Physiology of Pain (Week 2--Melega)

Question 1

Examples of natural analgesics

Answer 1

Opium from poppy

Salicin from willow tree bark

Menthol from peppermint

Capsaicin from peppers

Cocaine from coca leaves

THC from cannabis

Question 2

Nonpharmacologic approaches to pain treatment

Answer 2

Deep brain stimulation

Dorsal column of spinal cord stimulation (for low back and leg pain)

Vagal or trigeminal nerve stimulation

Transcutaneous electrical nerve stimulation (TENS)

Surgical ablation (medial thalamotomy, cingulotomy)

Question 3

What is pain?

Answer 3

Unpleasant sensory and emotional experience that is associated with actual or potential tissue damage, but also may be reported in absence of actual tissue damage

Pain can be adaptive–early warning to protect the body from tissue injury

Question 4

Nociception

Answer 4

Process of detecting noxious or potentially noxious stimuli and converting that stimuli into neural impulses that are transmitted to the CNS

Intense pressure, chemicals, thermal stimuli above 43C are 3 classes of nociceptive stimuli

Nociceptors are specialized peripheral sensory neurons that convey noxious stimuli from periphery to CNS

Question 5

Two components of the pain process

Answer 5

1) Sensory component: sensory afferents that detect nociception and transmit it via neural pathways from periphery to CNS
2) Perceptual component: conscious experience of nociceptive stimuli that arrives to brain from periphery

Note: activation of brain regions that modulate nociceptive stimuli can also occur in the absence of peripheral nociception

Question 6

Somatic pain source

Answer 6

Skin, muscle, joints, bones, ligaments (MSK pain)

Receptors activated: nociceptors for heat, cold, vibration, stretch, inflammation, oxygen starvation

Characteristics: sharp and well localized, can often be reproduced by touching or moving the area or tissue involved

Question 7

Visceral pain source

Answer 7

Internal organs (heart, lungs, liver, kidneys, spleen, bowel, bladder, womb, ovaries)

Receptors activated: nociceptors for stretch, inflammation, oxygen starvation

Characteristics: poorly localized, may feel like vague “deep squeezing” ache, sometimes cramping or pressure-like; frequently produces referred pain

Question 8

Neuropathic pain

Answer 8

Damage to neural tissue that results in spontaneous discharge and abnormal activity of pain transmission pathways in peripheral or central nervous systems (“alarm system” is malfunctioning)

Sensitization is what causes pain

Pain may persist for months or years after initial insult

Characteristics: burning, electric, tingling, shooting, numbness, lancinating, can be continuous or paroxysmal

Can be classified by hyperalgesia, allodynia, hyperpathia

Results from nerve injury, peripheral or central sensitization of nociceptive pathways

Ex: peripheral neuropathies, complex regional pain syndrome (CRPS), post-herpetic neuralgia

Note: no COX or opioid sensitivt components, so CANNOT treat with NSAIDs or opioids

Question 9

Acute pain

Answer 9

Nociceptive

Secondary to chemical, mechanical, thermal stimulation of A-delta and C-polymodal pain receptors

Generally is a well-defined pattern to pain, with recent onset and hyperactivity of ANS

Symptom of disease process in or around injured tissue

Self-limiting and serves protective function by acting as warning of potential or ongoing tissue damage; disappears with resolution of pathological problem

Question 10

Chronic pain

Answer 10

Often neuropathic

Body unable to restore homeostasis because initial injury has exceeded body’s capacity for recovery

Serves no useful purpose

Less well-defined, duration >3 months with alterations of ANS

Ex: chronic back pain, fibromyalgia

Question 11

Nociceptive pain transmission pathway

Answer 11

1) Nociceptor stimulation leads to generation of action potentials in primary afferent neurons (cell bodies in DRG)
2) APs conducted to dorsal horn of spinal cord by primary afferents, then synapse onto secondary neurons there
3) Secondary neurons send axonal projections to the brain (thalamus –> cortex)
4) Peripheral nociceptic stimuli perceived as pain within the brain (cortex is where you get “ouch” part!)
5) Descending axonal projections from neurons in the brain descend down spinal cord and synapse onto cell bodies that transmit nociception from periphery to the brain to modulate/decrease extent of ascending nociceptive input to brain

Question 12

Peripheral transduction at the nociceptor

Answer 12

Remember, 3 classes of nociceptors: chemical, mechanical, thermal (receptors that respond to all 3 classes of stimuli are polymodal)

Stimuli causes ion channels to open and Ca and Na influx which translates to AP

Question 13

Where are cell bodies of nociceptors?

