L43: nociception (pain)

MCQ: what neurotransmitter plays a key role in the descending analgesia pathway?

endorphin

what is pain?

an unpleasant sensory and emotional experience associated with actual or potential tissue damage

what is the purpose of pain?

1. protection from a harmful event

2. protection from further damage during healing

where are most nociceptive neurons located?

most numerous in the skin (somatic superficial pain)

where will nociceptive neurons NOT be located?

none in the brain itself

what are nociceptive neurons?

peripheral pain-sensitive neurons with receptors located in their free nerve endings

what are the 3 types of nociceptors?

1. mechanical

2. chemical

3. thermal

what is the most common type of nociceptors?

chemical

what do chemo-nociceptors respond to?

chemicals released during cell injury and inflammation

what are the two neuron types that carry nocicpetive pain?

A-delta and C

what is the main neurotransmitter of A-delta neurons?

glutamate

glutamate is…

fast to enter synapse but short-acting

A-delta neurons correlate with…

first, fast, mostly superficial pain

what axons do a-delta neurons have and what does this mean?

small myelinated axons meaning will have fast propogation of nerve signal

what receptor does glutamate bind to?

AMPA and NMDA receptors

what is the main nociceptor of A-delta neurons?

mechanoreceptors

what is the stimuli of A-delta neurons?

initial mechanical force of injury of body surface = superficial pain

what 2 events occur after A-delta neurons have been stimulated?

1. pain reflex

2. pain perception and response

explain what happens with the pain reflex in regards to A-delta neurons?

first order neurons synapse with LMN in spine to instantly withdraw the affected limb (WITHDRAW REFLEX)

describe the process of pain perception from A-delta neurons

1. first order neurons enter dorsal horn to synapse with second order neurons

2. second order neurons enter lateral spinothalamic tracts to ARAS

3. third order neurons project from ARAS to somatosensory cortex for pain perception and localization

what is important to understand about the second order axons in pain perception with A-delta neurons?

majority (70%) of the axons will cross but others (30%) will not cross → this means that pain transmission occurs bilaterally

what is important to understand about the second order axons in pain perception with A-delta neurons in primates?

100% of the axons will cross

C-neurons are associated with…

second, slow, and deep pain

which neuron is more numerous: A-delta neurons or C-neurons?

A-delta neurons

what is the main neurotransmitter of C-neurons?

substance P

substance P is…

slow-release and long-acting

what does substance P bind to?

neurokinin-1 (NK1) receptors (major receptor of pain processing system)

what are the noiceptors of C-neurons?

mechano, chemo, and thermo receptors

what do C-neurons most strongly respond to?

chemicals released during tissue injury with subsequent pro-inflammatory mediators (inflammatory soup)

what inflammatory mediators are involved with “inflammatory soup”?

1. prostaglandins

2. cytokines

3. protons

4. K

5. bradykinin

6. nerve-growth factor

describe the process of pain perception from C neurons

1. first order neurons enter dorsal horn to synapse with second-order neurons

2. second order neurons ascend bilaterally via medial spinothalamic tracts to ARAS

3. third order neurons distribute to multiple parts of the brain

what happens when third order C- neurons go to the hypothalamus?

hypothalamus initiates sympathetic response to pain

what happens when third order C- neurons go to the limbic system/amygdala?

initiate emotional responses, behavioral responses, and memory of pain

how long will second pain last for?

lasts as long as noiceptive pro-inflammatory chemicals are present

what is the purpose for second/deep pain?

enables the animal to protect itself or the damaged body part while it is healing, and to avoid future exposure

what is the clinical relevance of C-fiber injury?

due to deep location and multiple bilateral pathways spinal cord injuries must be severe and extensive to abolish deep pain sensation

neuropathic pain

damage to the nervous system leads to spontaneous action potentials in the affected pain neurons (ectopic firing)

what are the causes of neuropathic pain?

1. nerve compression (IVDD, pinched nerve)

2. external nerve injury

3. neurogenic infection

4. metabolic nerve damage (diabetic neuropathy)

how is neuropathic pain described?

 tingling, burning, shooting, electrifying, stabbing pain, “pins & needles”

what are examples of neuropathic pain?

1. phantom pain (amputation pain)

2. trigeminal-mediated headshaking syndrome in horses

what is trigeminal-mediated headshaking syndrome in horses?

facial pain caused by spontaneous firing of the trigeminal nerve (cause is unknown)

explain phantom pain

because of point-to-point projection, pain is localized to where the hyperactive neurons originally came from

what is the purpose of inhibitory pain modulation?

suppress pain signaling to avoid overstimulation of the brain at times of survival

what are the two mechanisms that help inhibit pain?

1. spinal cord circuit

2. descending analgesia pathways

what neurotransmitters are inhibitory?

GABA and glycin

what happens if there is simultaneous pain and touch stimulation in the same area?

