Pain and temperature - anterolateral system Flashcards
Cool receptors are geared to what temperature?
- 10-37 degrees C
* Way more of these (10X) than warm receptors
Warm receptors are geared to what temperature?
• 30-48 degrees C
How do temperature receptors encode intensity?
• Intensity of temperature sensation is encoded in the frequency in which the receptors fire action potentials
At what temperature do cold and warm receptor afferents have similar firing rates?
• 33 degeres celsius, or the thermoneutral point
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
Typically, warm and cool receptor afferents are associated with what class of fibers?
- Warm - C fibers
* Cool - a-delta
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
The spinothalamic tract is what?
- Conscious appreciation of skin temperature
* Follow the temperature afferents from skin to cortex and that’s the spinothalamic tract
What is the spinoreticular tract?
- Conveys information via the reticular formation to the hypothalamus
- Information important for control of body temperature (ANS)
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
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
The spinomesencephalic tract projects what where?
- Projects to midbrain periaqueductal gray region (PAG)
* Important for descending control of pain
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
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
How are pain receptors classified?
• Based on the stimuli that activate them
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
Extreme hot temperatures are typically associated with what classificaiton of fiber?
- A-delta
* Intense pressure and mechanical nociceptors are also A-delta
Thermal nociceptors are activated when?
Thermal nociceptors are activated when?
• Extreme temperatures
• Less than 5 degrees celsius
• More than 43 degrees celsius
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
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
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
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
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
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
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)
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
How does aspirin help with pain?
• By inhibiting the production of prostaglandins, it inhibits the sensitization of nociceptors
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
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”
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”
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
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
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
Substantia gelatinosa is also known as
• Rexed’s lamina II
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Naloxone does what?
- Blocks opiates binding opiate receptors in CNS
* Blocks analgesia produced by PAG or central opiate admin
What are endogenous opiates?
- Enkephalins
- Beta-endorphin (endorphins)
- Dynorphins (endorphins)
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
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
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
The placebo effect is blocked by what?
- Naloxone, which blocks opiate receptors
* Thus, placebo effect is limbic system - PAG invovled
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
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
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
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’)
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