Answer 13

For the body, in DRG

For the face, in trigeminal ganglion

Note: have central axonal branch that innervates spinal cord!

Question 14

Chemical nociceptors

Answer 14

Chemical nociceptors are activated by bradykinin, prostaglandin, etc (which are released when there is tissue injury)

Bradykinin activates sensory primary afferent (nociceptor) but in doing so, causes that neuron to release substance P from its collaterals –> substance P is pro-inflammatory and tells mast cells to secrete histamine –> swelling, inflammation

Potentiate initial nociceptive stimulus with other substances released locally

Multiple types of nociceptors on peripheral afferents that trigger AP to spinal cord

Question 15

Substance P

Answer 15

Peptide (11 AAs) that can act as NT and as neuromodulator to alter excitability of nociceptive afferents

Pro-inflammatory; causes mast cells to degranulate and release histamine, thus preipheral vasodilation

Question 16

Thermal nociceptors

Answer 16

Activated only by temperatures greater than 43C

Silent until reach 43C, then start firing (so we ca distinguish between warmth and damaging heat)

Note: nociceptors have higher stimulation threshold and higher magnitude of firing compared to thermoreceptors (that detect changes in all temp and respond linearly up to 40C then plateau)

Question 17

Peripheral nerve fibers

Answer 17

A-alpha and A-beta: large diameter, myelinated; motor and proprioception

A-gamma: smaller diameter, myelinated; muscle tone

A-delta: smallest myelinated; transmit acute pain signals; fast speed to raise alarm (first pain and temp); pain, temperature, touch

C: unmyelinated; transmit chronic slow pain signals; slow speed; pain, temperature, touch

Question 18

Mechanical nociceptors

Answer 18

Respond to strong pressure, not light touch

Question 19

Neurogenic inflammation

Answer 19

First pain (primary hyperalgesia): initial localization due to A-delta fibers

Second pain (secondary hyperalgesia): spreading inflammation due to C-polymodal nociceptors

Question 20

Inflammatory pain mechanisms in the periphery

Answer 20

Substance P (SP): increase vascular permeability, induce release of cytokines, attract leukocytes to site of injury

Bradykinin (BK): cause vasodilation, increase SP release, sensitize nociceptors

Prostaglandins (PG): contribute to nociceptive sensitization

NE: activate nociceptive terminals

Question 21

Transmission of signal to spinal cord

Answer 21

Both A-delta and C fibers send branches to innervate neurons in Rexed’s lamina I, II (substantia gelatinosa)
–> synapse with secondary neurons which cross midline and project to brain via spinothalamic tract (major ascending pathway for conveying info about nociception from periphery)

Gate control theory: input from A-beta primary afferents activate inhibitory intereurons in substantia gelatinosa which reduce stimulation/effectiveness of nociceptive input from C fibers to the brain

Question 22

Gate Control Theory

Answer 22

Gate is located at level of dorsal horn of spinal cord and acts to suppress pain (why you can rub arm after injury to dull the pain); closed gate reduces effectiveness of nociceptive input from C fibers in activating projections to brain

Firing of the projection neuron determines the extent of pain transmission from C fibers in periphery

Inhibitory interneuron decreases chances that projection neuron will fire

C fibers inhibit inhibitory interneuron (indirectly), increasing chances projection neuron will fire

Firing of A-beta fibers activates inhibitory interneuron, reducing chances that projection neuron will fire, even in presence of firing nociceptive C fiber

Input from descending neurons in the brain can also modulate synaptic activity and neurotransmission (NOT the gate control theory??)

Question 23

Neuromatrix Theory

Answer 23

Pain is a multidimensional experience produced by characteristic “neurosignature” patterns of nerve impulses that are generated by a widely distributed neural network

Can be thought of as expansion of central control processes in original Gate Control Theory, now encompassing cognitive-evaluative, motivational-affective, and sensory discriminative systems

Question 24

Two theories of pain transmission

Answer 24

Neuromatrix Theory: multidimensional experience

Gate Control Theory: modulation of ascending nociceptive stimuli

Question 25

Glutamate

Answer 25

Most prominent NT in the body

AA that functions as excitatory NT

Question 26

Glutamate receptor subtypes

Answer 26

Two are named after agonists that bind them: AMPA and NMDA

Ionotropic glutamate receptors: form ion channels that open when glutamate binds receptor; NMDA, AMPA and Kainate

Metabotropic glutamate receptors: act through signaling cascade that involves G proteins; L-AP4, ACPD, L-OA

Question 27

Which receptors are involved in primary afferent synapse in the spinal cord?

