Lecture 3: Pain Flashcards
(34 cards)
Signaling molecules involved in pain perception
K+ - directly depolarizes the nociceptive cell
H+ - activates acid-sensing ion channel (ASIC and VR1)
ATP - binds to purinergic receptors
Bradykinin - a neuropeptide that binds to BK2 receptors (bradykinin also modulates nociceptors)
What is nociception?
the neural encoding of stimuli that damage or threaten to damage normal tissue (nociceptive or noxious stimuli)
Why is the perception of pain a critical sensory function?
Provides important sensory information that allows us to avoid injury or death
Pain-induced sensitization (hyperalgesia & allodynia) is also beneficial; prevents injured regions of the body from being further damaged
Nociception may be one of the oldest and most evolutionarily important sensory processes.
Describe the mechanochemical signaling mechanism of nociception
The detection of painful mechanosensory stimuli appears to utilize a “mechanochemical” signaling mechanism in which painful mechanostimuli or tissue damage elicits the release of several different chemical signals by the damaged cells that activate nociceptive neurons.
There is also a classic mechanosensitive channel involved, but its’ identity is unknown at this time.
Aδ fibers (describe them, what do they transmit?)
Aδ fibers are the smallest diameter myelinated afferent; respond to either nociceptive
mechanical stimuli or mechanical and thermal stimuli
Aδ fibers transmit 1st Pain, the early sharper component of a painful stimulus (transient, localized and
better tolerated)
What are C fibers and what do they transmit?
C fibers smallest diameter fiber and unmyelinated; typically response to nociceptive mechanical, thermal and chemical stimuli – said to be polymodal nociceptors
C fibers transmit 2nd Pain, the later component of a painful stimulus (longer lasting, more diffuse, less tolerated)
Show graphically the difference between Aδ and C fibers
What is thermal nociception?
The detection of heat as painful (at a certain temperature threshold)
Nociceptive thermal stimuli are detected by heat-activated ions channels called vanilloid receptors (VR-1) or transient receptor potential vanilloid 1 (TRPV1) channel
What are TRPV1 receptors?
There are different sensory receptors for detecting non-painful versus painful thermal stimuli. Nociceptors only respond when the increase in temperature reaches a certain threshold
heat-activated ions channels called vanilloid receptors (VR-1) or transient receptor potential vanilloid 1 (TRPV1) channel
Are part of a larger family of TRP channels that have members that respond to light, cold & heat
Also responds to capsaicin (plant compound), why spicy food imparts a sensation of heat
Also respond the H+, so may contribute to nociceptive mechanosensory response
TRPV1 channels rapidly desensitize, which is why capsaicin applied to the skin has analgesic properties
TRPV1 receptors appear to be expressed throughout the CNS (brain and spinal cord), but their role there is poorly understood; one possibility is that they are endocannabinoid receptors
What is non-nociceptive thermal reception?
Non-nociceptive thermoreceptors respond at lower temperatures, but their response saturates when the temperature reaches the painful levels (TRPV3 & 4 detect warm temps)
When nociceptive afferents enter the spinal cord they ________ to form tracts that ascend and descend 1-2 spinal segments called _________.
bifurcate; tract of Lissauer
Describe the nociceptive spinal pathways.
When nociceptive afferents enter the spinal cord they bifurcate (fork) to form tracts that ascend and descend 1-2 spinal segments (tract of Lissauer).
Axon collaterals branch off from this tract and enter the dorsal horn.
In the dorsal horn, these afferents synapse onto 2nd order nociceptive neurons, primarily in the superficial lamina of the dorsal horn (lamina I & II).
Axons from the 2nd order neurons (called dorsal horn neurons) project to the contralateral side and then ascend up the spinal cord (via the spinothalamic tract) to the brainstem, thalamus and cerebrum.
The spinothalamic tract and dorsal columns cross the midline at different sites. What’s the significance of this?
Following a unilateral (1 side) lesion of spinal cord, sensory deficits in touch and pressure (Aβ fibers) will be ipsilateral to the lesion site, whereas sensory deficits for pain and temperature (Aδ & C fibers) will be contralateral to the lesion.
The spinothalamic tract sends information to different parts of the brainstem/forebrain. Show this.
