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IMS: Neuroanatomy > Pain > Flashcards

Pain Flashcards

1
Q

Pain Pathway

A

Perception of pain is a product of the brain’s abstraction and elaboration of sensory inputs.

Varies with individuals, circumstances, and past experience.

Pain can be perceived with or without activation of nociceptors.

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2
Q

Asymbolia for Pain

A

Caused by bilateral lesion to the insular cortex.

Patient can describe the painful stimuli but not be emotionally affected by it.

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3
Q

Physiological Pain

(Nociceptive)

A

Results from direct stimulation of nociceptors.

Serves a protective biological function by warning against on-going tissue damage.

Responds well to opiods and NSAIDS.

Permanant damage can result from inability to feel pain.

Congentital insensitivity to pain

Acquired insensitivity (diabetic neuropathy, neurosyphilis)

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4
Q

Mechanical Nociceptors

A
  • Activated by strong stimuli
    • pinch, sharp objects that penetrate, squeeze.
  • Associated with A-delta fibers (conduction at 5-30 m/s)
  • Provide a sharp or pricking pain sensation
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5
Q

Thermal Nociceptors

A
  • Activated by temperatures > 45°C or < 5°C
  • Associated with A-delta fibers (conduction at 5-30 m/s)
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6
Q

Polymodal Nociceptors

A
  • Activated by
    • high-intensity mechanical stimuli
    • irritant chemicals
    • noxious heat
    • noxious cold stimuli
  • Associated with C-fibers (conducting at 1 m/s)
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7
Q

Ion Channel

Nociceptive Transduction Proteins

A

Receptors associated with a channel ⇒ fast response

  1. Transient receptor potential (TRP) family
    • Vanilloid receptor TRPV1
      • stimulated by capsaicin, protons, noxious heat
      • creates burning sensation associated with spicy food
    • TRPA1 receptor
      • stimulated by mustard oil, garlic, cold, and acrolein
      • accounts for toxic and inflammatory actions of tear gas, vehicle exhaust, tobacco somke, RA, MS, lupus
  2. ATP ⇒ P2X
    • pain associated with tissue injury
  3. Acid sensing ion channel (ASIC)
    • stimulated to ↓pH or high threshold mechanical stimuli
    • accounts for pain associated with ischemia, inflammation
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8
Q

G-Protein or 2nd Messenger

Nociceptive Transduction Proteins

A

Slower Response

  1. G protein-coupled receptors
    • Involved in nociception
    • stimulated by bradykinin and prostaglandin
    • activation of receptor activates 2nd messengers
      • Ca2+
      • PKA
      • PKC
  2. Receptors for neurotrophins and cytokines
    • stimulated by
      • nerve growth factor family
      • glial cell line-derived neurotrophin
      • cytokines (IL-1, IL-6, TNF-𝛼)
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9
Q

Nociceptor Projection

A

Nociceptors project to dorsal horn of spinal cord.

  • Lamina I neurons receive input from:
    • A-delta nociceptive afferents
    • C fibers via interneurons in lamina II
  • Lamina V neurons are predominantly wide-dynamic range type.
    • Receive:
      • non-noxious input from A-beta fibers
      • noxious input from A-delta fibers
      • noxious input from C fibers via l_amina II interneurons_
    • Can be activated by hair movement or weak mechanical stimuli
    • Maximal response with intense stimulation
    • Participate in encoding intensity of noxious stimuli
  • Lamina II neurons receives input from C fibers
    • Relays info to other neurons and laminae via interneurons
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10
Q

Nociceptor Synaptic Transmission

A

A-delta and C-fibers Neurotransmitters

  • Glutamate and peptides onto dorsal horn neurons
  • Substance P
    • co-released with glutamate
    • enhances and prolongs glutamate action
    • diffuses and affects other neuron populations
      • due to no specific reuptake mechanism
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11
Q

Peripheral Sensitization

Nociceptors

A

Due to changes in nociceptor sensitivity.

Increased sensitivity to pain develops in the injured region and adjacent regions of skin.

