Pain physiology Flashcards
Nociceptive pain
Due to damage to non-neural tissue and driven by activation of nociceptors
Examples: sprains, bruises, bone fractures, burns, inflammation (from e.g. an infection or arthritic disorder)
Neuropathic pain
Due to a lesion or disease of the somatosensory nervous system (peripheral or central nerves)Example: nerve trauma, carpal tunnel (nerve entrapment ), post herpetic neuralgia (viral), diabetic neuropathy (metabolic), chemotherapy-induced neuropathy (toxic)
Nociplasticpain
Altered nociception despite no clear evidence of actual or threatened tissue or nerve damage/disease. (Distrubance in central pain processing)
Example: fibromyalgia
Define peripheral nociceptors
Peripheral nociceptors are pseudo bipolar neurons with cell bodies located in ganglia
Multipolar neurons:Located in CNS (brain, spinal cord) and autonomic ganglia. More than two processes emanating from cell body. (e.g. interneurons)
Pseudobipolarneurons:(also called unipolar) Peripheral nociceptors, cell bodies located in spinal and cranial nerve ganglia (dorsal root ganglia and trigeminal ganglia, respectively)
Where are the cell bodies of peripheral nociceptors located?
Aß fiber mechanoreceptor
, myelinated, very fast
responds to touch, pressure, vibration, limb movement
senses touch, pressure, vibration, Discriminative touch
delta fibers:
Mechanoreceptors
Thermoreceptors
Chemoreceptors
Thinly myelinated, fast
responds to nocuous mechanical, thermal, chemical stimuli
Type I > 53◦C (medium mechanical)
Type II > 43◦C (high mechanical)
senses well localized, sharp, pricking pain, fast or 1st pain
C fiber:
Mechanoreceptors
Thermoreceptors
Chemoreceptors
Unmyelinated, slow
responds to nocuous mechanical, thermal, chemical stimuli
senses diffuse, dull, aching, burning pain
Slow or 2nd pain
Unimodal nociceptive afferent subtype
Mechanonosensitive – respond to intense mechanical stimulation that threaten to damage the tissue.
Thermosensitive – respond to temperatures >42 °C or <17 °C.
Chemosensitive –respond to the H+, K+, capsaicin, bradykinin etc
Polymodal nociceptive afferent subtype
Responds to several/all types of nociceptive stimuli
Silent nociceptive afferent subtype
Not responsive to mechanical or thermal stimuli during normal conditions, but activated during inflammation and then activated by mechanical and thermal stimuli
What is the primary neurotransmitter for nociception?
Glutamate
How is stimulation converted to pain signals? Give two common examples
“Transient receptor potential (TRP)” channels: ligand-gated ion channels responsive to heat, low pH, chemical and cold stimuli. (chili)
Acid-sensing ion channels (ASIC): responsive to chemical irritants, including low pH (e.g. during inflammation, ischemia.
Describe the route from heat stimuli to perception
Describe the route from chemical stimuli to perception
Describe the route from mechanical stimuli to perception
Describe the route from cold stimuli to perception
What are the central terminals of C-and A𝛿-fibers connect to dorsal horn cells
First-order neurons in the pain pathway
These are pseudounipolar neurons which have cells bodies within the dorsal root ganglion. They have one axon which splits into two branches, a peripheral branch (which extends towards the peripheries) and a central branch (which extends centrally into the spinal cord/brainstem).
Second-order neurons in the pain pathway
The cell bodies of these neurons are found in the Rexed laminae of the spinal cord, or in the nuclei of the cranial nerves within the brain stem. These neurons then decussate in the anterior white commissure of the spinal cord and ascend cranially in the spinothalamic tract to the ventral posterolateral (VPL) nucleus of the thalamus.
Third-order neurons in the pain pathway
The cell bodies of third-order neurons lie within the VPL of the thalamus. They project via the posterior limb of the internal capsule to terminate in the ipsilateral postcentral gyrus (primary somatosensory cortex). The postcentral gyrus is somatotopically organised. Therefore, pain signals initiated in the hand will terminate in the area of the cortex dedicated to represent sensations of the hand.
What factors are released upon tissue damage which leads to the activation of nociceptors?
Arachidonic acid
Potassium
5-HT
Histamine
Bradykinin
Lactic acid
ATP
Describe the pain pathway
Dorsal horn interneurons
critical role in transmission and gating of nociceptive transmission
present in all lamina, but the majority are concentrated in lamina II
excitatory (glutamate) or inhibitory (e.g. GABA, glycine, enkephalin)
Nociceptive primary afferents…
connect to projection neurons in lamina I and V, which cross the midline (decussate) and ascend in the spinothalamic (lateral) tract
Dorsolateral tract of Lissauer (Lissauer’s tract) contain branches of the primary afferents that run 1-2 segments upwards or downwards before entering the grey matter of the dorsal horn
Anterolateral system
Collection of ascending pathways that carry pain and temperature, as well as related touch, sensations from the spinal cord to the brainstem or thalamus.
