Pain and temperature - anterolateral system Flashcards Preview

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Flashcards in Pain and temperature - anterolateral system Deck (60):
1

Cool receptors are geared to what temperature?

• 10-37 degrees C
• Way more of these (10X) than warm receptors

2

Warm receptors are geared to what temperature?

• 30-48 degrees C

3

How do temperature receptors encode intensity?

• Intensity of temperature sensation is encoded in the frequency in which the receptors fire action potentials

4

At what temperature do cold and warm receptor afferents have similar firing rates?

• 33 degeres celsius, or the thermoneutral point

5

How does the body both recognize a change in temperature and absolute, steady temperature?

• Change in temperature is encoded in the transient frequency of warm and cold receptors
• After a new steady state is reached there is a consistent frequency of afferent firing which gives us the sense of absolute temperature

6

Typically, warm and cool receptor afferents are associated with what class of fibers?

• Warm - C fibers
• Cool - a-delta

7

Temperature afferents synapse where first?

• DRG and trigeminal neurons send axons into the CNS and form a first synapse in the dorsal horn of the spinal cord and the spinal trigeminal nucleus, respectively
• The sensory neurons in the periphery are considered first-order neurons and the contacted neurons in the CNS 2nd order
• 2nd order neurons synapse in thalamus
• 3rd order neurons from thalamus to cortex

8

The spinothalamic tract is what?

• Conscious appreciation of skin temperature
• Follow the temperature afferents from skin to cortex and that's the spinothalamic tract

9

What is the spinoreticular tract?

• Conveys information via the reticular formation to the hypothalamus
• Information important for control of body temperature (ANS)

10

What tracts does the anterolateral system contain?

• Spinothalamic, spinoreticular and spinomesencephalic tracts
• That's ANS thermoregulation and temperature sensation
• Describes the midline switching of these fibers and anterolateral spinal cord localization

11

The spinothalamic tract carries what where?


• A Principal pathway and conveys pain information to the thalamus
• Projects to the nuclei of the ventrobasal thalamus, including VPL
• Neurons in these nuclei process information related to localization of pain and project to somatosensory cortex

12

The spinomesencephalic tract projects what where?

• Projects to midbrain periaqueductal gray region (PAG)
• Important for descending control of pain

13

The spinoreticular tract projects what where?

• Conveys pain inputs that lead to forebrain arousal and elicits emotional/behavioral responses via connections to the emotional circuits of the brain
○ Limbic system
• Terminates in the medulla and pons, the site of the reticular formation

14

What cortical regions are involved in pain sensation and control?

• Cingulate gyrus and insular cortex
• Cingulate is part of limbic system and is involved with emotional component of pain
• Insular cortex is a processing center for the autonomic component of pain

15

How are pain receptors classified?


• Based on the stimuli that activate them

16

Extreme cold temperatures are typically associated with what classificaiton of fiber?

• C fibers
• Polymodal nociceptors that are activated by high intensity mechanical, chemical or thermal stimuli are in this category too

17

Extreme hot temperatures are typically associated with what classificaiton of fiber?

• A-delta
• Intense pressure and mechanical nociceptors are also A-delta

18

Thermal nociceptors are activated when?

Thermal nociceptors are activated when?
• Extreme temperatures
• Less than 5 degrees celsius
• More than 43 degrees celsius

19

What is the vanilloid receptor?

• Vanilloid moiety-containing compounds activate it, and thus the name
• Type of molecular receptor for pain
• VR-1 = capsaicin receptor
• Strongly activated by capsaicin and weekly by acid
• Also activated by moderate heat (43 degrees C)
• Expressed on polymodal nociceptors

20

What do acids and ATP have to do with nociceptors?

• They are ligands for NSC's on nociceptors
• ATP opens ionotropic P2X receptors
• Acid-sensing channels are known as ASICs, 4 different ones expressed in C fiber nociceptors

21

Difference between A-delta and C fibers?