Answer 27

Multiple receptors of different NT systems

Activation/inhibition modulates synaptic activity of released glutamate and SP from primary afferent

Glu and substance P are main NTs at central

However, glutamate released by primary afferent nociceptor fibers acts on AMPA receptors, NOT on NMDA receptors for pain transmission from nociceptors in the periphery

Question 28

Hyperalgesia

Answer 28

Heightened response to painful stimulus

Something went wrong so now you’re responding more sensitively so get pain with lower degrees of stimuli

Question 29

Allodynia

Answer 29

Pain due to touch/temp stimulus that wouldn’t normall provoke pain (no/low stimulation and get full pain response)

Serious problem because hard to treat pharmacologically

Question 30

Hyperpathia

Answer 30

Heightened response to a stimulus, with increased threshold

Hard to get the pain, but once you do, the rise in magnitude is steeper

Question 31

Peripheral vs. Central sensitization

Answer 31

Peripheral: sensitization of peripheral processes result in increased nociceptive activity transmitted to spinal cord

Central: sensitization of neurons in spinal cord that receive peripheral nociceptive activity contributes to increased nociceptive activity being transmitted to the brain

Question 32

How can neuropathic pain occur following nerve injury?

Answer 32

Release of inflammatory cytokines

Loss of neurotrophic support (can result in altered gene expression in both injured and adjacent uninjured nerve fibers and won’t go away when nerve repairs itself)

Question 33

How can neuropathic pain occur after peripheral sensitization?

Answer 33

Ion channels open more frequently (hyperalgesia) due to sensitization factors

Peripherally released sensitizing agents –> enhanced ion flux in response –> reduced activation threshold for voltage-sensitive Na channels –> increase in second messenger/signal transduction pathways –> increased pain (neuropathic)

Question 34

How can neuropathic pain occur after central sensitization?

Answer 34

Wide dynamic range (WDR) neurons in spinal cord respond to broad range of intensity of stimulation by peripheral nerves –> change in response of WDR neurons in dorsal horn of spinal cord –> increased magnitude and duration of firing, reduced thrshold of neuronal firing, expansion in receptive fields in spinal cord

Long term potentiation can increase efficacy of synaptic transmission

This type of progressive increase in response of nociceptive spinal neurons to repeated C-fiber stimulation occurs through glutamatergic NMDA receptors, a phenomenon called the “windup”

Question 35

Molecular mechanisms underlying central hypersensitization

Answer 35

Excessive frequency of nociceptive input to primary afferent fibers, primarily from C fibers leads to persistent net increase in amount of glutamate in synaptic cleft and depolarization of secondary afferent neurons –> now NMDA receptors become activated and both short- and long-term excitability of synapses is enhanced

Question 36

Capsaicin

Answer 36

Pungent ingredient in hot peppers

Capsaicin has high binding affinity for thermal nociceptor, and activates it

Initial application of capsaicin causes burning feeling because of thermal nociceptor activation and release of SP –> after a few days to weeks, no more burning (thermal nociceptor desensitized) and analgesic because have depleted SP stores by overactivating thermal receptors!

Question 37

Capsaicin as analgesic

Answer 37

Capsaicin-induced desensitization and cell toxicity due to:

1) Depletion of SP and prevention of reaccumulation in nerve endings
2) Massive accumulation of intracellular Ca2+
3) Ca2+ activated proteases and other degradative enzymes destroy cytoskeletal organization

Further capsaicin tx results in mild swelling of axons or even terminal degeneration (acts as neurotoxin)

Without SP, local pain impulses are not effectively transmitted to spinal cord, and this is how capsaicin provides pain relief

Question 38

Clinical application of capsaicin

Answer 38

Once applied, duration of action is 4-6 hours; pain relief within 2 weeks after start of therapy; max effect may not be observed for 4-6 weeks

Significant adverse reactions: itching, stinging, erythema, transient burning on application diminishes with repeated use, low patient compliance

Question 39

Anesthetic vs. analgesic

Answer 39

Anesthetic blocks conduction of impulses for all sensations: touch, pressure, heat, vibration

Analgesics just block conduction of painful impulses carried by type-C fibers (ex: capsaicin)