1. touch collaterals will stimulate inhibitory interneurons

2. pain transmission between 1st and second pain neuron is inhibited

3. gates that filter signals to the brain are closed = inhibition of pain

what is the principle of “counter irritation” treatments?

gate control circuits are used to manipulate pain via rubbing, touching, and licking a painful area to reduce transmission of pain

where does the descending analgesia pathway originate?

midbrain

what activates the descending analgesia pathway?

incoming pain and stress

what are the neurotransmitters of the analgesia pathway?

1. endogenous opioids

2. serotonin (5-HT)

3. norepinephrine

what is the route for the descending analgesia pathway?

midbrain → descending tracts to spinal cord → dorsal horn

what do neurotransmitters of the descending analgesia pathway block or reduce?

signal transmission from first to second order pain neurons

what are the 3 groups of endogenous opioids?

1. endorphins

2. encephalins

3. dynorphins

what do opioids induce?

1. hypoalgesia or complete analgesia

2. reduction in pain processing, stress, and anxiety

3. can induce euphoria (reward center → hypothalamus)

what effect does serotonin induce on pain?

activates inhibitory interneurons to inhibit pain transmission → “analgesic effect”

what effect does norepinephrine have on pain?

1. blocks release of calcium neurotransmitters to reduce pain transmission → analgesic

2. activates auto-inhibitory alpha-2 receptors → sedative

what else can activate the analgesia pathway besides pain?

1. intense exercise

2. extreme excitement

3. acupuncture

what is sensitization of pain?

strong and repetitive pain signals can initiate functional and structural changes in pain pathway to worsen pain

what structures are involved in the sensitization mechanism?

1. peripheral sensitization (free nerve endings)

2. central sensitization (synpases in dorsal horns and brain)

what does the sensitization mechanism do?

lowers the pain threshold making mild pain stimuli or touch stimuli be perceived as painful

what is the purpose of the pain sensitization mechanism?

increases the protection of the injured area during healing (physiological)

what are the two forms of sensitization?

1. hyeralgesia

2. allodynia

what is hyperalgesia?

an exaggerated pain response to a noxious (painful) stimulus

what is allodynia?

a painful response to a non-noxious (non-painful) stimulus

what does physiological sensitization involve?

functional changes in neurons (central and peripheral) that are FULLY REVERSIBLE as the injury heals

what causes physiological sensitization?

continous exposure to inflammatory mediators

what happens to physiological sensitization as healing occurs?

healing → reduced inflammatory stimuli → regression of functional sensitization → return to normal pain threshold

which type of sensitization occurs within minutes or hours of the injury?

physiological sensitization

which type of sensitization occurs within days to weeks of the injury?

pathological sensitization

what does pathological sensitization involve?

structural changes in pain pathways that are mostly IRREVERSIBLE even after healing is completed

what neuromodulation mechanisms can occur with pathological sensitization?

1. activation of microglial cells to release inflammatory mediators

2. chloride gradient shift to reverse GABA function

what can exist in the absence of an adequate injury with pathological sensitization?

pathological pain; NO FUNCTIONAL PURPOSE

what can pathological sensitization predispose the patient to?

chronic pain

how long must pain last for it to be considered chronic?

more than 3-6 months

what causes chronic pain?

persistent inflammatory pain due to an ongoing disease leading to extended physiological pain

what is often involved with chronic pain?

• irreversible sensitization → pathological pain

• nerve damage → neuropathic pain

what is important to remember about chronic pain?

often therapy resistant → prevent development of chronic pain using pre-emptive multimodal analgesia

how can unmanaged pain cause stress responses?

heightened sympathetic outflow and cortisol release in response to pain

what is key to know if the animal is in pain?

OBSERVATION

what things do we observe to tell if the animal is in pain>

1. mobility

2. activity

3. behavior

4. body posture

5. facial expression

6. vitals

what do we do to determine if the animal can feel pain?

observe the animal’s RESPONSE to a stimulus (touch or pain)

what is important to distinguish when determining if an animal can feel pain)

withdrawal reflex vs. behavioral response to the stimulus

what does it mean if the animal shows a withdrawal reflex during stimulus?

does not require perception of the stimulus in the brain

what does it mean if the animal shows a behavioral response during the withdrawal reflex?

animal has felt the stimulus and the pathway to the brain is open meaning the animal can feel the pain/touch

MCQ: the pain section of the somatosensory cortex is damaged on the left side. What are the consequences of pain sensation in this animal?

• left cortex will not receive pain signals from either side of the body

• right cortex works normally

• reduced pain sensation in entire body, but worse on the right side

MCQ: due to a disc prolapse, the spinal cord at L1/L2 is severely damaged, affecting all pain transmitting pathways. What are the consequences on pain sensation in this animal?

• bilateral analgesia caudal to the lesion

• hindlimb reflexes will still be working

• no sensations in animals hindlimb (paraparalysis)

MCQ: due to a disc prolapse, the right lateral spinothalamic tract is damaged at L1/L2. what are the consequences on pain sensation in this animal?

• bilateral hypoanalgesia caudal to the lesion

• left hindlimb will be more effected (ispsilateral tract = open, contralateral tract = blocked)

• right hindlimb (ispsilateral tract =blocked, contralateral tract = open)

• spinal reflexes will remain intact