Pain Physiology: Peripheral and Central Mechanisms of Pain

What is nociception?

The sensory process that detects potentially damaging stimuli and provides signals that can trigger pain.

What is pain?

An unpleasant sensory and emotional experience associated with actual or potential tissue damage.

Why is pain considered more than a sensory experience?

Because it contains: Sensory-discriminative components, Emotional-affective components, Cognitive components, Behavioural responses.

What behavioural responses are associated with pain?

Facial expressions of distress, Vocal expressions, Altered posture and gait, Avoidance behaviours, Negative emotional responses.

What are common descriptors of pain?

Sharp, Fast, Burning, Colicky, Slow, Dull, Aching.

What are the three major categories of pain?

Nociceptive pain, Inflammatory pain, Pathological pain.

What are the characteristics of nociceptive pain?

Adaptive, Protective, High threshold, Triggered by noxious stimuli, Prevents injury.

Give examples of nociceptive pain.

Touching a hot stove, Stepping on a sharp object.

What are the characteristics of inflammatory pain?

Adaptive, Low threshold, Occurs during tissue damage, Protects injured tissue, Promotes healing.

Give examples of inflammatory pain.

Sprained ankle, Surgical wound, Infection.

What are the characteristics of pathological pain?

Maladaptive, No protective value, Caused by abnormal nervous system activity.

What are the two major forms of pathological pain?

Neuropathic pain, Dysfunctional (nociplastic) pain.

What is neuropathic pain?

Pain caused by injury or disease affecting the peripheral or central nervous system.

Examples of neuropathic pain?

Diabetic neuropathy, Trigeminal neuralgia, Post-herpetic neuralgia.

What is nociplastic pain?

Pain occurring without: Clear tissue injury, Active inflammation, Identifiable nerve lesion.

Examples of nociplastic pain?

Fibromyalgia, Some chronic pain syndromes.

What is chronic pain?

Pain that persists beyond the normal healing period.

Why is pain important for survival?

It: Warns of tissue damage, Promotes withdrawal, Encourages healing behaviours, Prevents repeated injury.

What can occur in congenital absence of pain?

Joint degeneration, Vertebral degeneration, Repeated injuries, Severe infections, Reduced lifespan.

Characteristics of cutaneous pain?

Originates from skin, Sharp, Well localised, Easy to identify source.

Examples of cutaneous pain?

Pinprick, Burn, Cut.

Characteristics of visceral pain?

Originates from internal organs, Dull, Aching, Poorly localised, Associated with autonomic responses, Often referred.

Examples of visceral pain?

Cardiac pain, Intestinal pain, Gallbladder pain.

What are nociceptors?

Specialised sensory receptors that detect noxious stimuli.

Where are nociceptors found?

Skin, Muscles, Joints, Viscera, Connective tissue.

What type of nerve endings are nociceptors?

Free nerve endings.

Compare Aδ and C fibres.

Feature, Aδ, C Myelination, Myelinated, Unmyelinated Conduction, Fast, Slow Pain, First pain, Second pain Quality, Sharp, Dull/aching Localisation, Good, Poor Receptors, Thermal/mechanical, Polymodal/silent.

What is first pain?

Mediated by Aδ fibres, Rapid onset, Sharp, Well localised.

What is second pain?

Mediated by C fibres, Slow onset, Burning, Aching, Poorly localised.

What activates thermal nociceptors?

Heat >45°C, Cold <5°C.

What activates mechanonociceptors?

Strong pressure, Pinprick, High-threshold mechanical stimulation.

What are polymodal nociceptors?

C-fibre nociceptors responding to: Mechanical stimuli, Thermal stimuli, Chemical stimuli.

What are silent nociceptors?

Nociceptors normally inactive that become highly responsive during inflammation.

Silent nociceptors are especially important in?

Visceral tissues, Inflammatory pain.

What is transduction?

Conversion of a harmful stimulus into an electrical signal.

What are TRP channels?

Transient receptor potential channels that convert thermal, chemical and mechanical stimuli into receptor potentials.

What activates TRPV1?

Heat, Capsaicin.

What activates TRPA1?

Irritant chemicals, Mustard oil.

What activates TRPM8?

Cold, Menthol.

Outline TRP-mediated transduction.

Noxious stimulus activates TRP channel, Channel opens, Cations enter, Depolarisation, Receptor potential generated, Threshold reached, Action potentials produced.

What is the role of Nav1.7?

Critical for action potential initiation and pain signalling.

Which gene encodes Nav1.7?

SCN9A.

What results from loss-of-function mutations in SCN9A?

Congenital insensitivity to pain.

Roles of Nav1.8 and Nav1.9?

Sustained nociceptor excitability, Action potential propagation, Sustained pain signalling.

What is unique about Nav1.8 and Nav1.9?

They are TTX-resistant sodium channels.

Outline the complete spinothalamic pathway.

Nociceptor activated, DRG neuron fires, Dorsal horn entry, Synapse in laminae I, II, V, Projection neuron crosses midline, Ascends in spinothalamic tract, Reaches VPL thalamus, Projects to S1/S2 cortex.

Functions of the spinothalamic tract?

Pain location, Pain intensity, Pain quality.

