Lecture 3: Pain Flashcards
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.
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
Explain the example of descending opioid modulation of pain.
Descending input from the Raphe nucleus (part of the RVM) activates enkaphalin- containing neurons in the dorsal horn of the spinal cord.
These neurons in terms synapse onto the presynaptic terminals of nociceptive afferents (C fibers), inhibiting synaptic transmission to the 2nd order neurons (projection neurons).
Describe Gate control of pain (also, use of TENS).
Non-nociceptive mechanosensory stimuli activate Aβ fibers, which decrease the response of 2nd order neurons in the dorsal horn to nociceptive input carried by C fibers.
Aβ fibers stimulate GABAergic inhibitory neurons that suppress activation of projection neurons that receive input from the C fibers
Therefore, if the Aβ fibers are active at the same time as the C fibers, the level of C-fiber induced activation of the projection neurons is reduced.
Probably more to it than just stimulating GABAergic neurons, e.g. activation of opioid-containing neurons or descending inputs.
The use of TENS (transcutaneous electrical neurostimulation) units to control pain is based on Gate Control.
What is referred pain?
Referred pain is pain that actually occurs internally, but is felt as pain on the surface of the body.
– A classic example is a person having a myocardial infarction will feel pain in both the chest and left arm.
• Referred pain results from the convergence of nociceptive inputs from both internal organs and from cutaneous regions onto the same projections neurons in the in the dorsal horn.
– The upstream targets of the projection neurons cannot distinguish between activity due to input that arouse internally or cutaneously, therefore the brain incorrectly perceives the internal pain as arising from the skin.