Spinothalamic tract
Spinoreticular tract
Spinotectal tract
Spinothalamic tract
(lateral and anterior) destined for thalamus, important for localization of painful stimuli and thermal stimuli
Spinoreticulartract
destined for reticular formation, causes alertness and arousal in response to painful stimuli
Spinotectaltract
destined for tectum, orient eyes and head towards stimuli
What are the two main pathways that carry nociceptive signals to higher centers in the brain?
The spinothalamic and the spinoreticulartracts
What is the difference between the two adjacent spinothalamic tract pathways: anterior and lateral.
Lateral: information about pain and temperature
Anterior: information about crude touch.
Describe the ascending visceral pathway for pain
Name the three types of opioid receptors which regulate the neurotransmission of pain signals
These receptors are called mu, delta, and kappa opioid receptors.
They are all G protein-coupled receptors and their activation leads to a reduction in neurotransmitter release and cell hyperpolarisation, reducing cell excitability.
Name the three types of endogenous opioids:
Β-endorphins – which predominately binds to mu opioid receptors
Dynorphins – which predominately bind to kappa opioid receptors
Enkephalins – which predominately bind to delta opioid receptors
General definition of pain sensitization
Increased responsiveness of nociceptive neurons to their normal input, and/or recruitment of response to normally subthreshold inputs.
Hyperalgesia
An increased response to a stimulus which is normally painful
Allodynia
Pain due to a stimulus that does not normally provoke pain.
Mechanisms for peripheral activation and sensitization of nociceptors during inflammation
Describe the role of antidromic axon reflexes in neurogenic inflammation
antidromic axon reflexes induce release of neuropeptides from peripheral terminals
Primary hyperalgesia (including allodynia)
Increased sensitivity to pain at the site of injury due to sensitization of peripheral nerve endings (peripheral sensitization)
Secondary hyperalgesia (including allodynia)
Increased sensitivity to pain at locations adjacent or remote from the site of injury due to changes in the spinal cord and higher brain areas (central sensitization).
Central sensitization
Definition: Increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input Note: This may include changes in endogenous descending pain control systems.
Processes leading to central sensitization (facilitation)
Sustained release of glutamate and neuropeptides (e.g. substance P) →increased activation of their respective postsynaptic receptors
Removal of NMDA receptor Mg+block →increases influx of calcium →activation of many intracellular pathways that contribute to reduction of threshold for activation of postsynaptic neuron (e.g. modified ion channel responsiveness and increased expression of ion channels and receptors)
Altered activity in interneurons (increased activity in excitatory interneurons, decreased activity in inhibitory interneurons)
Central sensitization: Secondary hyperalgesia
Facilitation: Impulses from the injured area cause a state of stimulation in the central neurons with increased excitability -> magnification of the pain impulses arising from the area of secondary hyperalgesia
Convergence: Afferent from the healthy area converge on the same second order neurons that receive pain signals from the injured area
”Gate control -theory”
Observation: •Rubbing a jammed finger reduces the pain i.e. activation of low-threshold mechanoreceptors reduce sensation of sharp pain
Explanation:
Mechanoreceptive afferents activate local neuronal inhibitory circuits in the dorsal horn (“closing the gate”)•In “competition” with nociceptors that inactivates the inhibitory neurons (“opening the gate”)A likely mechanism behind the pain relieving effect of transcutaneous electrical nerve stimulation (TENS)
Functional endogenous pain modulation
- ACC –endogenous opioids or opioid drugs activate descending pain inhibition
- RVM –Cholecystokinin (CCK) antagonizes opioid-induced analgesia
Dysfunctional pain modulation in chronic pain, example from fibromyalgia (FM)
- ACC and 2. Thalamus not activated normally during pain in FM.
Association between:
1) Reduced ACC activation
2) reduced availability of opioid receptors in ACC
3) pain intensity
FM patients with longer FM duration has
Smaller ACC volume
Reduced placebo response
Pharmacological pain treatment to nociceptive pain
Paracetamol/acetaminophen
NSAIDs
opioids
tramadol
SNRIs?
Pharmacological pain treatment to Neuropathic pain
amitryptilin
SNRIs
gabapentin
pregabalin
tramadol
opioids
Topical: lidocain, capsaicin
Pharmacological pain treatment to Nociplasticpain
amitryptilin
SNRIs
gabapentin
pregabalin
tramadol
Projected pain
pain projected from a damaged structure in the peripheral or central nervous system. Projectedpain is neuropathic.
Referred pain
pain felt in a part of the body other than its actual source (distant to the site of injury). Referred pain is nociceptive.
Referred pain clinical picture
Diffuse and variable
Distribution related to pain intensity
Distribution lacks neuroanatomic correlate
No pathognomonic sensory abnormalities
Anaesthetic blocks of primary pain focus can normalize sensitivity
Projected pain (peripheral) clinical picture
Distinct
Distribution relatively stable over time
Distribution in accordance with nerve root or nerve
No pathognomonic sensory abnormalities
Anaesthetic blocks do not normalize sensitivity
