Pain
An unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damageCognitive or emotional response to nociception that occurs in the higher centers of the CNS
Nociception
the physiologic processes related to pain perception or a noxious stimulus
What is the purpose of pain?
protection mechanism to withdraw from damage, to protect from further damage while healing, and to avoid damage in the future
Sensory System Conformation
nociceptors (which transduce a noxious stimulus) transmit stimuli via second and third order neurons to the brain for conscious perception of pain
True or False - nociception can be present without physical stimulus of pain
True - nociception is just the signal from the painful stimulus but may not always reach the brain to indicate that there is actual pain
What would be the nociceptive response to pain?
Withdrawal from the painful stimulus
Nociceptors
Pain neurons with free nerve endings and contain ligand-gated channels
True or false - nociceptors are present in all tissues
FALSE - they are present in all tissues EXCEPT the brain
Where is somatic superficial pain derived from?
Nociceptors in the skin
Where is somatic deep pain derived from?
Nociceptors in deep tissues - like muscles, joints, and joint capsules
Where is visceral pain derived from?
Viscera/organs ex. stomach ache, colic in young horses
What are the 4 different types of nociceptors?
1) Transient Receptor Potential Cation Channel/TRP channel/TRPV12) Acid-sensing ion channels/ACISs3) G protein-coupled receptors/GPCRs (ex. prostaglandins)4) Neurotropins/nerve growth factor receptor
What is the best ligand-gated receptor/channel complex?
TRP channel
What is the TRP channel activated by?
- Capsaicin (part of peppers that make it hot/spicy)- low pH- heat - endovanilloids (anandamide)
What ion can active nociceptors and why?
K+ because if a cell is damaged, this causes the concentration of extracellular K+ to increase, causing action potentials, leading to transaction
Nociceptors are mostly ________-________ chemocrecptors
poly-modal (one receptor can be stimulated by multiple different stimuli)ex. can carry several types of ligand-gated channels
Different types of poly-modal receptors:
- ATP acting as a neurotransmitter - Mechanical- Temperature - H+ ions - Substance P
How does ATP act as a nociceptor?
If a cell is injured, it will release its ATP, travel to the free nerve endings, bind to receptors, and will initiate the receptor potential
How are nociceptors activated?
Triggered by high threshold chemical/mechanical/thermal energy -> leads to tissue disruption -> release of chemical from damaged cells (via inflammatory mediators)
Transduction process of nociceptive pain:
Ligand binding -> ionic flow -> graded potential -> threshold -> opening of voltage-gated Na+ channels -> action potential -> transmission along 1st order neuron to spinal cord -> second order neuron (to brain stem and thalamus) -> third order neuron (projecting into cerebral cortex)
All fibers start on the right side then decussate to the contralateral side (left) called the ________ _________ tract.
Lateral spino-thalamic tract
What is first pain?
#VALUE!
Process of first pain:
triggered by initial mechanical force of injury -> damaged cells release chemicals -> activate a subset of nociceptors specific for these chemicals -> transduction and transmission to cortex via Medium diameter myelinated A-delta fibers (Speed of conduction is fast)
What is second pain?
0
What is inflammatory soup?
-maintains a burning/ diffuse/ nagging/ throbbing/ nauseating/ long-lasting pain sensation via unmyelinated C fibers -prostaglandins, histamine, substance P, bradykinins- contributes to peripheral sensitization in chronic pain
Second pain will last if ....
inflammatory mediators are continuing to be released
Steps of pain transmission and route through ascending pathway:
1st order neurons (A-delta and C fibers) enter spinal cord via dorsal root -> to dorsal horn -> synapse with 2nd order neurons (glutamate and Substance P work as neurotransmitters) -> axons enter spinothalamic tract (SST) in lateral funiculus -> SST synapses with 3rd order neurons in the thalamus projecting into somatosensory cortex and to RF and limbic system
The SST in the lateral funiculus is always _______ in primates and __________/________ in domestic animals.
contralateral in primates (will always crossover)ipsi- and contralateral in domestic animals (50% crossover and 50% remain)
Somatosensory cortex from the SST
Area of acute perception and localization of pain = discriminative pain pathway, receives mostly from A delta fibers = Acute First Pain
Reticular formation (RF) and limbic system from the SST
- Receives mostly C fibers- evokes dull, aching, burning, diffuse pain = Second Pain - evokes autonomic responses (increased BP, sweat)- evokes emotional and behavioral responses (fear, avoidance)- maintains arousal/wakefulness (ARAS)
Is pain only carried in the SST?
NO! Pain can be carried in many other tracts, for example the Fasiculus proprius
3 Areas of the nociception pathway:
1) Spinal cord 2) Thalamus 3) Cerebral cortex
What is neuromodulation?
