Pain detection

Why is pain important?

- Raises awareness of damage.

- Help immobilise damaged areas to facilitate healing.

What are the types of pain?

- Somatic

- Visceral

- Neuropathic

- Sympathetically-maintained pain

Describe somatic pain.

- From skin/musculoskeletal tissue or peritoneal membranes.

- Post-operative, post-exercise, mild trauma.

Describe visceral pain.

- The thoracic or abdominal organs.

- Post-operative, cancer-related, traumatic injury.

Describe neuropathic pain.

- From injury to the peripheral or CNS.

- Amputation, type 2 diabetes.

Describe sympathetically-maintained pain.

- Sensitisation of CNS causes neuropathic-like pain in distribution of a sympathetic nerve.

- Complex regional pain syndromes (CRPS).

What is nociception?

- Detection of noxious stimuli.

- Sufficient enough to trigger reflex withdrawal, autonomic responses and pain.

- Nociceptors detect this.

- Pain is subjective, with emotional components.

What are the types of noxious stimuli?

- Mechanical

- Thermal

- Polymodal

What are examples of mechanical noxious stimuli?

- Pinching

- Cutting

- Crushing

What are examples of thermal noxious stimuli?

Extreme temperatures (hot and cold)

What are examples of polymodal noxious stimuli?

Variety of damaging stimuli

Describe nociceptors.

- Free nerve endings

- Detect noxious stimuli.

- Perception of pain is modifiable.

Whar does afferent and efferent mean regarding nerve fibres (nociceptors)?

- Afferent means carries signals to CNS e.g., from skin to brain.

- Efferent means carries signals from CNS to muscles/skin to cause action e.g., move arm away from heat.

What are the types of nerve fibres in peripheral nociception?

- A

- B

- C

Describe A fibres.

- 2-20 micrometers

- They are myelinated.

- 4 subtypes: Aα, Aβ, Aγ, Aδ

What is Aδ fibres associated with?

Aδ are associated with nociception (afferent pain, cold, temperature, tissue damage)

What is Aβ fibres associated with?

Afferent, innervate muscle, touch sensation, pressure sensation

What is Aγ fibres associated with?

Efferent, muscle. spindle tone.

What are C fibres associated with?

Nociception

What types of nociceptors carry noxious stimuli?

- Aδ

- C

Where are Aδ fibers found?

In the skin

What is first pain?

- Rapid and sharp

- Forces movement away from danger.

- Informative pain.

- Aδ fibres mediates this.

What is second pain?

- Slow and dull

- Punishing pain

- Changes behaviour.

- C fibres mediate this.

How are nociceptors activated?

- Tissue trauma → release of mediators (e.g. ATP, bradykinin, prostaglandins) → nociceptor activation

- H⁺ ions lower local pH, further stimulating nociceptors

- Activated nociceptors release CGRP, substance P, and NGF, which promote vasodilation and immune cell activation

- This triggers the firing of action potentials that travel to the CNS, where pain is perceived

How are ion channels involved with nociceptor activation?

- TRPV1 channels respond to H⁺ ions, noxious heat (≥43°C), capsaicin, and endovanilloids, allowing Na⁺ and Ca²⁺ influx, leading to depolarisation.

- ASIC channels are activated by H⁺ ions, P2X channels respond to high ATP levels, both contributing to nociceptor depolarisation.

- Depolarisation opens voltage-gated Na⁺ channels, triggering an action potential.

What GPCRs support nociceptor activation?

- B2 receptor

- Prostanoid receptor

- Inhibitory GPCRs

How do B2 GPCRs support nociceptor activation?

- Bradykinin can bind to B2 GPCR leading to activation of protein kinase C.

- PKC then phosphorylates TRPV1 opening them allowing Na+ and Ca2+ to enter, enhancing depolarisation.

How do prostanoid GPCRs support nociceptor activation?

- Bradykynin can also stimulate Prostaglandins release.

- Prostaglandin can bind to prostanoid receptors leading to activation of protein kinase A.

- PKA phosphorylates voltage gated Na+ channels enhancing depolarisation of nociceptor.

- Also inhibits K+ channels preventing their movement out of neurone, supporting depolarisation.

What is NGF?

NGF (nerve growth factor) is a protein that promotes the growth, survival, and sensitisation of sensory neurons, especially pain-related nociceptors, playing a key role in inflammation and chronic pain.

How does NGF support nociceptor activation?

- Binds to TrkA leading to increased activity of TRPV1 and voltage gated Na+ channels.

- This supports depolarisation aiding action potential generation.

Summary

- Nociceptors (Aδ and C fibres) detect tissue trauma and noxious stimuli like prostaglandins, bradykinin, and H⁺ ions.

- H⁺ ions lower pH, activating TRPV1 channels, allowing Na⁺ and Ca²⁺ influx and neuronal depolarisation.

- ASIC and P2X channels are also activated by H⁺ and ATP, further supporting depolarisation.

- Bradykinin binds to B2 GPCRs, activating PKC, which phosphorylates TRPV1, increasing its activity.

- Bradykinin also promotes prostaglandin release, which activates prostanoid GPCRs, triggering PKA to phosphorylate voltage-gated Na⁺ channels and inhibit K⁺ channels, enhancing excitability.

- NGF binds to TrkA receptors, increasing TRPV1 sensitivity and promoting Na⁺ influx and depolarisation.