Physiology of Pain Flashcards
Sensory coding is effected by 4 factors:
What is modality?
How is sensory pain localized?
What is intensity in the context of sensory coding?
What determines the duration of sensory codes of pain?
What are graded potentials, and what determines the magnitude of stimulation?
Different receptors are stimulated by a trigger (heat, chemicals, pressure, etc) and generate a graded potential that must reach a axon threshold to produce an action potential. (Modality)
What is two point discrimination?
What is lateral inhibition?
Gradations in signal intensity is affected by what two factors?
- Depending on the amount of force (stimulus), more fibers can be recruited leading to a more intense graded potential -> thus more action potentials. (Spatial summation)
- Those fibers can increase the rate in which they fire, also depending on the amount of force (stimulus) (Temporal summation)
What is the process of hyperalgesia, where a lesion can cause local responses/actions from nerve endings leading to inflammation and sustained pain in deep tissues (that are normally insensitive)?
- When a lesion occurs, pain is induced by local factors released from the dermis layer of the skin (Bradykinin, serotonin, histamine, potassium ions, acids, and nerve growth factor (NGF))
- These factors create an inflammed environment that increases the firing rate of noiceptive afferent fibers
- The afferent nerve fibers create a positive feedback by releasing substance P and bradykinin that increase capillary permiability leading to more inflammation
- Mast cells are simulated by substance P and causing histamine release -> leading to more inflammation/nerve firing = pain
Mechanisms of Hyperalgesia - What is the membrane receptor that is activated by substance P, nerve growth factor (NGF) and bradykinin?
Bradykinin, Substance P and Nerve Growth Factor all activate TRPV1 and induce depolarization of nociceptive axons via Na+ & Ca2+ entry. This depolarizes the noiceptive axons, generating an action potential.
How do prostaglandins depolarize noiceptive axons (through what receptor)?
Prostoglandins activate the tetrodotoxin resistant Na+ channels (TTX-R) that depolarizes the axon, creating an action potential.
Since tetrodotoxin (puffer fish) inhibits voltage gated Na+ channels, this can lead to paralysis of the motor neurons in that area; however, because of the TTX-R channel -> pain can still occur. Nasty pufferfish!
What is the differences between tonic and phasic receptor activation in the skin?
Tonic receptors (slow activation) maintain a receptor potential over a longer period of time and give the body a sensitivity of the duration of exposure. For example, wearing a watch for the first time you feel it initially but after a few hours you barely notice it is there.
Phasic receptors (fast activation) fire during the initial stimulus and rapidly turn off. Once the stimulus is removed, they fire once more and turn off again.
What determines the length and duration of the firing of a nerve fiber?
The initial stimulus generates a graded potential and if strong enough it will create an action potential and travel down the axon. A longer and more intense stimulus will remain higher than the AP threshold longer so the AP will be sustained longer and fire more rapidly down the axon. Release of neurotransmitter is also proportional to the initial strength of the stimulus.
Practice question:
- Most rapidly adapting = B
- Slowly adapting = A
Practice question:
D. The greater the intensity of the stimuli, the greater the change in receptor potential amplitude.
What are the three different types of afferent nerve fibers?
- A-beta (Aß)
- A-delta fibers (Að)
- C fibers
Explain the anatomy of A-beta (Aß) fibers and how that contributes to the rate at which they conduct, and what neurotransmitter is associated with them?
A-beta (Aß) fibers are stimulated by non-noxious action potentials and have:
- Large diameter (little resistance)
- Myelinated (conduct very fast)
- NT=Glutamate
Non-noxious
Explain the anatomy of A-delta fibers (Að) and how that contributes to thier function. What type of receptors activate them, and what neurotransmitter are they associated with?
A-delta fibers (Að) are stimulated by AP from mechanical and thermal nociceptors and respond to crude touch and temperature sensations, they are:
- Thinner (more resistance)
- Myelinated (fast conduction)
- Neurotransmitter = Glutamate
“Fast” Sharp, well localized pain.
Explain the anatomy of C-fibers and how that contributes to thier function. What type of recetor stimulates them, and what neurotransmitter are they associated with?
