Pain and Nociception

Overview – Pain and Nociception

Pain and nociception are foundational to clinical neuroscience, anaesthetics, pain medicine, and emergency care. Nociception refers to the physiological transmission of noxious stimuli via specialised nerve fibres, while pain is the conscious experience of that input. Understanding the structure and function of nociceptors, their neurotransmitters, receptor types, and central processing pathways is critical for managing both acute and chronic pain — including neuropathic and referred pain syndromes.

Definition

• Nociception: Detection and transmission of noxious (tissue-damaging) stimuli to the CNS via nociceptors.
• Pain: The conscious perception of nociceptive input, with physical and emotional components.

Nociceptor Fibre Types

C Fibres

• Thin, unmyelinated → slow conduction
• Poorly localised, dull, achy, burning pain
• Polymodal (respond to multiple stimuli)

Aδ Fibres

• Thin, myelinated → faster conduction
• Well-localised, sharp, acute, searing pain
• Also polymodal

Note: Conduction speed increases with larger diameter and greater myelination.

Nociceptor Modalities

• Nociceptors are polymodal:
  • Respond to mechanical, thermal, and chemical stimuli
  • Require high-threshold stimulation to activate
  • Stimulus → cation channel opens → depolarisation → VG Na⁺ channel opens → AP

Key Nociceptive Receptors

• TRPV1 (Vanilloid): Heat, H⁺, capsaicin, mechanical stress, eicosanoids
• Bradykinin receptor: Activates TRPV1
• Prostanoid receptor: Opens Na⁺ channels, inhibits K⁺ → ↑Excitability
• Cannabinoid/opioid receptors: Open K⁺ channels → hyperpolarisation (↓ sensitivity)
• ASIC: H⁺ gated → acid-mediated nociception
• Other inputs: ACh, serotonin, ATP, histamine, noradrenaline, glutamate, GABA, somatostatin

Nociceptive Neurotransmitters

• Peptide NTs (made in dorsal root ganglion):
  • Substance P
  • Neurokinin A (NKA)
  • Calcitonin Gene-Related Peptide (CGRP)
• Amino acid:
  • Glutamate
• Transported in vesicles to central & peripheral terminals

Nociceptor Anatomy

1. Peripheral Terminals

• Free, unencapsulated endings in skin, viscera, joints
• Cell body in dorsal root ganglion

2. Dorsal Horn

• Central terminal synapses in substantia gelatinosa (modulates transmission)

3. Ascending Pathways

• Nociceptive input → spinal cord → brain via:
  • Spinothalamic tract (Neo & Paleo)
  • Spinoreticular tract
  • Trigeminal system (for face/head)

Process of Nociception

Step 1 – Noxious Stimulus

• High-threshold stimuli → activate TRPV1/ASIC etc.
• → Na⁺ influx → AP generation
• → Central neurotransmitter release (Substance P, Glutamate)
• → Peripheral neuropeptide release → local inflammation

“Productive Pain”

• Appropriate pain signalling in response to real tissue damage
• Stimulated by:
  • Heat
  • Acid (H⁺)
  • Capsaicin
  • Bradykinin
  • Prostaglandins
  • Mechanical trauma

Step 2 – Neuropeptide Release

• Dual-site release (central & peripheral terminals)
• Peripheral release contributes to neurogenic inflammation
  • ↓ activation threshold
  • → sustained pain sensitivity

“Non-Productive Pain”

• Ongoing stimulation without continued noxious input
• Common in:
  • Inflammation
  • Ischaemia
  • Chronic injury

Contributing chemicals:

• Substance P, NKA, CGRP
• Prostaglandins
• Bradykinin, Kallidin
• Histamine, serotonin, ACh
• ATP, ADP, lactic acid
• NSAIDs block prostaglandin synthesis → ↓ hypersensitisation

Step 3 – Central Synapse & Ascending Transmission

• Primary NTs:
  • Substance P
  • Glutamate
• Other mediators:
  • VIP, somatostatin, serotonin, GABA, opioids

Ascending Tracts

Spinothalamic Tract

• Neospinothalamic (Lateral)
  • Aδ fibres
  • Localisation & discrimination of pain
  • → Somatosensory cortex
• Paleospinothalamic (Medial)
  • C fibres
  • Poor localisation, alerting function
  • → Limbic areas, prefrontal cortex

Spinoreticular Pathway

• C fibres
• → Reticular Formation → Thalamus/Hypothalamus
• Involved in:
  • Arousal
  • HR/respiration changes
  • Conscious awareness of injury

Trigeminal Pathway

• For face/head nociception
• Projects to thalamus like STT

Summary – Pain and Nociception

Pain and nociception underpin clinical approaches to injury, chronic pain, and inflammation. The dual-fibre nociceptive system (Aδ and C fibres), polymodal TRPV1 and ASIC receptors, and their neurotransmitters form the neurochemical foundation of both productive and non-productive pain. Ascending spinothalamic and spinoreticular pathways explain both localisation and emotional responses. For a broader context, see our Nervous System Overview page.