes the triple response? What causes it, and by what mechanism?

Which parts require nerves?

Answer 13

Triple response: Reddening, wheal, and flare.

The reddening and wheal (edema) are due to the effects of bradykinin, which acts as a vasodilator (reddening), and causes increased capillary permeability (edema).

The flare is caused by Substance P release and subsequent sensitization of the field. Substance P serves as a mild vasodilator and sensitizer; hence, the sensitive, reddened area surrounding an injury. (Only released with repetitive, intense stimulation)

w/o nerves, still get bradykinin response (reddening, wheal)
w/ nerves get flare.

Can get flare w/o bradykinin response if you stimulated the nerve repeatedly.

Question 14

Stimulation of the Periaqueductal grey region (PAG) results in _____. Describe the complex physiology involved. What category of drug uses takes advantage of this pathway?

Answer 14

Analgesia. (Touch, pressure, temperature remain).

Serotonergic PAG neurons go to the nucleus raphe magnus in the medulla. Release of serotonin activates secondary inhibitory neurons which travel to the spinal cord through the dorsal lateral funiculus and use enkephalin as a transmitter.

Enkaphalin blocks presynaptic VGCC and opens postsynaptic K channels.

This is why SSRI can be used for chronic pain.

Question 15

Explain the placebo effect and stress-induced analgesia.

Answer 15

Both are due to limbic system activation of the PAG, which leads to inhibition of second-order neurons in the dorsal horn.

Question 16

Describe the phenomenon of referred pain.

Answer 16

Essentially, ascending secondary neurons in the dorsal horn receive inputs from cutaneous and visceral primary neurons.

Few, if any, visceral afferents have dedicated secondary neurons, so they share with cutaneous afferents. Activation of these shared afferents leads to referred pain symptoms.

Question 17

Gallbladder pain is referred to the ___.

Answer 17

Scapula

Question 18

Appendix pain is referred to the ____.

Answer 18

periumbilical anterior abdominal wall

Question 19

Bladder pain is referred to the ___.

Answer 19

Perineum

Question 20

Uretral pain is referred to the ___.

Answer 20

Lower abdominal wall.

Question 21

Why does rubbing an injury make it feel better? What therapy is based on this theory? What pathologic condition affects this same pathway?

Answer 21

Rubbing activates non-nocioceptive afferents (eg touch receptors and Aβ fibers), which have an inhibitory effect on the nocioceptive synapses.

TENS units stimulate Aβ fibers.

Tabes dorsalis, associated with advanced stages of syphilis, is characterized by damage to large diameter myelinated primary afferents and consequent hyperalgesia

Question 22

If the dorsal lateral funiculus were to be cut, what would you expect to happen in response to PAG stimulation?

Answer 22

Stimulation of the PAG would have no analgesic effect.

Question 23

What peripheral mechanism can lead to neuropathic pain?

Answer 23

Malfunctioning Nav channels cause spontaneous discharge.

Can treat with Na blockers, but…side effects.

Question 24

What central mechanisms can lead to neuropathic pain (3)?

Answer 24

1) GABA is the major neurotransmitter in the dorsal horn. INjury to a C fiber decreases nerogenic substance, leading to loss of GABA inhibitory neurons. This leads to reduced dampening of signal and inappropriate pain.
2) After injury, Aβ fibers regrow inappropriately, invading the substantia gelatinosa and innervating the secondary neurons. non-noxious stimuli can thus trigger pain.
3) Macrophages release TNF, which leads to release of BDNF from microglial cells. BDNF has the effect of reversing the GABA Cl channel, leading to hyperalgesia.

Question 25

Hyperalgesia

Answer 25

Heightened response to painful stimuli.

Question 26

Allodynia

Answer 26

Normal sensation causes pain (eg shower on a sunburn).

Question 27

A small dose of local anesthetic will first block which type of fiber? What type of pain sensation does this fiber type carry?

Which goes next?

Answer 27

C fibers are blocked first, which carry the dull, second pain.

Alpha delta fibers are next, which carry sharp pain.

Alpha beta fibers are last.

Question 28

Name the sensation, 1st sensory neuron cell body location and decussation level for the Anterolateral system.

What are the three tracts within the ALS? What does each carry? TO what destination

Answer 28

1st sensory neuron - DRG. Ad and C fibers.
1st synapse in the dorsal horn, decussation in the spinal cord.

Spinothalamic (thalamus) - pain, temp
Spinoretucular (reticular formation, then hypothalamus/limbic system)- pain, temp
Spinomesocephalic (midbrain, PAG) - descending control of pain (no temperature)

Question 29

Which pain occurs first, the sharp or dull? Why?

Answer 29

Sharp pain, carried by Ad afferents.

Then dull pain, carried by C afferents.

Question 30

What do each of the following receptors sense:
ASIC
P2X
VR-1

Answer 30

ASIC - Acid sensing ion channel
P2X - Purinergic receptor (senses ATP. Cells spill guts)
VR-1 - vanilloid receptor 1 (capsaicin has a vanilloid moiety)

Question 31

Which aspects of the triple response can occur without innervation? What aspect requires innervation?

Answer 31

The red center and wheal occur based on bradykinin release (vasodilation and increased capillary permeability)

However, substance P release is required for the allodynia/hyperalgesia in the tissue surrounding the wound site, and this requires consistent, repetitive stimulation of the nerve.