C-fibers are stimulated by APs from nociceptors (mechanical, thermal, chemical) and are:
- Very thin (more resistance)
- Unmyelinated (conduct very slow)
- Respond to “warm and cold”
- Neurotransmitter = substance P
“Slow” Dull, aching, burning, throbbing, diffuse pain.
Rate of conduction of A-beta (Aß) fibers
Rate of conduction of A-delta fibers (Að)
Rate of conduction of C-fibers
Receptor subtype: Hair follicles
Types of fibers:
Afferent response:
Stimulus:
Receptive field:
Perceptual functions:
Rapid (phasic)
Example: Bugs crawling on your skin
Receptor subtype: Meissner corpsucle
Types of fibers:
Afferent response:
Stimulus:
Receptive field:
Perceptual functions:
Rapid (phasic)
Example: Braille
Receptor subtype: Pacinian corpsucle
Types of fibers:
Afferent response:
Stimulus:
Receptive field:
Perceptual functions:
Rapid (phasic)
Example: Chinese drums “tapping”
Receptor subtype: Merkel cell-neurite complex
Types of fibers:
Afferent response:
Stimulus:
Receptive field:
Perceptual functions:
Slow (tonic)
Example: Recognizing difference in coins
Receptor subtype: Ruffini corpsucle
Types of fibers:
Afferent response:
Stimulus:
Receptive field:
Perceptual functions:
Slow (tonic)
Example: Pinching or stretching your skin
Receptor subtype: C-fiber LTM
Types of fibers:
Afferent response:
Stimulus:
Receptive field:
Perceptual functions:
Slow (tonic)
Example: Shaking someones hand (non-noxious)
Receptor subtype: Mechanical-nociceptor/Polymodal nociceptor
Types of fibers:
Afferent response:
Stimulus:
Receptive field:
Perceptual functions:
Slow (tonic)
Example: Pain, temperature
2 Pathways for transmission of sensory information
What homunculus is associated with the postcentral gyrus?
What homunculus is associated with the precentral gyrus?
Ascending Neural Pathways of Somatosensory System
For Touch & Pressure
Dorsal Column System
After a stimulation (touch or pressure)
1st order ascending never fibers travel through dorsal root fibers (Large myelinated fibers (Aβ)) and decusate with 2nd order neurons at the medulla
2nd order neurons travel up through the medulla oblongata, medial lemniscus (pons), and midbrain to connect with 3rd order neurons at the thalamus
4th order neurons relay the information to the somatosensory cortex of the brain where the sensation is perceived depending on the location (spatial fidelity because of the homunculus)
Ascending Neural Pathways of Somatosensory System
For Pain & Temp
(tickle, itch, sex sensations)
Anterolateral System
(Spinothalmic tract)
After receptors are stimulated 1st order neurons activate 2nd order fibers (Smaller myelinated (Að) & unmyelinated (C) fibers) at the level of the spinal cord and decusate
2nd order fibers travel through the anterolateral pathway where sensations can be lossed at the level of the medulla (spinoreticular tract) and the mesencephalon (spimomesencephalic tract) before reaching the thalamus
Once in the brain, 3rd order fibers take the sensation to 4th in postcentral gyrus of the cerebral cortex
Therefore, there is low spatial fidelity due to the loss of sensation below the thalamus
Difference Between Fast Sharp vs Slow Dull Pain
Fast Sharp
A-delta fibers
Neurotransmitter = Glutamate
Neospinothalmic tract (anterolateral/spinothalmic tract)
Localized pain with rapid adaptation (phasic receptors)
Slow Dull
C-fibers
Neurotransmitter = Substance P
Paleospinothalmic tract (anterolateral/spinothalmic tract)
Poorly localized pain that spreads (tonic receptors)
Where does fast sharp pain usually terminate?
Thalamus/cortex
Where does slow dull pain usually terminate?
Lower brain regions (pons/medulla) and ~10-25% terminate in the thalamus
This is the reason slow dull pain is poorly localized, because the action potential terminates before it actually reaches the higher brain centers (thalamus)
What are symptoms a patient would have if they have damage to the somatosensory area I (1, 2, 3) also known as the “Brodmann Area”?
What type of nerve endings and fibers are associated with pain receptors (Nociceptors)?
Free nerve endings of unmyelinated C fibers and small diameter myelinated A-beta fibers
What are the 4 distinct process of Nociception?