• Both are small and not fully myelinated
• C are smaller and slower and have no myelination
• A-delta are still small but lightly myelinated
• A-delta have smaller receptive fields
○ Leads to spatial discrimination

22

Pain is sensed as 2 types separated by time

• First comes a tolerable localized pricking pain
○ A-delta fiber
• Then comes a burning intolerable, diffusely localized pain
○ Burning pain is C fiber pain

23

Why, with increasing pressure does the sensation profile change?

• Has to do with metabolically active (related to size) of the fibers
• A-alpha and A-beta fibers are cut-off by pressure first because they are faster to respond to hypoxia
○ Lost proprioception, light touch, vibration and motor
• A-delta fibers are next, leaving only C fibers and purning pain is left

24

Describe the dose-related effect of anesthetics

• Lower doses are preferential for smaller fibers
• Burning pain first
• Pricking pain second
• Motor last with high doses

25

What molecules are activators of pain receptors?

• Bradykinin is the classic example
• Comes from cleavage of inactive precursor that only happens with necrosis and cytoplasmic enzymes being spewed out
• Potassium, acid and serotonin are also activators
• Bradykinin activates directly A-delta and C nociceptors (pricking and burning pain)

26

Describe the process of sensitization

• Lowers the threshold for a nociceptor to fire an action potential
• Makes it easier to feel pain in an injured area
• Substance P is released by C fibers that are activated for long periods of time
• ATP, ach and 5-HT are sensitizers separately or together
• Activators and sensitizers are often present together

27

How does aspirin help with pain?

• By inhibiting the production of prostaglandins, it inhibits the sensitization of nociceptors

28

Hyperalgesia?

• Sensitiaztion of nociceptors is known as primary hyperalgesia
• Mechanism leading to the increased sensitivity to pain occurs at the first site of the pathway
• Allodynia is such a sensitization that non-noxious stimuli trigger pain

29

Reddening, wheal and flare come together to form…

• The triple response
• Bradykinin plays an important role
• Tissue damage leads to local production of bradykinin
• Bradykinin is both vasodilator and activator
○ Heat and redness
• Also increased capillarly permeability, leading to the edema in a wheal
• Around the inflamed area is the pink-colored flare
• Remember that C fibers have large receptive fields and poorly localized signals and that is largely from a large and complex network of terminals
• C fiber action potential goes toward cell body but also to the collateral terminals in ever-peripheral locations
• Substance P produces vasodilation but lesser extent than bradykinin
• "axon reflex"

30

Describe how the "axon reflex" creates the flare in an injured skin location.

• Remember that C fibers have large receptive fields and poorly localized signals and that is largely from a large and complex network of terminals
• C fiber action potential goes toward cell body but also to the collateral terminals in ever-peripheral locations
• Substance P produces vasodilation but lesser extent than bradykinin
• "axon reflex"

31

Why does the flare hurt, even though its pretty far away from the injury site?

• The flare is created by vasodilation by substance P
• Substance P is a sensitizer of nociceptors
• Thus, less stimulus is needed to activate a nociceptor in the flare

32

What's up with modality segregation in pain sensation?

• C fibers terminate in the supstantia gelatinosa in the dorsal part of the spinal cord
• Nociceptive afferent fibers form synapses in the dorsal horn of the spinal cord, bu they are organized based on modality
• There is preservation of a certain modality signal all the way to the cortex
• They segregate into different regions of the dorsal horn (laminae)
• C fiber afferents terminate in the Rexed's laminae

33

In general, when thinking about a 2nd order neuron in the pain pathway we are talking bout

• Neuron with cell body in substantia gelatinosa that recieves input from C fibers

34

Substantia gelatinosa is also known as

• Rexed's lamina II

35

Describe: "there is a convergence of inputs at the level of the dorsal horn neuron".


• Some pain-activated dorsal horn neurons receive inputs from cutaneous as well as visceral pain afferents
• The mixing of signals is the basis of referred pain
• Few if any dorsal horn neurons are dedicated to visceral pain alone

36

What are some common referred pain examples?

