Peripheral Pain Mechanisms (Pharm)

Question 1

What are the two type of peripheral pain neurons? Which are myelinated? They are each responsible for what types of pain transmission?

Answer 1

• Adelta fibers:
  
  • myelinated
  • “fast” pain response - sharp, stabbing
• C fibers:
  
  • unmyelinated
  • “slow” pain response - burning, aching

Question 2

Where does the first synaptic connection for primary nociceptors occur?

Answer 2

• dorsal horn of spinal cord
  
  • Adelta: terminating lamina I & V
  • C: terminating lamina I & II

Question 3

What is excitatory NT used by nociceptors on their way to the cerebral cortex?

Answer 3

glutamate

Question 4

What is the path for secondary nociceptors?

Answer 4

After synapsing, decussate & ascend in spinothalamic tract

Question 5

How can neurons in the dorsal horn inhibit pain transmission?

Answer 5

inhibitory interneurons that releaseGABA onto secondary nociceptors to inhibit activity & block pain transmission to higher centers

Question 6

Describe the steps to generate an AP in the secondary nociceptor starting from the initial noxious stimuli.

Answer 6

• Noxious stimuli activate peripheral terminal receptor
  
  • directly activate ion channels
• → produces receptor potential that is passively propagated to spike-generating zone
• → AP will be generated if the receptor potential exceeds threshold
  
  • AP propagated by activation Na_v along the axon to synaptic terminal in dorsal horn
  • AP activates Ca_v2.2 which permits Ca²⁺ influx into synaptic terminal
  • triggers release glutamate → activates AMPA in secondary nociceptor
    
    • this creates the excitatory postsynaptic potential (EPSP) → induce AP generation in secondary nociceptor if threshold is exceeded at axon hillock

Question 7

What are the transducing channels located at the peripheral terminal of the nociceptor & what are their activating stimuli?

Answer 7

• TRPA1 - cold activated
• Mechanosensitive (MA) - intense pressue
• Acid-sensing ion channel (ASIC) - acid
• TRPV1 - heat
• Purine2 (P2X)- ATP
• G-protein coupled receptors (GPCR)
  
  • pro-nociceptive (prostaglandin E2)
  • analgesic (mu-opioid receptor)

Question 8

How do drugs like gabapentin & pregablin reduce pain signaling?

Answer 8

bind to the Ca_va2delta-subunit to down-regulate Ca_v2 & reduce glutamate release from nociceptors to reduce pain signaling

Question 9

What type of afferent fibers signal fine touch & proprioception?

Answer 9

largest diameter & fastest conducting axons

Aalpha & Abeta

Question 10

What type of afferent fibers signal pain and temperature?

Answer 10

slower & smaller diameter axons

Adelta & C

Question 11

How do the pain signals differ between Adelta & C?

Answer 11

• Adelta: myelinated - transmit AP much faster
  
  • fast pain - reach CNS faster
• C fibers: unmyelinated
  
  • slow pain -propogate more slowly

Question 12

Pain is classified by what variables?

Answer 12

• duration (acute vs. chronic)
• source (nociceptive vs. inflammatory vs. neuropathic)
• location (visceral vs. somatic)

Question 13

What is the difference in definition between acute vs. chronic pain?

Answer 13

acute pain < 3-6 mo.

chronic > 3-6 mo.

Question 14

What is the difference in activation of nociceptive pan vs. inflammatory pain? What is an example of each?

Answer 14

• Nociceptive Pain:
  
  • direct activation by noxious stimuli, tissue injury is apparent
  • osteoarthritis
• Inflammatory Pain:
  
  • direct activation by inflammatory agents (ie. TNFa), can be associated with redness, warmth & swelling
  • Rheumatoid arthritis

Question 15

What is the cause of neuropathic pain? What does it feel like? Example?

Answer 15

d/t nervous system malfunction resulting from injury to either peripheral or central nervous system (transection, compression, ischemia or metabolic injury) - tissue injury may not be obvious

burning, tingling, shooting, and/or electric

diabetic neuropathy & stroke-induced neuropathy

Question 16

What is the difference in location of somatic vs. visceral pain?

Answer 16

somatic: bone or muscle
visceral: internal organs

Question 17

What are “silent nociceptors” ?

Answer 17

they are not activated by noxious stimuli, but cause pain when activated by inflammatory agents

Question 18

What are the inflammatory agents?

