Transmission of Pain

Question 1

What differentiates sensory neurons?

Answer 1

They are in the dorsal horn of the spinal cord.

Substantia gelatinousa is where we are focused on for pain pathways.

Question 2

How are pain signals transmitted into the central nervous system? What anatomic sites and neurochemicals are of potential significance for pain transmission or endogenous regulation of pain?

Answer 2

The pain signals are transmitted through the spinal cord, through the substantial gelatinosa. The anatomic sites that these neurons synapse on are called lamina, and vary based on type. C fibers synapse in the substantial gelatinosa, and A-delta fibers synapse in lamina 1, 2, or 3. The WDR neurons are most endogenously regulated. Substance P, CGRP, and glutamate are used in pain transmission.

Question 3

How might normal pain processing be disrupted? How could these disruptions result in chronic or neuropathic pain?

Answer 3

There are three mechanisms that show how chronic or neuropathic pain can be generated.

1. Abnormal processing
2. Loss of inhibitory interneurons
3. Sensitization

Question 4

What are secondary neurons?

Answer 4

They are neurons that send a signal to the brain. There may be one or more connections on the way.

Question 5

What are the Rexed lamina?

Answer 5

They are cells of the brain that defined functionally and anatomically. 2 and 3 make up the substantial gelatinousa. Huge areas for interactions of pain-conducting neurons that will eventually send a signal to the brain.

Question 6

What are secondary neurons?

Answer 6

They are neurons that send a signal to the brain or brainstem. There may be one or more connections between the primary afferent and the secondary neuron on the way.

Question 7

What are the most important secondary neurons?

Answer 7

Wide dynamic range neurons. The run all the way to the brain or brainstem. They are most easily regulated by us/highly regulated by endogenous systems.

Question 8

What part do the microglia and astrocytes have in pain transmission?

Answer 8

They are equivalent to immune competent cells in the initiation phase. Therefore they have a role in sensitization of receptors and lowering the depolarization threshold.

Question 9

Where do A-delta fibers synapse? Which pathway are the neurons that they activate located in?

Answer 9

They synapse in lamina 1, 2, or 3. The neurons that A-delta fibers activate are located in the neospinothalmic pathway, which go to the thalamus.

Question 10

Where do A-delta fibers synapse? Which pathway are the neurons that they activate located in?

Answer 10

They synapse in lamina 1, 2, or 3. The neurons that A-delta fibers activate are located in the neospinothalmic pathway, which go to the thalamus.

Question 11

Where do the C fibers synapse? Which pathway are the neurons that they activate located in?

Answer 11

They synapse in the substantial gelatinosa. They activate the paleospinalthalmic pathway.

Question 12

What is the difference between neuropeptides and neurochemicals in terms of speed of transmission?

Answer 12

The neurochemicals (like glutamate) are rapid (pop open Na channels), while neuropeptides such as CGRP and substance P provide sustained depolarization, and tend to build behind glutamate.

Question 13

What receptor is used to regulate Substance P?

Answer 13

NK1 receptor

Question 14

What are examples of three endogenous regulators released by interneurons that synapse on the NK1 receptor that suppress the pain signal perceived at the brain?

Answer 14

NE
GABA
Endogenous opioid (enkephalin)

Question 15

How do the interneurons that influence the signal sent by WDR neurons regulate?

Answer 15

They usually have an axon projecting from the brainstem to the dorsal horn to release the endogenous regulators.

Question 16

What do glial cells do?

Answer 16

They are there to cause sensitization.

Question 17

What is wind-up?

Answer 17

It is abnormal processing, one of three mechanisms for chronic pain(assuming neuropathic pain is a type of chronic pain). Sustained stimuli causes glutamate to be released in high amounts (CGRP and substance P come behind). AMPA channels are what glutamate preferentially bind to. NMDA channels are what glutamate binds to when AMPA are full. Ca as well as Na come in with open NMDA channels. Huge increases in calcium activates kinases (causing phosphorylation of channels, causing them to stay open longer). This also causes changes in gene expression in how the neuron functions. Both changes cause wind-up (with a lot of potential energy). Sensitizes postsynaptic terminal, so that much less glutamate is needed to cause significant and high-frequency firing of the WDR neuron.

Question 18

What is the loss of inhibitory neurons/disinhibition?

Answer 18

It is one of three mechanisms for chronic pain (assuming neuropathic pain is a type of chronic pain). There is always some tonic inhibition going on.

Question 19

Where do opioids act?

Answer 19

They mimic endogenous opioids released from interneurons that act on presynaptic and postsynaptic G-coupled receptors. presynaptically they decrease Ca+ influx to help not depolarize the cell, and work postsynaptically to increase potassium influx to hyper polarize the cell, making it harder to generate an action potential. So they work to decrease pain transmission though this mechanism.