  1. Cell injury releases an inflammatory cocktail including:
    • prostaglandins and leukotrienes
    • bradykinin
    • substance P
    • histamine
    • calcitonin gene related peptide (CGRP)
    • serotonin
    • potassium
    • ATP, NGF, and cytokines
  2. Inflammatory cocktail promotes:
    • inflammation, increased vascular permeability, plasma extravasations
    • sensitization and activation of nociceptors
      • changes in kinetics
      • lowered threshold
      • number of receptors and channels
      • enhances responsiveness of receptors and channels
  3. Inflammation invades adjacent tissue via the axon reflex
  4. Results in:
    • lower threshold for pain at site of injury and adjacent tissues
      • hyperalgesia
      • allodynia
    • spread of edema
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12
Q

Axon Reflex

A
  • Depolarization of nociceptor generates action potential
    • travels along sensory neuron ⇒ dorsal horn of spinal cord
    • depolarizes other branches of the nociceptor
  • Nociceptor locally release
    • substance P
    • calcitonin gene related peptide (CGRP)
  • Results in
    • vasodilation and increased vascular permeability
    • plasma transvasation
    • histamine release by mast cells
    • serotonin release by platelets
  • Process contributes to the spread of inflammation and hyperalgesia to adjacent regions of the skin
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13
Q

Sun Burn

A
  1. Sun burn results in skin injury releasing prostaglandin (PGE2)
  2. Acts on the GPCR EP2
  3. Activates PKA and second messenger system
  4. Promotes modulation via phosphorylation of TRPV1 and Na+ channels
    1. Changes kinetics and threshold
    2. Increases number of receptors and channels
  5. Results in enhanced responsiveness of existing receptors/channels
  6. Warm shower perceived as burning after sunburn due to lowering of threshold of TRPV1 receptors ⇒ peripheral sensitization
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14
Q

Wind-up Phenomenon

Central Sensitization

A
  1. Nociceptor stimulation results in synaptic release
    • glutamate
    • substance P
    • CGRP
  2. Elicits slow synaptic potentials in dorsal horn neurons lasting several hundred milliseconds
  3. Repeated nociceptor stimulation results in progressive increase in firing of dorsal horn neurons
  4. Summation of slow synaptic potentials depolarizes the dorsal horn pain signaling neuron more and more ⇒ wind-up phenomenon
  5. Repeated mechanical or noxious heat stimuli perceived as more and more painful even if stimulus intensity constant
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15
Q

Central Sensitization

Mechanism

A
  1. Repeated nociceptor stimulation promotes wind-up phemonenon and progressive dorsal horn neuron depolarization
  2. Increased depolarization removes the voltage-dependent Mg2+ blockade of NMDA receptor ion channels
    • NMDA channels now primed for activation by glutamate
    • Firing-response of the neuron increases for each individual stimulus
  3. Entry of Ca2+ via NMDA channels leads to activation of second messengers
    1. PKA
    2. PKC
    3. NO synthase
  4. Results in alterations in ion channel properties, receptor activity, and receptor trafficking.
  5. Leads to changes in gene expression
  6. Produces long-term changes in dorsal horn neuron excitability ⇒ central sensitization
  7. Causes hyperalgesia, allodynia, and spontaneous pain
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16
Q

Neuropathic Pain

(Intractable)

A
  • Caused by injury leading to permanent damage of PNS or CNS
  • Results in rearrangement of PNS or CNS connections
  • Serves no apparent biological function
  • May persist for months or years beyond healing of any damaged tissues
  • Tends to be only partially responsive to opioid therapy
17
Q

Neuropathic Pain

Conditions

A
  1. Peripheral neuropathy
    • caused by nerve damage in DM, ETOH abuse, chemotherapy, or vitamin deficiencies
  2. Entrapment neuropathy
    • carpal tunnel syndrome
  3. Post-herpetic neuralgia
    • hypersensitivity following herpes zoster reactivation
  4. Fibromyalgia
    • chronic pain originating mainly GTO and muscle spindles
    • “proprioceptive allodyania”
  5. Complex regional pain syndrome (CRPS)
    • two types: sympathetlically dependent and independent
  6. Multiple sclerosis
  7. Neuroma
  8. Phantom limb pain
  9. Thalamic pain syndrome
    • rearrangement of local circuits following central lesion or stroke
18
Q

Neuropathic Pain

Mechanisms

A
  1. PNS injury results in formation of neuromas
  2. Sprout of sympathetic fibers in DRG of injured nerves
    • DRG neurons develop adrenergic receptors
    • Acquire sensitivity to catecholamines
  3. Formation of ectopic neuronal pacemakers
    • Due to increased density of abnormal or dysfunctional sodium channels
  4. Ephaptic cross talk
    • Abnormal electrical connections between adjacent axons
    • Cross talk between A & C fibers
    • Connections between sensory and sympathetic fibers
  5. Inflammation of nerve sheaths
    • Releases inflammatory agents
    • Contributes to neuropathic pain
19
Q

Allodynia

Mechanism

A

Reorganization results in neuropathic pain.