Answer 18

TNFa

interleukins

bradykinin

ATP

histamine

prostaglandins

Question 19

In addition to activating “silent” nociceptors, how can inflammatory agent potentiate pain? How?

Answer 19

positive modulators of noxious nociceptors to induce hyperalgesia

they lead to the activation of Protein Kinase C (PKC) & Protein Kinase A (PKA) → phosphorylate TRPV, MA & Na_v channels to enhance their activity → increased nociceptor activity

Question 20

What is hyperalgesia?

Answer 20

increased sensitivity to pain stimuli

Question 21

What stimuli are activators of both nociceptive & inflammatory pain?

Answer 21

acid (H⁺)

pressure

heat

Question 22

What are the 6 examples of neuropathic pain provided ?

Answer 22

1. chronic nerve damage (carpal tunnel syndrome)
2. diabetic neuropathy
3. postherpetic neuralgia
4. cancer (disease & treatment)
5. spinal cord injury
6. stroke

Question 23

Chronic nerve damage can result in what ion channel changes?

Answer 23

• increased Na_v channel levels -
  
  • enhance primary nociceptor excitability
• increased levels of Ca_va₂d subunit in voltage-dependent calcium channels -
  
  • enhance neurotransmitter (glutamate) release from primary nociceptors
• decreased K_v channel levels -
  
  • enhance primary nociceptor excitability

Question 24

Why does chronic nerve damage result in ion level changes?

Answer 24

altered gene activity that chronically modify the number of ion channels expressed by the injured neurons

Question 25

What is allodynia?

Answer 25

pain resulting from non-painful stimulus

Question 26

Inflammatory agents can induce what two forms of peripheral pain sensitization?

Answer 26

hyperalgesia allodynia

Question 27

Explain how a sunburn illustrates both allodynia & hyperalgesia

Answer 27

* _Allodynia_: sunburned area is painful to touch even though touch did not elicit pain prior to the sunburn * _Hyperalgesia_: pain associated with heat (ie. hot tub) is much more intense in sunburned areas than prior to the burn

Question 28

What is one mechanism behind allodynia?

Answer 28

reduce threshold for activation of TRPV, MA, and Na_v channels so that stimuli that previously failed to activate these channels no produce pain

Question 29

What are the two mechanisms behind hyperalgesia?

Answer 29

* increase size of depolarization produced by TRPV and MA channels → noxious stimuli now produce larger receptor potential & generate higher frequency AP → perception of more intense pain * Phosphorylation of K_v channels, which decreases their activity → higher frequency AP generation in nociceptor & perception more intense pain

Question 30

Chronic nociceptor activation can lead to what transcription changes in ion channel levels? This has what effect?

Answer 30

* Increase * TRPV & Na_v * Decrease * K_v both of these changes make the nociceptor more excitable → produce more AP for given noxious stimulus → perception of increased pain intensity

Question 31

What is the mechanism behind the gene transcription modification that causes changes in ion channel levels in long-term peripheral sensitization?

Answer 31

the signals that generate long-term potentiation involve Ca²⁺ activation of PKC - & with chronic activity, these signals are transmitted back tot he cell body → alter gene transcription

Question 32

What is the underlying cause of neuropathic pain?

Answer 32

long-term sensitization of nociceptive system

Question 33

What is Gate-Control of Pain?

Answer 33

non-nociceptors (AB-sensory afferents) contact secondary nociceptors indirectly via inhibitory interneurons to suppress pain signaling

Question 34

“rub it better” is an example of what phenomenon?

Answer 34

gate-control of pain rubbing the area around an injury site reduces the pain

Question 35

Describe the mechanism behind Gate-control of pain?

Answer 35

interneurons that are activated by touch receptors (AB-sensory afferents) use GABA to inhibit secondary nociceptors → thereby decreasing pain sensation

Question 36

How can activation of Merkel cells lead to a reduction in pain signaling?

Answer 36

Primary touch receptors make direct excitatory synapses onto inhibitory interneurons in the dorsal horn via collateral axons these inhibitory interneurons are in direct contact with secondary nociceptors therefore, activation of Merkel cell touch receptors can indirectly inhibit the activity of secondary nociceptors & reduce pain signals

Question 37

What is an example of a treatment that utilizes Gate-Control?

Answer 37

Transcutaneous Electric Nerve Stimulation (TENS) electrical stimulation is though to primarily activate AB afferents → inhibit pain signaling