nociception I-III

Question 1

Know the pathways for processing of pain and temperature information.

Answer 1

Anterolateral system

Question 2

For anterolateral system: what are the primary sensory neurons, where is the first synapse, where does it corss

Answer 2

Ad and C type fibers in periphery (free nerve endings), 1st synapse in spinal cord at dorsal horn, second order neuron crosses in spinal cord the ascends in the anterolateral system (to thalamus as spinothalamic, to reticular system as spinoreticular or midbrain)

Question 3

What is the thermo-neutral point, what temps do cool receptors and warm receptors detect, and which has more receptors

Answer 3

At a skin temperature of 33°C, we sense neither coolness nor warmth, and this is the thermo-neutral point. cool receptors, fire in the range of 10-37°C, while warm receptors are activated at temperatures ranging between 30-48 °C. There are 10 times as many cool receptors as there are warm receptors

Question 4

compare receptor firing at thermo neutral point

Answer 4

same rate of firing in cool and warm receptors

Question 5

Do temp receptors detect gradual or fast change better

Answer 5

fast changes are detected better than gradual. Ie. When fast temp change is occuring, firing rate changes more drastic than at gradual temp change

Question 6

Where is temperature information first detected?

Answer 6

Temperature information from the periphery is transduced into a receptor potential, which can then trigger action potentials. The frequency of action potentials provides information about the intensity of
the stimulusTemperature information from the periphery is transduced into a receptor potential, which can then trigger action potentials. The frequency of action potentials provides information about the intensity of
the stimulusTemperature information from the periphery is transduced into a receptor potential, which can then trigger action potentials. The frequency of action potentials provides information about the intensity of
the stimulusTemperature information from the periphery is transduced into a receptor potential, which can then trigger action potentials. The frequency of action potentials provides information about the intensity of
the stimulus

Question 7

Compare action potential firing in cold vs warm receptors as temp changes from 33 to 28 deg C

Answer 7

At 33 deg C, both warm and cold receptors fire at similar rates. As temp decreases to 28, cold receptors increase their firing rate, and warm receptors decrease firing rate. As temp is increased back to 33, cold receptors stop firing until 33 deg is reached, then begin firing at the same steady state as the beginning. As temp is increased back to 33, warm receptors increase firing rate until 33 is reached, then begin firing at same steady state as the beginning.

Question 8

Know the pathways for processing of temperature and pain information.

Answer 8

Warm/cool receptors in skin on free nerve endings or pain receptors > cell bodies in dorsal root (trunk and limbs) or trigeminal (head and neck) ganglia > axons form synapse on second order neurons in dorsal horn (DRG) or spinal trigeminal nucleus (trigeminal) > anterolateral system: second order axons either go to thalamus then somatosensory cortex via spinothalamic tract (concious appreciation of tmp) OR second order axons go to the hypothalamus via the reticular formation in the spinoreticular tract (autonomic control of body temp)

Question 9

What kind of fibers are cool and warm receptors

Answer 9

Typically, cool receptors are associated with Aδ fibers, whereas warm receptors tend to be on C fibers.

Question 10

Does temperature and pain ascend ipsilaterally or contralaterallyin the spinal cord with respect to the site of origin of sensory information?

Answer 10

contralaterally- fibers cross in the spinal cord at the level of the dorsal horn where the first synapse occurs

Question 11

list three anterolateral system tracts

Answer 11

spinothalamic, spinoreticular and spinomesencephalic

Question 12

Pathway of spinothalamic tract

Answer 12

This tract projects to the nuclei of the ventrobasal thalamus, which includes VPL. Neurons in these nuclei process information related to localization of pain and project to somatosensory cortex.

Question 13

pathway of spinoreticular tract

Answer 13

This tract projects to the reticular formation in the medulla and pons which then sends fibers to hypothalamus and various thalamic nuclei. Conveys pain inputs that lead to forebrain arousal and elicits emotional/behavioral responses via connections to emotional circuits of brain (limbic system)

Question 14

pathway of spinomesencephalic tract

Answer 14

Projects to the midbrain periaqueductal gray region (PAG) and is important for descending control of pain

Question 15

Two cortical regions activated when pain/temp is being processed

Answer 15

cingulate gyrus (limbic system- emotional component) and insular cortex (autonomic component)

Question 16

Trigeminal pathway

Answer 16

trigeminal axons enter CNS at pons >descend to caudal position then form first synapse in spinal trigeminal nucleus (btw brainstem and spinal cord)

Question 17

Types of pain receptors and their associated fibers

Answer 17

1. Thermal nociceptors: activated by extreme temperatures, 43°C. Nociceptors activated by extreme hot temperatures (>43°C) are associated with Aδ fibers; Nociceptors that signal extremely cold temperatures (<5°C) are associated with C fibers. 2. Mechanical nociceptors: activated by intense pressure, associated with afferent Aδ fibers. 3. Polymodal nociceptors: activated by high intensity mechanical, chemical or thermal stimuli, C fiber afferents

