Biology 6

Advanced Concepts in Pain

  • Focus on congenital analgesia and analgesic drug discovery.

  • Presenter: Lodewijk Dekker

Lecture Aims

  • Understand the importance of pain in human experience.

  • Recognize consequences of pain insensitivity.

  • Explore genetic causes of congenital analgesia.

  • Learn how congenital analgesia informs analgesic drug development.

Congenital Analgesia 선천성 진통제

  • Definition: inability to feel pain due to genetic factors.

  • Common Misconceptions: Pain is often viewed only negatively, though it serves protective functions.

  • Historical Background: First reported in 1932 with cases showcasing individuals completely devoid of pain sensation.

  • Notable Case: Edward H Gibson, known as 'the Human Pincushion' in the 1920s, demonstrated a lack of pain sensation despite injuries.

Similar Cases in Modern Context

  • Instances reported in Pakistan involving children exhibiting severe injuries without pain sensation.

  • Example of a 10-year-old with unaddressed lip and tongue injuries.

  • Notable to differentiate between pain insensitivity and normal sensory responses (pressure, temperature).

Genetic Analysis of Congenital Analgesia

  • Chromosomal focus: 2q24 region linked to congenital analgesia.

  • Key Gene Identified: SCN9A, responsible for the voltage-gated sodium channel Nav1.7, crucial in pain pathways.

  • Reference: Cox et al., Nature (2006) discusses Nav1.7's importance.

Further Studies on Nav1.7

  • Genetic deletion studies in mice confirmed Nav1.7's role in pain signaling.

  • Concept: Designing inhibitors that mimic the loss-of-function of Nav1.7 can lead to effective analgesic strategies.

Gain of Function Mutations in Nav1.7

  • Certain mutations can cause heightened pain sensitivity (e.g., inherited erythromelalgia).

  • Symptoms can be elicited by non-painful stimuli, suggesting complex Na+ channel activity.

  • Treatment options such as carbamazepine for paroxysmal pain disorder show the therapeutic implications of Nav1.7 mutations.

Mutations in Other Sodium Channels (Navs)

  • Nav1.9 mutations also linked to congenital insensitivity to pain.

  • Complex interaction with Nav1.7 and Nav1.8 channels affecting nociceptive signaling.

  • Specific mutation patterns observed in inflammatory bowel disease (IBD) patients.

Importance of Pain

  • Pain serves as a biological function to prevent further injuries and ensure survival.

  • Proteins like Nav1.7 are critical for understanding pain signaling and drug targeting.

Mechanism of Action

  • Initiation of action potentials through sodium channel activity.

  • Nav1.7 serves as the primary responder during mild depolarization; Nav1.8 contributes to the overall action potential.

Voltage-Gated Sodium Channel Blockers

  • Channels can exist in various states; understanding this is crucial for targeting pain effectively.

  • Different drug mechanisms include pore blockers and gating modifiers.

Nav1.7 Inhibitor Discovery

  • TTX toxin inhibits Nav1.7 but lacks specificity, raising safety concerns.

  • Clinical developments: State-dependent selective blockers under trial phases, demonstrating efficacy in certain pain conditions.

Developments in Nav1.8 Inhibitors

  • Ultra-selective Nav1.8 blockers show improved clinical outcomes in cases of postoperative pain with minimal side effects.

Other Proteins Related to Congenital Analgesia

  • Investigate proteins NTRK1, NGF, PRDM12, and ZPHX2 for potential treatment pathways.

  • Targeting these proteins may reveal new analgesic therapies.

NGF Antibodies Development

  • NGF antibodies neutralize nerve growth factors, showing promise for pain management in clinical trials, although resulted in safety concerns and trials halted in 2021.

Conclusion

  • The ability to feel pain is integral to human physiology.

  • Understanding mutations in pain-related proteins presents opportunities for drug development.

  • Current drug efficacy and future directions remain challenges.