Question 20

Where are there the most opioid receptors?

Answer 20

In the spine, specifically the substantial gelatinosa.

Question 21

How do adrenergic agents inhibit pain?

Answer 21

They mimic NE release from inhibitory interneurons that work to inhibit pain transmission. They are in the same pace and have the same action as opioid receptors (decrease calcium presynaptically and increase potassium postsynaptically).

Question 22

What adrenergic agents are used to inhibit transmission?

Answer 22

Alpha2 agonists, NE reuptake inhibitors, mixed action agents, and GABA.

Question 23

What alpha2 agonists are used to inhibit transmission? Common side effects?

Answer 23

Clonidine (used for synergism with opioids, lowers bp) or dexmedetomide (significant sedation)

Question 24

What NE reuptake inhibitors are used to inhibit transmission?

Answer 24

TCA’s, SNRIs (not SSRIs - serotonin reuptake inhibition not effective). Nortiptyline is more selective than amitriptyline, can be agent of choice. Is more excitatory.

Question 25

What mixed action agents are used to inhibit transmission?

Answer 25

tramadol and trapentadol. These have opioid actions as well as NE reuptake inhibition. Tramadol even has some serotonin reuptake inhibition in the R,R enantiomer.

Question 26

How does GABA work to inhibit transmission?

Answer 26

When GABA is released from the interneuron it interacts with GABA-B receptors, which seem to have the same action on calcium and potassium as opioids (especially calcium). GABA-a receptors open chloride channels that also make it harder for the post-synaptic cell to depolarize.

Question 27

What does dysfunction of GABA systems tend to lead to? Are there any GABA selective drugs?

Answer 27

Hyperalgesia. No GABA selective drugs, maybe baclofen.

Question 28

What type of drugs are gabapentin and pregabalin? Where do they bind to?

Answer 28

They inhibit transmission through blocking calcium channels (as well as ziconotide used intrathecally to do a nerve block). They bind to the alpha2 subunit of the calcium channel to close it, and then decrease calcium flow that way.

Question 29

Which drugs inhibit voltage-gated sodium channels? What is known about the mechanism?

Answer 29

Lidocaine, carbamazepine, mexilitine, and lamotrigine. Bind to sodium channels, leave inactive. The precise mechanism is not known, but there are sodium channels on C fibers that overlay with substance P (1.7 and 1.8).

Question 30

Which drugs inhibit transmission through NMDA receptor blockade?

Answer 30

Ketamine, methadone, dextromethorphan, memantidine. Blocks wind-up, may be a reason to use methadone for neuropathic pain.

Question 31

What do cannabinoids do to block transmission?

Answer 31

Similar to opioids mechanistically. CB1 act like opioid receptors (calcium pre, potassium post). Not very effective as analgesics. CB2 actions are to decrease release of immunologic mediators that cause sensitization. Cannabidiol doesn’t act at CB1 or CB2 receptors.

Question 32

How do NSAIDS inhibit transmission?

Answer 32

They inhibit the synthesis of prostaglandins (which would be released to cause sensitization). Central and peripheral effects.

Question 33

What is the mechanism of opioids? How does this differ from mechanisms at peripheral sites?

Answer 33

Opioids presynaptically to lower calcium influx, and postynaptically to increase potassium efflux. This decreases the likelihood of depolarization. This is different from peripheral site mechanisms where sensitization can occur with inflammatory mediators that may make it easier to set off an action potential, or wind-up that also changes how the neuron is set up and increases the likelihood of an action potential.

Question 34

If changes lead to decreased effectiveness of opioids, why might other options be helpful?

Answer 34

Because opioids have one mechanism of action, and drugs like alpha2 agonists, calcium-channel blockers, sodium-channel blockers, GABA, mixed agents, NMDA receptor blockers, NSAIDs, etc. have different ways of working. Some medications might respond to different types of pain more than others, and sensitization in one area may not carry over into another mechanism.

Question 35

How does the gate theory offer a mechanistic rationale for complementary therapies in pain management?

Answer 35

The gate theory proposes that counter-irritants or things like massage may stimulate large nerve fibers (like A-alpha pr A-beta), which also stimulates the inhibitory interneuron.

Question 36

How do the non-opioid mechanism compare to opioids?

Answer 36

Alpha2 agonists: same as opioids
Reuptake inhibitors: adrenergic agonists act like NE, which act the same as opioids
Mixed action: opioid action and NE reuptake, same as opioid
Ca channel blocker: Indirect and direct blockade (GABA-B indirectly on calcium channels, GABA-A on chloride post-synaptically)(gabapentin directly on alpha2 subunit to close channel)
Na channel blocker: different: inactivates sodium channel
NMDA antagonist: blocks wind-up from occurring (analgesic or maybe blocks opioid tolerance)
NSAIDS: halts prostaglandin synthesis