Peripheral Pain Mechanisms (Pharm) Flashcards
What are the two type of peripheral pain neurons? Which are myelinated? They are each responsible for what types of pain transmission?
-
Adelta fibers:
- myelinated
- “fast” pain response - sharp, stabbing
-
C fibers:
- unmyelinated
- “slow” pain response - burning, aching
Where does the first synaptic connection for primary nociceptors occur?
- dorsal horn of spinal cord
- Adelta: terminating lamina I & V
- C: terminating lamina I & II
What is excitatory NT used by nociceptors on their way to the cerebral cortex?
glutamate
What is the path for secondary nociceptors?
After synapsing, decussate & ascend in spinothalamic tract
How can neurons in the dorsal horn inhibit pain transmission?
inhibitory interneurons that releaseGABA onto secondary nociceptors to inhibit activity & block pain transmission to higher centers
Describe the steps to generate an AP in the secondary nociceptor starting from the initial noxious stimuli.
- 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 Nav along the axon to synaptic terminal in dorsal horn
- AP activates Cav2.2 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
What are the transducing channels located at the peripheral terminal of the nociceptor & what are their activating stimuli?
- 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)
How do drugs like gabapentin & pregablin reduce pain signaling?
bind to the Cava2delta-subunit to down-regulate Cav2 & reduce glutamate release from nociceptors to reduce pain signaling
What type of afferent fibers signal fine touch & proprioception?
largest diameter & fastest conducting axons
Aalpha & Abeta
What type of afferent fibers signal pain and temperature?
slower & smaller diameter axons
Adelta & C
How do the pain signals differ between Adelta & C?
-
Adelta: myelinated - transmit AP much faster
- fast pain - reach CNS faster
-
C fibers: unmyelinated
- slow pain -propogate more slowly
Pain is classified by what variables?
- duration (acute vs. chronic)
- source (nociceptive vs. inflammatory vs. neuropathic)
- location (visceral vs. somatic)
What is the difference in definition between acute vs. chronic pain?
acute pain < 3-6 mo.
chronic > 3-6 mo.
What is the difference in activation of nociceptive pan vs. inflammatory pain? What is an example of each?
-
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
What is the cause of neuropathic pain? What does it feel like? Example?
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
What is the difference in location of somatic vs. visceral pain?
somatic: bone or muscle
visceral: internal organs
What are “silent nociceptors” ?
they are not activated by noxious stimuli, but cause pain when activated by inflammatory agents
What are the inflammatory agents?
TNFa
interleukins
bradykinin
ATP
histamine
prostaglandins
In addition to activating “silent” nociceptors, how can inflammatory agent potentiate pain? How?
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 & Nav channels to enhance their activity → increased nociceptor activity
What is hyperalgesia?
increased sensitivity to pain stimuli
What stimuli are activators of both nociceptive & inflammatory pain?
acid (H+)
pressure
heat
What are the 6 examples of neuropathic pain provided ?
- chronic nerve damage (carpal tunnel syndrome)
- diabetic neuropathy
- postherpetic neuralgia
- cancer (disease & treatment)
- spinal cord injury
- stroke
Chronic nerve damage can result in what ion channel changes?
- increased Nav channel levels -
- enhance primary nociceptor excitability
- increased levels of Cava2d subunit in voltage-dependent calcium channels -
- enhance neurotransmitter (glutamate) release from primary nociceptors
- decreased Kv channel levels -
- enhance primary nociceptor excitability
Why does chronic nerve damage result in ion level changes?
altered gene activity that chronically modify the number of ion channels expressed by the injured neurons
What is allodynia?
pain resulting from non-painful stimulus
Inflammatory agents can induce what two forms of peripheral pain sensitization?
hyperalgesia
allodynia
Explain how a sunburn illustrates both allodynia & hyperalgesia
- 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
What is one mechanism behind allodynia?
reduce threshold for activation of TRPV, MA, and Nav channels so that stimuli that previously failed to activate these channels no produce pain
What are the two mechanisms behind hyperalgesia?
- 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 Kv channels, which decreases their activity → higher frequency AP generation in nociceptor & perception more intense pain
Chronic nociceptor activation can lead to what transcription changes in ion channel levels? This has what effect?
- Increase
- TRPV & Nav
- Decrease
- Kv
both of these changes make the nociceptor more excitable → produce more AP for given noxious stimulus → perception of increased pain intensity
What is the mechanism behind the gene transcription modification that causes changes in ion channel levels in long-term peripheral sensitization?
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
What is the underlying cause of neuropathic pain?
long-term sensitization of nociceptive system
What is Gate-Control of Pain?
non-nociceptors (AB-sensory afferents) contact secondary nociceptors indirectly via inhibitory interneurons to suppress pain signaling
“rub it better” is an example of what phenomenon?
gate-control of pain
rubbing the area around an injury site reduces the pain
Describe the mechanism behind Gate-control of pain?
interneurons that are activated by touch receptors (AB-sensory afferents) use GABA to inhibit secondary nociceptors → thereby decreasing pain sensation
How can activation of Merkel cells lead to a reduction in pain signaling?
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
What is an example of a treatment that utilizes Gate-Control?
Transcutaneous Electric Nerve Stimulation (TENS)
electrical stimulation is though to primarily activate AB afferents → inhibit pain signaling