• Anoxia in heart muscle is referred to upper chest wall, left arm and hand
• Gallbaldder pain is referred to the scapula
• Uretral pain (nephroliathisis) referred to lower abdominal wall
• Bladder pain is referred to perineum
• Inflamed appendix gives rise to referred pain in the periumbilical anterior abdominal wall

37

If a dorsal horn neuron shares pain information between visceral and cutaneous, and both are firing, which one wins?

• Cutaneous has greater representation and smaller receptive fields
• Few if any dorsal horn neurons are dedicated to visceral pain
• Thus, cutaneous pain wins out

38

Why can glutamate evoke two different types of potentials in the dorsal horn neurons?



• AMPA and NMDA receptors both
• AMPA is fast, NMDA is slow

39

What does NMDA receptor activation in nociceptors lead to in the long term?

• Long lasting changes in excitability
• Phosphorylation by PKC and tyrosine kinases
• Removes requirement for depol. To activate
• They essentially become AMPA at that point
• Central sensitization

40

What's the "wind-up" in C fibers?

• Glutamate at first just opens AMPA
• If there is a prolonged and intense stimulus, NMDA will open too
• The result is a larger post-synaptic response which is the wind-up
○ Form of central sensitization

41

In the dorsal horn, what neurotransmitters are being used to convey painful stimuli?

• The pre-synaptic nociceptor will release glutamate
• It will also release substance P in a prolonged stimulation
• Substance P blocks potassium channels
• Central sensitization
*this form of sensitization is broader and lasts longer because substance P is not taken up into glial cells like glutamate

42

Trace the nociceptors through the trigeminal system.

• Pain and temperature inputs from head and neck
• Trigeminal ganglion neurons with central axons entering CNS at level of pons and descent to a caudal position before forming firs synapses
• Spinal trigeminal nucleus is site of first synapse
• Functionally analogous to dorsal horn of spinal cord
• From there they cross the midline and go to thalamus

43

Why does rubbing an owie help with pain?

• At the level of dorsal horn synapse
• When rubbing, activating non-nocieptive afferent pathways
○ Touch and a-beta fibers
• This leads to activation of dorsal horn interneurons that inhibit the inputs of nociceptive fibers

44

What does the condition tabes dorsalis show?

• Tabes dorsalis is a symptom of advanced syphilis
• Characterized by damage to large diameter myelinated primary afferents
• The result is hyperalgesia
• The converse of TENS, shutting down a-beta fibers will lead the dorsal horn neurons to listen to nothing but nociceptor inputs
• Illustrative as gate control theory

45

What therapy modality claims it is stimulating A-beta fibers preferentially to suppress pain?

• TENS - transcutaneous electrical nerve stimulation
• Selective activation of a-beta fibers
• This leads to activation of dorsal horn interneurons that inhibit the inputs of nociceptive fibers

46

Stimulation produced analgesia involves what area of the CNS?


• Periaqueductal gray region - PAG (midbrain)
• Example of DESCENDING control of pain
• The gate control theory is ascending control pain
• The only information getting through is touch pressure and temp, only pain is attenuated

47

How does PAG stimulation result in analgasia? (trace the pathway)

• PAG - periaqueductal gray region - midbrain
• Neurons project to nucleus raphe magnus in medulla
• Neurons in medullar region are serotonergic and project to spinal cord via the dorsal lateral funiculus
• In spinal cord, serotonin leadst o inhibition of 2nd order neurons of dorsal horn
• Excites inhibitory interneurons that use enkaphalin
• Enkaphalin is an endogenous opiate
• Blocks voltage gated calcium current in pre-synaptic cell and opens potassium channels in post-synaptic cell
○ In the dorsal horn pain pathway that is
• Thus SSRIs are sometimes used to treat chronic pain conditions

48

Sometimes depression and chronic pain are treated with the same drug. What's up with that?

