Ephrins & Pain

Question 1

What are EphB receptors?

Answer 1

• Cell membrane proteins
• Belong to the largest subfamily of receptor protein-tyrosine kinase
• they bind to bind to ephrinB1-B3, which are transmembrane molecules.
• Crucial in embryonic development processes.

Question 2

What are ephrins?

Answer 2

• Ligands for EphB receptors.
• Also membrane-bound proteins.
• Activate EphB receptors through cell-to-cell interactions.

Question 3

What are the two types of EphB receptors, and what do they bind to?

Answer 3

EphA’s and EphB’s.
EphA’s bind to ephrinA1-5 (GPI anchor).
EphB’s bind to ephrinB1-B3 (transmembrane).

Question 4

Do EphB receptors have specific antagonists and agonists?

Answer 4

• EphB receptors do not have specific antagonists or agonists.
• They are promiscuous in binding to ligands with varying affinities.

Question 5

How is IgG used in regulating EphB receptors?

Answer 5

-Fc region of IgG attached to EphB receptors.
- Forms chimeric molecules
- Acts as an antagonist by preventing ephrin binding.

Question 6

Can chimeric molecules be created for ephrins as well?

Answer 6

• Yes, chimeric molecules can be made with ephrinB and IgG Fc.
• Acts as an agonist, but lacks specificity for target receptors.

Question 7

What are the effects of ephrinB2 on pain sensitivity in rats, and what does this suggest?

Answer 7

• EphrinB2 induces long-term structural changes in neurons
• Causes rapid hyperalgesia, implying involvement in central sensitization

Question 8

How do EphB receptors affect pain behaviour modulation?

Answer 8

• EphB receptors act as agonists or antagonists
• Involved in thermal hyperalgesia, mechanical allodynia, and neuropathic pain

Question 9

What is the role of EphrinB activation in chronic pain, both in onset and maintenance?

Answer 9

• EphrinB activation plays a crucial role in both the onset & maintenance of chronic pain.
• can rapidly increase pain sensitivity in DH of the spinal cord

Question 10

How are NMDA receptors related to EphrinB2-induced hyperalgesia?

Answer 10

• NMDA receptors are involved in chronic pain induction.
• Blocking NMDA receptors with MK801 can prevent the hyperalgesic effects of EphrinB2.

Question 11

How does EphB receptor activation rapidly increase responses in DH neurons?

Answer 11

• EphB receptor activation increases synaptic strength by recruiting the non-receptor tyrosine kinase src.
• Src phosphorylates NMDA receptor subunit NR2B, enhancing channel open probability and Ca influx.

Question 12

What activates ephrinB2 in nociceptive neurons and how does it affect pain?

Answer 12

• EphrinB2 is constitutively expressed but activated by strong stimuli, inflammation, or nerve injury.
• Activation leads to pain sensitization by recruiting more ephrinB2 to the cell membrane

Question 13

How are EphB receptors and ephrins altered in models of chronic pain?

Answer 13

• They interact more in chronic pain models
• More ephrinB2 is expressed in the presynaptic membrane, leading to EphB1 receptor activation and downstream effects

Question 14

Are EphB-ephrinB interactions involved in microglial activation?

Answer 14

• EphB-ephrinB interactions may not activate microglia.
• In ephB1 receptor KO mice, there is reduced activation of microglia.

Question 15

Do EphB receptors exist on peripheral terminals, and what role might they play?

Answer 15

• EphB receptors exist on peripheral terminals but their activation triggers are unknown.
• Their role in pain onset & effects on central or peripheral receptors need further study

Question 16

What are the various mechanisms that can produce pain?

Answer 16

nociception, inflammation, nerve damage, peripheral and central sensitization, ectopic excitability & decreased inhibition.

Question 17

How do ephrins and Eph receptors interact, and what type of complex is formed?

Answer 17

• Ephrin-Eph interaction requires cell-to-cell contact and results in the formation of a tetrameric complex.
• Each ligand interacts with two receptors, and each receptor interacts with two ligands

Question 18

What evidence suggests the involvement of ephrins and Eph receptors in pain modulation?

Answer 18

• that ephrins and Eph receptors are involved in the modulation of different types of pain.

Question 19

How are ionotropic NMDA receptors related to nociceptive signaling and chronic pain development?

Answer 19

• Ionotropic NMDA receptors play a significant role in nociceptive signaling and are implicated in the primary mechanisms for the development of chronic pain through central sensitization

Question 20

What happens when C fibers fire for an extended period, and how does it relate to sensitization?

Answer 20

-Prolonged firing of C fibers leads to the release of glutamate, which activates NMDA receptors in the spinal cord.
- Activation of these receptors makes spinal cord neurons more responsive to all inputs, resulting in sensitization.