Physiology of Pain (Week 2--Melega) Flashcards
Examples of natural analgesics
Opium from poppy
Salicin from willow tree bark
Menthol from peppermint
Capsaicin from peppers
Cocaine from coca leaves
THC from cannabis
Nonpharmacologic approaches to pain treatment
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)
What is pain?
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
Nociception
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
Two components of the pain process
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
Somatic pain source
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
Visceral pain source
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
Neuropathic pain
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
Acute pain
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
Chronic pain
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
Nociceptive pain transmission pathway
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
Peripheral transduction at the nociceptor
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
Where are cell bodies of nociceptors?
For the body, in DRG
For the face, in trigeminal ganglion
Note: have central axonal branch that innervates spinal cord!
Chemical nociceptors
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
Substance P
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
Thermal nociceptors
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)
Peripheral nerve fibers
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
Mechanical nociceptors
Respond to strong pressure, not light touch
Neurogenic inflammation
First pain (primary hyperalgesia): initial localization due to A-delta fibers
Second pain (secondary hyperalgesia): spreading inflammation due to C-polymodal nociceptors
Inflammatory pain mechanisms in the periphery
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
Transmission of signal to spinal cord
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
Gate Control Theory
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??)
Neuromatrix Theory
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
Two theories of pain transmission
Neuromatrix Theory: multidimensional experience
Gate Control Theory: modulation of ascending nociceptive stimuli
Glutamate
Most prominent NT in the body
AA that functions as excitatory NT
Glutamate receptor subtypes
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
Which receptors are involved in primary afferent synapse in the spinal cord?
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
Hyperalgesia
Heightened response to painful stimulus
Something went wrong so now you’re responding more sensitively so get pain with lower degrees of stimuli
Allodynia
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
Hyperpathia
Heightened response to a stimulus, with increased threshold
Hard to get the pain, but once you do, the rise in magnitude is steeper
Peripheral vs. Central sensitization
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
How can neuropathic pain occur following nerve injury?
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)
How can neuropathic pain occur after peripheral sensitization?
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)
How can neuropathic pain occur after central sensitization?
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”
Molecular mechanisms underlying central hypersensitization
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
Capsaicin
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!
Capsaicin as analgesic
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
Clinical application of capsaicin
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
Anesthetic vs. analgesic
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)