Sensory discriminative
To VPL/VPM →Somatosensory cortex – physical aspects of painful stimuli such as location, intensity quality;
spinothalamic and dorsal column axon synapse onto different thalamic relay cells, so nociceptive vs. non-nociceptive input remains separated all the way to the somatosensory cortex.
Affective/motivational
Spinothalamic directly to subcortical and cortical (amygdala) regions – generates the emotional component of a painful stimulus (fear, anxiety) and the accompanying autonomic component
There is also component that goes though midline thalamic nuclei and then to the insular cortex and anterior cingulate cortex (likely play a role in coordinating the other emotional/motivation centers with higher cortical regions)
Describe the pathways mediating discriminative aspects of pain/ temperature for the body
Describe the pathways mediating discriminative aspects of pain/temperature for the face
CN V descends then ascends.
Phantom Pain
People who have had a limb amputated or other body part removed surgically/accidentally often report continuing sensation and even pain from the missing structure.
This is a result of central sensory elements (most likely cortical, primary cortex) still being active even when they are no longer receiving input from the periphery.
Phantom limb pain is resistant to surgically lesioning of the spinothalamic tract, sensory regions of the thalamus or even S1
There is even reorganization of the somatosensory cortex so that neurons that previously responded to the missing limb are now getting input from other, undamaged regions.
So stimulation of an intact part of the body can elicit sensation from the phantom limb.
Hyperalgesia
An experience with a painful stimulus can produce hypersensitivity to subsequent stimuli.
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Hyperalgesia-an increase in response to nociceptive stimuli following a prior painful stimulus.
a. Primary hyperalgesia occurs at the initial site of injury and affects responsiveness to both mechanical and thermal stimuli. It probably involves a peripheral mechanism such as an increase in the response of the nociceptive sensory neurons (peripheral sensitization).
b. Secondary hyperalgesia -occurs in undamaged areas that surround the initial injury; only the response to mechanical stimuli is changed. The likely mechanism is a change at the level of the CNS (e.g. the spinal cord; central sensitization). increase excitability at the dorsal root, etc.
Allodynia
Allodynia-condition in which non-noxious stimulus produces a painful response; has both central and peripheral components (peripheral and central sensitization).
A clinical test of allodynia is the brush test, in which the affected area of skin is stroked with a brush, a mechanosensory stimulus that should not be nociceptive.
A-beta fibers may be recruited into that pain circuit; uninhibitory AB inputs!
Describe how the inflammatory response and peripheral sensitization are related to primary nociception.
Peripheral sensitization involves an interaction between the primary nociceptive afferents and the inflammatory soup that results from tissue damage
Examples
TRPV1 response to heat can be enhanced by bradykinins
Prostaglandins (via metabotropic receptors coupled to cAMP/PKA pathway) enhance the response properties of Na+ channels so that the threshold for action potential initiation is enhanced in primary nociceptors.
Nociceptive afferents themselves release modulatory transmitters that contribute to the inflammatory response (e.g. Substance P and calcitonin gene-related peptide (CGRP), which stimulate vasodilation).
Nonsteroidal anti-inflammatory drugs (NSAIDS) inhibit cyclooxygenase (COX) which is critical for prostaglandin synthesis
How do nonsteroidal anti-inflammatory drugs (NSAIDS) work?
They inhibit COX which is critical for prostoglandin synthesis. Prostaglandins are involved in pain reception and in the inflammatory response
Prostaglandins (via metabotropic receptors coupled to cAMP/PKA pathway) enhance the response properties of Na+ channels so that the threshold for action potential initiation is enhanced in primary nociceptors.
What is central sensitization?
Sensitization that occurs in the dorsal horn.
What’s being enhanced? Nociceptive afferent input to 2nd order neurons (hyperalgesia) or non-nociceptive input to these same 2nd order neurons (allodynia)?
What is wind up?
A type of central sensitization?
Wind-up – repeated stimulation of nociceptive afferents leads to a progressively enhanced response by the dorsal horn neurons (2nd order neurons); may be the result of NMDAR-mediated LTP.
What are ways that central sensitization occurs other than wind up?
Modulation of dorsal horn neuron excitability by neurotransmitters, e.g. prostanglandin and substance P that are released in the spinal cord. Increase firing strength, sensitization pathway similar to aplysia learning.
Again, peripheral and central sensitization are normal processes that play an important, protective role. However, these sensitization processes can sometimes trigger a much longer-lasting and pathological increase in nociceptive activity – chronic pain.