  1. Nerve injury results in greater loss of small fibers than large fibers.
  2. Axons of surviving A-beta fibers sprout new branches
  3. Make central connection to dorsal horn neurons vacated by lost C fibers
  4. Non-noxious stimuli can now activate dorsal horn pain signaling neurons and evoke pain ⇒ allodynia
20
Q

Immune and Glial Cells

Role in Neuropathic Pain

A

Involves Schwann cells, satellite cells in DRG, immune system components, spinal microglia and astrocytes.

  1. Nerve injury causes recruitment and activation of immune cells at site of lesion, DRG, and grey matter of spinal cord.
    • IL-1 and IL-6 from macrophages
    • NGF and neurotrophin-3 from satellite cells
  2. Inflammatory cytokines trigger sprouting of sympathetic fibers into DRG.
    • Sensitized to catecholamines ⇒ neuropathic pain
  3. Activated microglia causes loss of GABA inhibition on dorsal horn lamina I neurons.
    • Maintains neuropathic pain
21
Q

Phantom Limb Pain

A

Produced by at least 4 mechanisms:

  1. Spinal cord “experiences” amputation causing central sensitization.
  2. Formation of neuromas.
  3. Sympathetic innervation of DRG leads to catecholamine sensitization.
  4. Reorganization of central connections.

Non-pharmacologial treatments:

  • Mirror box
  • Virtual reality googles
22
Q

Gate Control Theory

A

Noxious and non-noxious inputs interact in the spinal cord.

Inhibitory interneurons activated by A-beta fibers act as a gate.

Controls transmission of pain stimuli by C fibers to higher centers.

Non-noxious stimuli can decrease pain transmission.

  • Ex. rubbing skin near injury can decrease pain because it stimulates light touch associated A-beta fibers
  • Applications:
    • TENS
    • Dorsal column stimulation
    • Acupuncture
23
Q

Referred Pain

A

Pain sensation from viscera inappropriately perceived as arising from surface structures.

May be due to visceral and somatic pain fibers converging on the same STT cells.

24
Q

Nociceptive Pathways

A

3 pathways contribute to the nociceptive anterolateral system:

  1. Spinothalamic tract
    • cell bodies in laminae I, II, and V
    • cross midline and terminate in VPL thalamus
    • project to primary somatosensory cortex
    • carries information about localization, intensity, duration, and type of pain stimulus
  2. Spinoreticular tract
    • ascend in the anterolateral system
    • terminates in both reticular formation and intralaminar nuclei of thalamus
    • projects to insula, cingulate gyrus, amygdala, and hypothalamus
    • participates in the arousal and affective component of pain
  3. Spinomesencephalic tract
    • axons ascend inside and out of anterolateral system
    • terminate in mesencephalic reticular formation, periaqueductal gray matter (PAG), and parabrachial nucelus
    • projects to insula, cingulate gyrus, amygdala, and hypothalamus
    • participates in affective component of pain
    • provides pain feedback information to PAG which is the center for suppresion of pain
25
Q

Thalamic Nociceptive Nuclei

A
  • Ventral posterior lateral nucleus (VPL)
    • receive inputs via STT from neurons in laminae I and V
    • infarcts can produce thalamic pain syndrome
  • Ventral posterior medial nucleus (VPM)
    • receive inputs via STT from trigeminal nerve
  • Intralaminar (IL) nucelus
    • receive inputs from spinoreticular and spinomesencephalic tracts
    • involved in processing of nociceptive information
    • activation of nonspecific arousal system and motivational-affective aspects of pain
26
Q

Cerebral Cortex

Nociceptive Centers

A
  1. Somatosensory cortex (SI)
    • localization, quality, duration, and intensity of pain stimuli
    • more active when pain perceived as more intense
    • opiod dose relationship to suppress pain-related activation
  2. Cingulate cortex and insular cortex
    (amygdala, insula, anterior cingulate cortex)
    • emotional components of pain
    • more active when pain perceived as more unpleasant
    • lower threshold for opioid action
    • lesion results in asymbolia for pain
    • contain empathic pain neurons
      • subjective affective dimension of pain in this area activated with empathy for the pain of others
27
Q

Periaqueductal Gray

(PAG)

A

Responsible for the descending control of pain.