Inflammatory soup (like prostaglandins) can lead to temporary changes in transduction channels, occurs in 4 ways
4 Ways neuromodulation can occur:
1) via phosphorylation of channel proteins which extends opening opening of channels (pain is enhanced)2) via gene expression (growth factor goes to DNA, stimulates gene expression to code and make new things like new channels and increased neurotransmitter production)3) via recruitment of "silent" nociceptors (lie dormant until awaken by continuous inflammation (pain is sensitive to even light touch)4) changing ionic flow and amplification of signal transmission (nociceptors become more sensitive to stimuli)
2 forms of sensitization:
hyperalgesia and allodynia
Hyperalgesia
exaggerated response to noxious (painful) stimuli (feels more painful than it should)
Allodynia
pain response to a non-noxious stimulus (ex. gentle touch)
Sensitization typically resolves as the injury heals. If it persists in the absence of injury, this is called ______ ______.
Chronic pain
Neuropathic/Neurogenic Pain
A pain caused by a lesion or disease of the somatosensory nervous system; the cerebral cortex interprets stimulation anywhere along its neurons pathways originating from its nociceptive ending (point-to-point projection/labeled line principle)
How is neuropathic pain elicited?
By an increased action potential frequency along a neuron due to nerve damage, presence of a disease.
Causes of neuropathic pain:
- spinal cord injuries caused by traumatic injury - ischemic stroke, hemorrhages - demyelinating neuropathies (distemper) - mutation in genes can give rise to changes in receptors and ion channels that underlie rare neuropathic conditions (eythromelagia and paroxysmal extreme pain disorder)
Phantom Pain
pain experienced in a body part that is no longer there, caused by hyperactive neuromas at the amputation site, creating action potentials. Point-to-point projection principle localizes the stimulation to where these neurons originally came from.
How many of our patients suffer from phantom pain?
1/3 of patients - that's why sooner the amputation is prescribed, the less likely phantom pain will occur)
How does chronic pain lead to phantom pain?
During chronic pain, all nerves are sensitized leading to phantom pain after limb is removed
Trigeminal-mediated headshaking in horses
Caused by a low threshold of firing of the trigeminal nerve. - behaviors include: sudden jerking of the head with downward and upward head motion, rubbing nose on thoracic limbs or walls, lip movements, excessive snorting, noted mostly during exercise - neuropathic pain that is manifested as an itching, burning, tingling, or electric-like - could be seasonal
What is chronic pain also known as?
Pathological pain or "bad pain
What is the purpose of chronic pain?
There is no purpose and persists in the absence of tissue injury
How is chronic pain characterized?
Its characterized by hypersensitivity of the pain transmission system (hyperalgesia and allodynia) which can last for months or years.
Neuroplasticity
the ability of neural networks in the brain to change through growth and reorganization (modifying expression of genes/receptors changes the way pain is understood or located in the body)
Nerve Growth Factor (NGF)
a substance that markedly affects the growth of neurons in spinal ganglia and in the ganglia of the sympathetic nervous system
2 Mechanisms of neuroplasticity:
1) Peripheral Sensitization = nociceptor remodeling induced by inflammatory mediators (outside CNS)2) Central Sensitization or "Wind Up" = hyper-excitability of neurons at synapses within the CNS (neuropathic pain) upon strong stimulation; triggered. by bursts of nociceptor activity
The key to preventing chronic pain is _______ ________.
polymodal analgesia
How can pain be moderated/inhibited?
via descending analgesia pathways
Mechanism of descending analgesia pathway:
Originate in cortex, thalamus, and brainstem -> descend in lateral funiculus close to spinothalamic tract -> analgesic pathway activated by incoming pain -> neurotransmitters released (nor epi and serotonin) -> target forms synapses with ascending pain neurons and end on inhibitory interneurons in dorsal horns -> inhibitory neurons release inhibitory neurotransmitters to block transmission of pain signals
General analgesia and euphoria caused by:
release of endorphins into bloodstream by hypothalamus
Major effect of acupuncture?
endorphin release (enhances analgesic pathway)
unmanaged/chronic pain can lead to multiple stress responses via?
sympathetic nervous system and cortisol release
Ways you can inhibit CNS?
via descending analgesia system affecting pre- and post- synaptic transmission: opioids, alpha 2 adrenoceptor agonists, serotonin and nor epi (re-uptake inhibitors), paracetamol, cannabinoids
Ways you can inhibit axon transmission?
local anesthetics (block Na-voltage gated channels)
Ways you can inhibit nociception?
NSAIDs via inhibition of prostaglandin production (to decrease inflammation), monoclonal antibodies against NGF
2 Questions to ask when evaluating pain:
1) "Is the animal in pain?" = observation is KEY2) "Can the animal feel pain?" = neurological exam (skin prick, pinch digits/joints)
Doing a skin prick detects for what kind of pain and what location is it testing?
superficial pain largely in spinothalamic tract
Pinching the digits/joints with a hemostat detects for what kind of pain and what location is it testing?
deep pain runs in deeper tracts - fassiculus proprius
Watching for a behavioral response allows you to test what location?
that pain perception is functional so the cortex is functional
What is indicative if the withdrawal reflex is positive?
pain perception is not necessary and the local reflex arc is functional