What does the dorsal root ganglion contain?

Cell bodies of primary sensory neurons.

Which laminae receive nociceptive input?

Laminae I, II and V.

Characteristics of Lamina I?

Receives Aδ and C fibres, Contains nociceptive projection neurons.

Characteristics of Lamina II?

(Substantia Gelatinosa), Dense C-fibre input, Pain modulation, Gate control, Opioid actions.

Why is the substantia gelatinosa important?

Rich in interneurons, Rich in opioid receptors, Major site of spinal pain modulation.

Characteristics of Lamina V?

Contains WDR neurons, Viscerosomatic convergence, Referred pain.

What does the sensory-discriminative pain system determine?

Where? How strong? What type?

Pathway of the sensory-discriminative system?

Spinothalamic tract → VPL → S1/S2.

What does the affective-motivational system determine?

Unpleasantness, Fear, Distress, Emotional suffering.

Major pathways of affective-motivational pain?

Spinoreticular, Spinomesencephalic, Spinohypothalamic, Spinoparabrachial, Amygdala pathways.

Key brain regions involved in affective pain?

ACC, Insula, Amygdala.

What are LT neurons?

Low-threshold neurons responding to innocuous touch.

What are NS neurons?

Nociceptive-specific neurons responding only to noxious stimuli.

Where are NS neurons mainly located?

Lamina I.

What are WDR neurons?

Wide dynamic range neurons responding to both innocuous and noxious stimuli.

Where are WDR neurons mainly located?

Lamina V.

Functions of WDR neurons?

Referred pain, Viscerosomatic convergence, Central sensitisation.

What is wind-up?

Frequency-dependent increase in dorsal horn excitability during repeated C-fibre stimulation.

Who proposed Gate Control Theory?

Ronald Melzack and Patrick Wall (1965).

What is the central idea of Gate Control Theory?

Inhibitory interneurons regulate pain transmission to projection neurons.

How do Aβ fibres affect pain?

They activate inhibitory interneurons, reducing pain transmission.

Why does rubbing an injury reduce pain?

Rubbing activates Aβ fibres → inhibitory interneurons → gate closes → less pain.

How do C fibres affect the gate?

They inhibit inhibitory interneurons, increasing pain transmission.

What mediators are released during tissue damage?

Bradykinin, Prostaglandins (PGE₂), ATP, Histamine, Cytokines, H⁺, NGF, Proteases.

What is the inflammatory soup?

The collection of inflammatory mediators released after tissue injury.

Effects of inflammatory mediators?

Activate nociceptors, Lower thresholds, Increase excitability, Increase firing.

Result of inflammatory mediator action?

Hyperalgesia, Allodynia.

What is neurogenic inflammation?

Inflammation caused by activated nociceptors releasing neuropeptides.

Which neurotransmitters mediate neurogenic inflammation?

Substance P, CGRP.

Actions of Substance P?

Mast cell activation, Plasma extravasation.

Actions of CGRP?

Vasodilation.

What is the axon reflex?

Antidromic release of Substance P and CGRP from peripheral nociceptor branches causing inflammation.

What positive feedback loop occurs in neurogenic inflammation?

Substance P → mast cells → histamine/NGF → nociceptor sensitisation → more Substance P release.

Define hyperalgesia.

Increased pain response to the same noxious stimulus.

Example of hyperalgesia?

Sunburned skin hurting excessively from a pinprick.

Define allodynia.

Pain caused by a normally non-painful stimulus.

Example of allodynia?

Light touch becoming painful.

What is peripheral sensitisation?

Increased responsiveness of peripheral nociceptor endings.

Where does peripheral sensitisation occur?

At nociceptor terminals.

Features of peripheral sensitisation?

Lower thresholds, Increased firing, Increased spontaneous activity, Greater responses.

Ion channels involved in peripheral sensitisation?

TRP channels, ASIC channels, Voltage-gated Na⁺ channels, Voltage-gated Ca²⁺ channels.

What is central sensitisation?

Increased excitability of neurons in the spinal cord and brain.

Causes of central sensitisation?

Repeated stimulation, Sustained stimulation, Inflammation, Silent nociceptor recruitment, Intense nociceptor activity.

Mechanisms of central sensitisation?

Increased synaptic strength, Wind-up, Reduced inhibition, Silent afferent recruitment, Expanded receptive fields.

Consequences of central sensitisation?

Hyperalgesia, Allodynia, Pain spread, Persistent pain.

What is viscerosomatic convergence?

Visceral and somatic afferents synapsing on the same WDR neurons.

Where does viscerosomatic convergence mainly occur?

Lamina V.

What is referred pain?

Pain perceived at a site different from its source.

Why does referred pain occur?

The brain misinterprets visceral activity as somatic pain due to shared spinal pathways.

Example of referred pain?

Heart pain referred to: Left arm, Shoulder, Jaw, Neck, Back.

What is the segmental rule of referred pain?

Pain is referred to skin supplied by the same spinal segments receiving visceral input.

Which pathway is particularly important for visceral pain?

Postsynaptic dorsal column pathway.

Why can midline myelotomy reduce severe visceral pain?

It interrupts the postsynaptic dorsal column pathway.