  • Receives pain information via the spinomesencephalic tract
  • Receives input from cortex, limbic system, and hypothalamus
    • behavioral states
    • whether to activate the pain control system
  • Descending pathways can be activated by stress, fear, exercise, certain disease states, and pain itself
  • Stimulation of PAG inhibits the activity of nociceptive specific neurons.
    • Regulates the transmission of pain information
  • Actions blocked by Naloxone (opioid antagonist)
28
Q

Active Emotional Coping

A
  • noxious stimuli perceived as an alarm
  • under emergency conditions poses a threat for survival
  • activates dorsal half of PAG
  • causes a short, non-opioid mediated “stress-induced analgesia”
  • mobilizes body for fight-or-flight via sympathetic system
29
Q

Passive Emotional Coping

A
  • Results from persistent inescapable pain
  • Causes a disengagement from the environment or withdrawal response
    • learnt helplessness
  • Evokes an opioid-mediated analgesia
  1. Stimulation of the ventral half of PAG
  2. Activation of neurons in raphe nucleus and locus coeruleus
  3. Projects to spinal cord and activates enkephalin-containing interneurons
  4. Enkephalin-containing interneurons inhibit dorsal horn projecting neurons via:
    • Pre-synaptic opiod receptors
      • decrease transmitter release from nociceptor by reducing calcium conductance
    • Post-synaptic opiod receptors
      • inhibits dorsal horn projecting neurons by increasing potassium conductance ⇒ hyperpolarization
30
Q

PAG Descending Pathway

A
  1. Passive emotional coping stimulates ventral half of PAG
  2. Activates of neurons in raphe nucleus and locus coeruleus
  3. Projects to spinal cord and activates enkephalin-containing interneurons
  4. Enkephalin-containing interneurons inhibit dorsal horn projecting neurons via:
    • Pre-synaptic opiod receptors
      • decrease transmitter release from nociceptor by reducing calcium conductance
    • Post-synaptic opiod receptors
      • inhibits dorsal horn projecting neurons by increasing potassium conductance ⇒ hyperpolarization
31
Q

Opiod

Pain Management

A

Endorphin, Enkephalin, Dynorphin

Modifies transmission in the dorsal horn.

  • Acts via GPCR opiod receptors ⇒ Mu, Delta, Kappa
  • Opiod agonists:
    • reduce neuronal excitability by increasing K+ conductance
    • inhibit neurotransmitter release by decreasing presynaptic Ca2+ influx
  • Anti-inflammatory action via inhibition of prostaglandin production
  • Acts on other pain centers
    • PAG
    • Anterior cingulate
    • Prefrontal cortex
  • Intrathecal or epidural injection of morphine into CSF of spinal cord
    • produces analgesia while limiting side effects & addiction
  • Acupunture, TENS, and dorsal column stimulation
    • may suppress pain by stimulating release of endogenous opiods
  • Placebo effect via activation of endogenous opiod system
32
Q

NSAIDS

A

Acts through inhibition of cyclooxygenase (COX)

Prevents formation of prostaglandins.

33
Q

Nerve Blockade

A
  • Local anesthetics alter nerve conduction via blockade of Na+ channels
  • Preferentially blocks unmyelinated C fibers conduction
  • Used for surface anesthesia, infiltration, spinal, or epidural anesthesia.
  • Used in combination with steroid to reduce local swelling.
34
Q

Antidepressant

Pain Management

A

Tricylics like desipramine and protriptyline.

  • Alleviation of depression
  • Blockade of reuptake of norepinephrine and serotonin
    • Facilitates descending pain inhibition pathways
  • Blocking effects on spinal NMDA recepros
    • Enhances efficacy of opioid binding to receptors
  • Promoting increased levels of anti-inflammatory IL-10
35
Q

Anticonvulsants

Pain Management

A

Main indication is neuropathic pain.

  • Carbamazepine
    • decreases sodium channel excitability
    • used to suppress abnormal firing of injured neurons due to abnormal expression of Na+ channels
  • Gabapentin and pregabalin
    • inhibits voltage-dependent calcium channels
    • decreases release of glutamate and substance P
    • increases GABA action
    • potentiates benzodiazepines and barbiturates

IMS: Neuroanatomy (23 decks)

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