- Transduction - Stimulus activates inflammatory substances that activate nociceptors and generate an AP
- Transmission - C fibers/A-beta fibers transmit the AP to lower areas of the brain and to the thalamus
- Peception - once the AP is in the pons/medulla/thalamus the pain is perceived
- Modulation - descending nerve fibers travel to location of pain and try to inhibit the nociceptors by releasing inhibitory substances (endogenous opioids)
Gate-Control Theory of Pain Mechanism
Pain Perception: Gate Control Theory
In the simpliest terms, Gate Control Theory is taking your “mind” off of the pain (small C-fibers) by activating larger A-beta/A-delta non-pain fibers that tend to inhibit the nociceptors.
Ex. Rubbing your shin after banging it on the coffee table, somehow activating those touch receptors/pressure receptors you can inhibit (close the gate) of some of the perceived pain fibers that were just activated
Types of pain:
Physiological Pain (Acute)
Types of pain:
Pathological Pain (Chronic)
How do thermoreceptors discern the difference between cold and hot and extreme cold and hot? What receptors and fibers are associated with each stimulation?
Location: Cold and warmth receptors are located immediately under the skin and most areas of the body have 3-10X as many cold “spots” as they do warm
- Cold fibers* are small A-delta myelinated nerve endings and some are type C-fibers
- Warm fibers* are mainly type C-fibers
A person determines different gradations of thermal sensations by the relative degrees of stimulation of the different types of endings
What type of receptors detect thermal pain (extreme hot/cold)?
TRP channels that are non-selectively permeable to Mg2+, Ca2+, and Na+
Why do you get a sensation of heat from Capsaicin cream (chili peppers) or Biofreeze, etc.?
Caspaicin binds to TRPV1 (heat pain receptors), resulting in:
- Inactivation of Na+ channels
- Cytoskeleton breakdown that interrupts fast axonal transport
- Activates proteases
- Results in dysfunctional mitochondria
Ultimately, degrades substance P so pain receptors are no longer activated
Question:
What is the clinical significance of dermatome mapping?
Visceral/parietal pain fibers converge in the same area that skin pain fibers do (dorsal root ganglia) and that activates those fibers to give the perception of pain in the skin. This is because during development all those visceral/parietal nerves originated in the same locations as the skin pain receptors so clinically we can use this information to understand ischemia, viruses, damage to internal organs, etc.
Question:
Where is the main location/target of anti-inflammatory drugs (NSAIDs)?
PNS by inhibiting COX-2 thus decreasing prostoglandin release and resulting in less inflammation
Where are the main targets of local anesthetics?
Can be on the skin to inhibit Na+ channels and decreasing pain AP or released locally on nerve fibers in the spine to also inhibit nerves at that location
Where is the main location/target of α2-Adrenoceptors agonists?
α2-Adrenoceptors agonists act on preganglionic neurons inhibiting the release of norephinephrine and thus shutting down the transmission of the AP down the nerve fiber. They can act in the brain and the dorsal horn of the spinal cord (PNS and CNS transmission)
Where are the main targets/locations of opioids?
Act in brain and spinal cord on opioid receptors inhibiting afferent nerves (pre and post synaptic) and descending nerve fibers to result in loss of pain transmission (analgesia/sedation)
What neurotransmitter activates AMPA/NMDA receptors on the post-synaptic neuron?
Glutamate Receptor = Ca2+/Na+
Explain the Endogenous Analgesia/Opiate System
Serotonin and norepenephrine release from the periaqueductal gray area of the brain are activated from afferent pain signals resulting in the release of NE, serotonin, enkephalin that send signals to the dorsal horns of the SC to secrete serotonin at their endings. The enkephalin is believed to inhibit pre/post synaptic type C and A-delta pain fibers where they synapse in the dorsal horn
Enkephalin (endorphin) & Morphine Pain Transmission
What are the ways opioids attentuate the effects of endogenous opioids inhibiting pain transmission?
Endogenous opioids only bind at the postsynaptic neuron decreasing the transmission of a pain AP
Whereas, opioids bind at the original location of the pain stimulus, the presynaptic neuron and post synaptic neuron inhibiting:
- Release of cAMP, Ca2+ influx and AP
- Reducing Ca2+ depolarization
- Hyperpolarizing the cell with K+ that decreases likelihood of AP
