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

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

Pain Flashcards by Quynh Tran

Pain Pathway

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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Asymbolia for Pain

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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Physiological Pain

(Nociceptive)

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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Mechanical Nociceptors

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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Thermal Nociceptors

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

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Polymodal Nociceptors

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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Ion Channel

Nociceptive Transduction Proteins

Receptors associated with a channel ⇒ fast response

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
ATP ⇒ P2X
- pain associated with tissue injury
Acid sensing ion channel (ASIC)
- stimulated to ↓pH or high threshold mechanical stimuli
- accounts for pain associated with ischemia, inflammation

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G-Protein or 2nd Messenger

Nociceptive Transduction Proteins

Slower Response

G protein-coupled receptors
- Involved in nociception
- stimulated by bradykinin and prostaglandin
- activation of receptor activates 2nd messengers
  - Ca²⁺
  - PKA
  - PKC
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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Nociceptor Projection

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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Nociceptor Synaptic Transmission

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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Peripheral Sensitization

Nociceptors

Due to changes in nociceptor sensitivity.

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

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
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
Inflammation invades adjacent tissue via the axon reflex
Results in:
- lower threshold for pain at site of injury and adjacent tissues
  - hyperalgesia
  - allodynia
- spread of edema

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Axon Reflex

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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Sun Burn

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

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Wind-up Phenomenon

Central Sensitization

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

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Central Sensitization

Mechanism

Repeated nociceptor stimulation promotes wind-up phemonenon and progressive dorsal horn neuron depolarization
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
Entry of Ca²⁺ via NMDA channels leads to activation of second messengers
1. PKA
2. PKC
3. NO synthase
Results in alterations in ion channel properties, receptor activity, and receptor trafficking.
Leads to changes in gene expression
Produces long-term changes in dorsal horn neuron excitability ⇒ central sensitization
Causes hyperalgesia, allodynia, and spontaneous pain

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Neuropathic Pain

(Intractable)

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

Neuropathic Pain

Conditions

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

Neuropathic Pain

Mechanisms

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

Allodynia

Mechanism

Reorganization results in neuropathic pain.

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

Immune and Glial Cells

Role in Neuropathic Pain

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

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
Inflammatory cytokines trigger sprouting of sympathetic fibers into DRG.
- Sensitized to catecholamines ⇒ neuropathic pain
Activated microglia causes loss of GABA inhibition on dorsal horn lamina I neurons.
- Maintains neuropathic pain

Phantom Limb Pain

Produced by at least 4 mechanisms:

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

Non-pharmacologial treatments:

Mirror box
Virtual reality googles

Gate Control Theory

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

Referred Pain

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.

Nociceptive Pathways

3 pathways contribute to the nociceptive anterolateral system:

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
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
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

Thalamic Nociceptive Nuclei

* **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

Cerebral Cortex Nociceptive Centers

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

Periaqueductal Gray | (PAG)

**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)

Active Emotional Coping

* 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

Passive Emotional Coping

* 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

PAG Descending Pathway

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

Opiod Pain Management

**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 Ca_²⁺ _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

NSAIDS

Acts through inhibition of cyclooxygenase (COX) Prevents formation of prostaglandins.

Nerve Blockade

* 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.

Antidepressant Pain Management

**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

Anticonvulsants Pain Management

**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