*the main concept is that descending pain control is serotonin-mediated. keeping serotonin around longer means more downward suppression of pain in dorsal horn spinal cord neurons
• PAG - periaqueductal gray region - midbrain
• Neurons project to nucleus raphe magnus in medulla
• Neurons in medullar region are serotonergic and project to spinal cord via the dorsal lateral funiculus
• In spinal cord, serotonin leadst o inhibition of 2nd order neurons of dorsal horn
• Excites inhibitory interneurons that use enkaphalin
• Enkaphalin is an endogenous opiate
• Blocks voltage gated calcium current in pre-synaptic cell and opens potassium channels in post-synaptic cell
○ In the dorsal horn pain pathway that is
• Thus SSRIs are sometimes used to treat chronic pain conditions

49

Activation of an opiate receptor in the CNS will generally do what?

• Inhibit that's neurons firing
• If they are on a neuron, they play an inhibitory role

50

Naloxone does what?


• Blocks opiates binding opiate receptors in CNS
• Blocks analgesia produced by PAG or central opiate admin

51

What are endogenous opiates?

• Enkephalins
• Beta-endorphin (endorphins)
• Dynorphins (endorphins)

52

What happens if you cut the dorsal lateral funiculus bilaterally?

• This is the tract of neurons from PAG to dorsal horn interneurons
• If cut bilaterally both stimulation-produced and systemic opiate-induced analgesia re blocked
• Thus PAGE simulation and systemic opiate admin involve the same descending pathway

53

What do cannabinoids do?

• Endogenous version of THC
• Endocannabinoids interact with cannbinoid receptors
• Modulate a wide variety of synapses leading to analgesic and psychosis-inducing effects
• Also interact with opiate system and thus modulate pain

54

What is the theory behind stress-induced analgesia

• Under stress, hyperactivity of limbic system activates PAG
• Leads to inhibition of 2nd order neurons in dorsal horn pain pathway
• But naloxone blocks some, not all of stress-induced analgasia
• Thus there is opiate receptor AND something else

55

The placebo effect is blocked by what?

• Naloxone, which blocks opiate receptors
• Thus, placebo effect is limbic system - PAG invovled

56

Sodium channel blockers can be used in cases of neuropathic pain. What's up with that?

• Part of the process of neuropathic pain is sodium channel-dependent
• TTX and TTX-resistant sodium channel types
• ATP will lead to activation of the TTX-resistant sodium channels preferentially
○ Leads to sensitization and more pain in injured area
• After nerve injury the expression profile of sodium channels goes haywire and there can be stimulus-INDPEDENDENT opening of channels and firing of pain action potentials
• Blocking all sodium channels helps, but there are obvisoulsy cross over side effects

57

The human disease familial primary erythermalgia is a problem with what?

• Neuropathic pain because of a sodium channel problem
• Mutation in SCN9A gene, TTX-resistant sodium channel

58

In terms of GABA, what happens in some cases of injury turning into neuropathic pain?

• Injury to C fibers will result in GABA supply going silent
• Without post-synaptic modulation or "signal" the neurons will start atrophying
• In the dorsal horn this results in neuronal loss, a reduction in GABA content and ecreased numbers of GABA and opiate receptors
• Such changes will lead to a reduction in inhibtion of dorsal horn neurons
• Treat this problem with opiates and GABA-A receptor agonists

59

What's up with sprouting and rewiring in neuropathic pain?

• Normally substantia gelatinosa is dedicated to C fibers (nociceptors)
• There is also an inhibitory interneuron circuit in place for gate control and descending control
• Damage to C fibers means that A-beta fibers (non-nociceptors) will sprout and fill in the vacuum of dying C fibers
• End result is non-noxious stimuli tell the dorsal horn neurons there is pain (when there isnt')

60

How can immune cells and glia maintain and worsen neuropathic pain?

• In the context of injury, macrophages will mediate inflammatory response in DRG
• Release of TNF binds TNFR1
○ Preferentially modulates TTX-resistant sodium channel, linked to pain sensitization
• Also, ATP (from cell damage) will modulate astrocytes to release BDNF
○ Change in chloride reversal potential
○ Now GABA activation (inhibition normally) leads to excitation
• End result is decreasing inhibition of pain pathway

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