Question 18

Why is capsaicin used for chronic pain

Answer 18

Used in conditions that involve spontaneous or aberrant activity of C fibers. Activation of capsaicin receptors causes massive secretion and eventual depletion of
Substance P from sensory fibers. Substance P is a neuropeptide transmitter found in pain afferentsUsed in conditions that involve spontaneous or aberrant activity of C fibers. Activation of capsaicin receptors causes massive secretion and eventual depletion of
Substance P from sensory fibers. Substance P is a neuropeptide transmitter found in pain afferentsUsed in conditions that involve spontaneous or aberrant activity of C fibers. Activation of capsaicin receptors causes massive secretion and eventual depletion of
Substance P from sensory fibers. Substance P is a neuropeptide transmitter found in pain afferents

Question 19

What is VR-1

Answer 19

Vanilloid receptor-1 is the capsaicin receptor, strongly activated by capsaicin and weakly activated by acids. Also activated by moderate heat (43 deg C). VR-1 is expressed on polymodal nociceptors (c fibers) and is part of an ion channel complex. When activted, the non-selective cation channel opens leading to depolarization

Question 20

Which nociceptor ion channels are gated by ATP and acids

Answer 20

ATP opens ionotropic P2X receptors. Acid-sensing channels are known as ASICs. Four different ASIC genes are expressed in C fiber nociceptors

Question 21

Where is pain information first detected? What types of fibers are they

Answer 21

Peripheral afferent fibers with free nerve endings detect pain, their cell bodies are located in dorsal root (trunk and limbs) or trigeminal (head and neck) ganglia. Afferent fibers are either Ad or C type

Question 22

First pain vs second pain

Answer 22

In response to a painful stimulus, one senses 2 types of pain that are temporally separated. First a tolerable, localized, “pricking” pain is detected (Ad fiber first pain). Then, an intolerable, diffusely localized, “burning” pain is experienced (C fiber second pain).

Question 23

Which peripheral fibers are more susceptible to anoxia

Answer 23

High pressure which induces anoxia will affect fibers with high metabolic demand first. These are the larger diameter Aa and AB fibers. As these fibers conductions are blocked, the individual would not sense touch, vibration or joint position/movement; the arm would be paralyzed. As pressure is increased, Aδ fibers would become blocked leaving only the sensation of burning

pain. Finally at higher levels of pressure, C fibers would also be blocked.High pressure which induces anoxia will affect fibers with high metabolic demand first. These are the larger diameter Aa and AB fibers. As these fibers conductions are blocked, the individual would not sense touch, vibration or joint position/movement; the arm would be paralyzed. As pressure is increased, Aδ fibers would become blocked leaving only the sensation of burning
pain. Finally at higher levels of pressure, C fibers would also be blocked.High pressure which induces anoxia will affect fibers with high metabolic demand first. These are the larger diameter Aa and AB fibers. As these fibers conductions are blocked, the individual would not sense touch, vibration or joint position/movement; the arm would be paralyzed. As pressure is increased, Aδ fibers would become blocked leaving only the sensation of burning
pain. Finally at higher levels of pressure, C fibers would also be blocked.

Question 24

Discuss electrical stimulation of peripheral sensory nerves

Answer 24

A single electrical shock of low intensity can activate Aα and Aβ fibers, resulting in sensations of touch, vibration, and joint movement – all without pain. A shock of slightly higher intensity will evoke a sensation of pricking pain. Yet higher intensity and repetitive stimulation is required to elicit the sensation of burning pain. Anesthetics work opposite to this (small dose blocks small fibers, etc)

Question 25

Activators of nociception

Answer 25

Bradykinin: Tissue damage cuases release of cytoplasmic proteases which cleave inactive kininogen into active bradykinin. Bradykinin directly activates pain receptors of Aδ and C fibers. Potassium, acid and serotonin (5-HT) can also act as activators. Acids interact with ASIC and VR-1

Question 26

Sensitization of nociception

Answer 26

Prostaglandins, substance P and ATP/acetylcholine /serotonin can sensitize nociceptors, decreasing the threshold for activation. Substance P is released from C fibers during repetitive activation. Also, bradykiinin increases synthesis of prostaglandins from neighboring cells, thus sensitizing them.

Question 27

Primary hyperalgesia vs allodynia

Answer 27

Sensitization of nociceptors is known as primary hyperalgesia. When the sensitization is extreme enough to allow non-noxious stimuli to trigger a painful sensation, the term allodynia is used.

