Lecture 22: Pain Modulation

Question 1

Pain modulation types/vocab

Answer 1

• Analgesia: absence of pain (opioids)
• Anesthesia: (unaware of everything) absence of any sensory perception
• hyperalgesia/ hyperaesthesia: increased sensitivity to painful stimuli
• Allodynia: non-noxious stimulus activates nociceptors (clothing hurting on a sunburn)
• Dysthesia/paraesthesia: unpleasant, painful abnormal sensations (pinched nerve)

Question 2

nociception and transmission of pain can be altered by changes in the behavior of:

Answer 2

• Receptors
• Dorsal horn neurons
• Descending pathways (“I didn’t even feel it”)

Question 3

Changes at the nociceptor during inflammation

Answer 3

• Activates “silent nociceptors” which lowers the threshold.
• regular nociceptors also have a lower threshold. So, they respond sooner and more vigorously.
• inflammatory mediators have a direct stimulus to nociceptors (bradykinins).

hyperaesthesia at nociceptor underlies “root signature sign”

Question 4

Gate control theory

Answer 4

There are projection neuron responsive to both noxious and non-noxious stimuli in the dorsal horn. This neuron is one of many responsible for both and are referred to as: WDR: Wide dynamic range neurons. A primary pain neuron, likely a C fiber, synapses on the WDR. There are also touch receptors that are non-noxious associated with another primary afferent and also synapses on WDR. Non-noxious information is getting put in to compete for bandwidth… but there is more! The non-noxious neuron also has axon collaterals that activates a pool of interneurons that are inhibitory, that inhibitory neuron also causes inhibitory actions (axon-axonic conection)

Question 5

windup

Answer 5

So, on the regular, there is glutamate and glutamate binds to AMPA.
[Glutamate: primary afferent neuron release, binds to ligand gated ion receptor (AMPA). ]
If you keep up a bunch of glutamate long enough a second population of glutamate receptors becomes responsive NMDA and has conductance for Ca2+ ion which is an important second messenger at post synaptic membrane and causes it to respond more vigorously.

[Increased duration and intensity - lots of glutamate - then NMDA receptors (entire membrane in depolarization changes, conductance for calcium ions(second messenger) and calcium starts changing response to post synaptic membrane - makes it more sensitive to subsequent noxious stimuli - hence the phrase “wind-up”) — lasts hrs to days. ]

Can prevent wind-up during surgery if you do a nerve block. Afferents also releasing: other neurotransmitters and bind to metabotropic receptors (they don’t open to ions, have cascades) which can change delta genetic expressions… long term or possibly permanently (chronic pain states). In this case, months to permanently. Chronic pain states can be resistant to opioids.