The Nociceptive System and Pain Perception The Peripheral Nervous System 2

Question 1

Examples of Transmitters and Inflammatory Mediators

- Neurotransmitter for A delta and C fibres

Answer 1

released centrally & peripherally
Substance P (SP) – a neurokinin, also in spinal cord, Calcitonin Gene-Related Protein (CGRP),

Question 2

Examples of Transmitters and Inflammatory Mediators

Neurotransmitters for the Brain:

Answer 2

common excitatory transmitter – Glutamate (also elsewhere), common inhibitory transmitter – GABA (aminobutyric acid)

Question 3

Examples of Transmitters and Inflammatory Mediators

Inflammatory mediators

Answer 3

Bradykinin (BK)
Prostaglandins (PGs) e.g. cyclo-oxygenase-2 (COX-2) proteinases, act to sensitise nociceptors
Histamine (His) for arteriole vasodilation and vessel permeability, Cytokines (e.g. Interleukin 1, or Tumor Necrosis Factor alpha)

Question 4

Hormones associated with inflammation, immune system upregulation and/or sensitisation

Answer 4

Adrenaline,

Nerve growth factor (NGF)

Question 5

Endogenous Opioid neurotransmitters, associated with blocking nociception include

Answer 5

Endorphins, Enkephalins, Dynorphins

Question 6

Phenotypic switch:

Answer 6

A beta fibres (deep touch) (normally mechanosensitive for touch) may switch to releasing substance P at the dorsal horn of the spinal cord – behaving like C fibres.

Question 7

Sprouting:

Answer 7

neurones advancing into regions that they would not normally be found e.g. sympathetic nervous system neurones sprouting into dorsal root ganglion.

Question 8

Orthodromic discharge:

Answer 8

action potential travelling in the most common direction, from dendrites to soma (cell body), axon and terminals.

Question 9

Antidromic discharge:

Answer 9

action potential travelling in the opposite direction to normal function (from CNS to periphery for sensory neurones). This is a mechanism for CNS activity to drive peripheral neurogenic inflammation.

Question 10

Peripheral nociceptors

Answer 10

Sensory nerves constantly adapt. They are replaced every few days. They produce neurotransmitter proteins and modulate their thresholds for detection and transduction.

Question 11

Detection:

Answer 11

receptors on the sensory nerve ending for thermal, chemical and mechanical stimuli.

Question 12

Transduction:

Answer 12

production of an action potential, to transmit a “warning of threat” signal to the central nervous system.

Question 13

Peripheral nociceptors
A delta (δ) fibres

Answer 13

medium diameter and lightly myelinated. — 5.0 – 30.0 m/s First input that can be perceived. Often well localised, sharp. Can be specific to
• Mechanical stimuli
• Thermal input >42°C or < 5° C.

Question 14

Peripheral nociceptors

C fibres:

Answer 14

Most prevalent, small diameter, slow conducting 0.5 – 2.0 m/s, for secondary often diffuse perception of input, dull, burning.
These are polymodal nociceptors, responding to
• Mechanical stimuli.
• Thermal: heat and cold with transient receptor
potential channels
• Chemical: could be via acid sensing ion channels, transient receptor potential or potassium ion channels
Many C fibres may be ‘silent nociceptors’ until activated with sensitisation.

Question 15

Peripheral sensitisation

Answer 15

Silent nociceptors are activated, and already active. A delta and C fibres respond to lower threshold stimuli, to detect and transduce action potentials. Contributors to peripheral sensitisation include
• damaged tissue
• cell disruption
• inflammation
• infection or
• ischaemia

Question 16

peripheral nerve injury

Answer 16

Injury to a peripheral nerve causes functional and biochemical changes not only at the site of injury, but also to other parts of the affected nerve and in due course to higher order neurons in the spinal cord and brain

Question 17

Peripheral sensitisation 2

Answer 17

With release of a range of chemical mediators, degranulation of mast cells to release histamine and increase vessel permeability (an ‘inflammatory soup’), to activate and/or sensitise receptors and ion channels.

Question 18

Neurogenic inflammation:

Answer 18

A delta and C fibres also release neuropeptides from their peripheral terminals (chemical feedback) at the site of injury,
• Substance P
• Glutamate and
• Calcitonin Gene-Related Peptide (CGRP)

Question 19

Peripheral sensitisation process

Answer 19

tissue injury causes the release of Inflammatory mediators
> active c fibres release CGRP and substance P which stimulates mast cells, which release histamine > CGRP and substance P released by C fibres cause the dilation of blood vessels

Question 20

Dorsal Root Ganglia

Answer 20

Nuclei in the DRG constantly modulate synthesis of receptors, ion channels and neurotransmitters.

• Exposure to inflammatory substances, nerve injury or sprouting from other neurones (such as from the sympathetic nervous system) or satellite glial cells can lead to sensitisation or even ectopic action potentials. Sapunar et al. 2012
• Gradual mechanical occlusion may be tolerated with far less symptoms than rapid changes in foramen space.