Question 28

What agent prevents nociceptor sensitization

Answer 28

Aspirin is a common, well-known analgesic agent. Aspirins inhibit the enzyme, cyclooxygenase, which converts arachidonic acid to prostaglandin. By preventing the synthesis of prostaglandins, aspirin prevents nociceptor sensitization.

Question 29

What is the triple response- what chemical mediators play a role

Answer 29

Result of injury and is characterized by reddening, wheal and flare. Tissue damage causes local production of bradykinin which activates nociception, plus acts as vasodilator (heat and redness) and increases permeability of capillaries, leading to fluid accumulation (edema/wheal). Bradykinin activates C fiber nociceptors leading to substance P release in region surrounding wound, producing a small degree of vasodilation and the pink color of the flare (axon reflex)

Question 30

describe modality segregation in spinal cord

Answer 30

Nociceptive afferent fibers form synapses in the dorsal horn of the spinal cord (trunk and limbs) or the trigeminal spinal nucleus (head and neck) on the same side as the intial site of sensory input. Afferents conveying information of different modalities segregate to different positions within the dorsal horn or spinal trigeminal nucleus.C fiber afferents terminate in several of the Rexed’s laminae (particularly laminae II aka substantia gelatinosa)

Question 31

Referred pain

Answer 31

Some pain-activated dorsal horn neurons receive inputs from cutaneous as well as visceral pain afferents, thus there is convergence of visceral and somatic pain. The cutanous input will dominate such that injury to internal organ will be perceived as injury to a cutaneous site.

Question 32

Where does pain from heart muscle anoxia, gallbladder, ureters, bladder and appendix refer?

Answer 32

heart: upper chest wall, left arm and hand. Gallbladder: scapula. Ureter: lower abdominal wall. Bladder: perineum. Appendix: periumbilical anterior abdominal wall

Question 33

AMPA vs NMDA receptors

Answer 33

AMPA: ionotropic, glutamate receptor, giving rise to rapid synaptic responses. NMDA: ionotropic, glutamate receptor, giving rise to slower excitatory potentials, require both glutamate and depolarization for channel to open.

Question 34

What is "wind Up"

Answer 34

A form of central sensitization: As C fibers are stimulated, post-synaptic AMPA receptors on dorsal horn neurons will be stimulated first. If C fiber stimulation is intense and persistent, both glutamate as well as post-synaptic depolarization will be present during the later periods of stimulation. Now, NMDA receptors will also be activated. Thus, repetitive firing of C fibers will lead to a progressively larger post-synaptic response.

Question 35

Describe long lasting changes in excitability related to NMDA

Answer 35

NMDA receptor becomes phosphorylated by the action of protein kinase C (PKC) and tyrosine kinases. Phosphorylation of the NMDA receptor removes the requirement for depolarization in order to activate it. This means that a single stimulus will produce a larger response now, this leads to hyperalgesia and increased pain

Question 36

Substance P actions

Answer 36

In periphery, substance P leads to sensitization following repetitive stimulation of C fibers. Centrally, repetitive stimulation leads to release of substance P from C fibers presynaptic terminal in dorsal horn (so glutamate and substance P will be released at the first synapse in pain pathway). Substance P binds to its receptor (also known as the neurokinin 1 receptor) and leads to closing of potassium channels and depolarization. Overall, Substance P’s effects lead to enhancement and prolongation of the actions of glutamate.

Question 37

Central sensitization

Answer 37

In addition to Wind up, substance P is not removed from synaptic cleft by re-uptake, so it diffuses to many dorsal horn neurons and causes broad central sensitization at the level of the dorsal horn.

Question 38

List mechanisms by which analgesia is produced

Answer 38

Gate control mechanism and descending mechanism from higher CNS levels

Question 39

How does rubbing an area diminish pain

Answer 39

When you stroke or rub an area evoking pain, you are activating non-nociceptive afferent pathways (e.g., touch receptors and Aβ fibers). Activation of non-nociceptive fibers leads to activation of dorsal horn inhibitory interneurons that in turn inhibit synapses activated by nociceptive fibers (both pre and post synaptically)When you stroke or rub an area evoking pain, you are activating non-nociceptive afferent pathways (e.g., touch receptors and Aβ fibers). Activation of non-nociceptive fibers leads to activation of dorsal horn inhibitory interneurons that in turn inhibit synapses activated by nociceptive fibers (both pre and post synaptically)

Question 40

How does transcutaneous electrical nerve stimulation work

Answer 40

In TENS, electrodes are used to stimulate large-diameter (Aβ) fibers that are in the injured area. The Aβ fibers will excite inhibitory interneurons that decrease the efficacy of nociceptive dorsal horn synapses. Alternatively, stimulation of dorsal columns can produce the same results

Question 41

Tabes dorsalis

Answer 41

Condition associated with advanced stages of syphilis, is characterized by damage to large diameter myelinated primary afferents and consequent hyperalgesia

Question 42

Gate control theory

Answer 42

Nociceptive inputs open and non-nociceptive afferents shut a gate that leads to central transmission of noxious information. An essential aspect of the gate control theory and the analgesia produced by non-nociceptive afferent stimulation is the anatomical specificity. The segments of the spinal cord in which the involved nociceptive and non-nociceptive afferents terminate are linked to same region of the body. To assuage pain in the arm, you stroke your arm, not your leg.Nociceptive inputs open and non-nociceptive afferents shut a gate that leads to central transmission of noxious information. An essential aspect of the gate control theory and the analgesia produced by non-nociceptive afferent stimulation is the anatomical specificity. The segments of the spinal cord in which the involved nociceptive and non-nociceptive afferents terminate are linked to same region of the body. To assuage pain in the arm, you stroke your arm, not your leg.

Question 43

Stimulation of periaqueductal gray does what

Answer 43

Stimulation of the periaqueductal gray region (PAG) in the midbrain produces a powerful analgesia. Touch, pressure and temperature sensations persist and only pain sensation is attenuated. This procedure is called stimulation–produced analgesia.

Question 44

Periaqueductal gray pathway

Answer 44

PAG neurons project to nucleus raphe magnus in medulla > serotonergic neurons in this medullar region project to spinal cord via dorsal lateral funiculus > serotonin leads to inhibition of second order neurons of dorsal horn by exciting an inhibitory interneuron > interneuron uses enkaphalin as transmitter and inhibition is acheived presynaptically (block of VG Ca current) and post synaptically (opening of K channels)

Question 45

How do opiates work

Answer 45

Powerful analgesics: opiate receptors are found throughout the CNS and body. They are G protein coupled receptors which when activated lead to inhibition of the neuron on which they are found through inhibition of presynaptic Ca channels or opening of K channels

Question 46

Which brain region is particularly sensitive to opiates

Answer 46

Periaqueductal gray pathway- opiates inhibit inhibitory interneurons in PAG leading to greater excitatory output from PAG. Opiates also inhibit transmission in dorsal horn of spinal cord, thus direct administration to spinal cord produces analgesia without systemic side effects (constipation, euphoria, etc)

Question 47

What does Naloxone do

Answer 47

blocks analgesia produced either by PAG stimulation or central opiate administration. Cutting the dorsal lateral funiculus bilaterally produces the same effect

Question 48

What do endocannibinoids do

Answer 48

interact with receptors, cannabinoid receptors, (CBs), and modulate a wide variety of synapses leading to analgesic and psychosis-inducing effects as well as many other actions. Cannabinoids also interact with the opiate system, providing an additional way to modulate paininteract with receptors, cannabinoid receptors, (CBs), and modulate a wide variety of synapses leading to analgesic and psychosis-inducing effects as well as many other actions. Cannabinoids also interact with the opiate system, providing an additional way to modulate pain

Question 49

Describe stress induced analgesia

Answer 49

Stress leads to increased activity in the limbic system, which in turn leads to activation of the PAG which will ultimately lead to inhibition of second-order neurons of the dorsal horn in the pain pathway. It involves both opioid and non-opioid mechanisms.

Question 50

Describe the placebo effect

Answer 50

The PAG receives inputs from the limbic system and the cortex. If a patient expects to receive a pain-relieving drug, this could lead to activity in the neocortex and/or limbic system that would result in PAG activation through increased secretion of endorphins. Ultimately, this will lead to inhibition of the second-order neurons in the dorsal horn of the pain pathway

Question 51

Peripheral mechanisms of neuropathic pain

Answer 51

Following nerve damage, the expression, distribution and function of sodium channels is profoundly altered leading to spontaneous discharge of pain primary afferents. Tetrodotoxin resistant Na channels play a role in setting inflammatory pain thresholds. There will be an increase in Na channel density, decreasing threshold and causing spontaneous firing. As a result, sodium channel blockers are used to treat many forms of neuropathic pain following nerve injury.

Question 52

Central mechanisms of neuropathic pain

Answer 52

GABA: Following nerve injury, neuronal loss leads to reduced GABA content and decreased GABA and opiate receptors. This causes sensitization. Sprouting and rewiring: Following injury of C fibers, Ab afferents sprout and invade the normally forbidden territory of the substantia gelatinosa, so now second order neurons in substantia (which are normally activated only by pain) are also activated by non-noxious stimuli. Glia/immune cells: macrophages secrete TNF that binds to its receptor on sensory neurons and modulates function of TTX-resistant Na channels. In Dorsal horn, microglia secrete BDNF that changes Cl reversal potential making GABA excitatory rather than inhibitory.