Neurophysiology of pain

what is the definition of pain?

“an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage

• • emphasizes how the nervous system and brain interpret and respond to sensory input

• integrates biological, psychological, and environmental factors

Mature Organism Model

what are key concepts of mature organism model?

• input

• processing 

• output 

what is input mechanisms ?

• Pain begins with nociceptive input from

  • – peripheral nervous system, outside of the dorsal horn

  • – peripheral nerves (e.g., C-fibers and Aδ fibers)

  • – environmental influences

what is processing mechanisms?

• Structures and processes inside the CNS

• Brain processing the info sent by various inputs

  • – Sensory

  • – Cognitive

  • – Emotional

what is output mechanisms?

• response to the input and interpretation of the experience 

• outputs include:

  • pain

  • effects on other biological systems

what happens during injury?

• A-delta and C fibers are nociceptive fibers, not “pain fibers”

• transmit danger signals (nociception) from injured tissues to the dorsal horn of the spinal cord

• These signals are relayed via second-order neurons to the brain,
  which decides whether to produce pain

Pain is not directly cause by tissue damage

It is a brain-generated output based on perceived threat

what is low back Input Mechanisms - Tissues and Imaging?

40% of asymptomatic individuals have a bulging disc on MRI

what is neck Input Mechanisms - Tissues and Imaging?

90% of asymptomatic individuals (even in their 20s) have bulging cervical discs

what is shoulder Input Mechanisms - Tissues and Imaging?

After successful rotator cuff surgery and rehab, 90% still show abnormal MRI findings, and 20% retain a complete tear—yet regain function

what is knee Input Mechanisms - Tissues and Imaging?

25–50% of asymptomatic individuals show degenerative changes on MRI.

what is hip Input Mechanisms - Tissues and Imaging?

• 73% of asymptomatic individuals show hip abnormalities on MRI.
• 69% have labral tears without symptoms.

•Tissue injuries, even slow- healing ones like intervertebral discs, can heal over time.
•In the acute/subacute phase, pain may correlate with injury— but in chronic cases, other
 actors often dominate.

Clinical Implications – Tissues Injuries

Pain is context-dependent

brain weighs environmental and emotional factors before generating pain

Not all injuries hurt immediately, and not all pain reflects

tissue damage

Therapists should educate patients that:

• Pain is a protective response, not a direct measure of injury.
• Nociception ≠ Pain—they are related but not synonymous.
• Understanding this can reduce fear and improve recovery.

no “pain receptors in the body only __

nociceptors

what do nociceptors do?

– detect and respond to potentially harmful stimuli
– found in skin, muscles, joints, and organs

what do nociceptors respond to?

• mechanical 

• thermal 

• chemical 

what are types of nociceptors?

• C fibers 

• A delta fibers 

what are C fibers?

– Unmyelinated, slow
– Produce dull, aching, poorly defined pain
– Polymodal Receptors

what are a delta fibers?

– thinly myelinated, fast
– Produce sharp, localized pain
– High threshold Mechanical and Mechanical Thermal Receptors

Once activated, nociceptors transmit

electrical impulses through peripheral nerves to the spinal cord, signaling potential harm

Nociception is only the detection of

possible injury and does not necessarily result in pain; the brain ultimately decides if pain is perceived.

1. stimulus application

2. activation of peripheral nerve endings

3. generates action potential

4. Propagation Along the Axon towards the spinal cord

5. entry into the SPC

Receptor Pathways - Mechanical and Thermal Stimulation

what is Stimulus Application?

• Mechanical or Thermal
• Activate nociceptors in the skin

what is Activation of Peripheral Nerve Endings

A-delta fibers, C fibers

what is Propagation Along the Axon towards the spinal cord

• A-delta fibers: Fast conduction via thin myelination.
• C fibers: Slow conduction due to lack of myelination

what is entry into the SPC?

Fibers enter via the dorsal root into the dorsal horn of the spinal cord.

1. chemical stimulus exposure 

2. activation of nociceptors in the skin 

3. generates action potential 

4. signal propagation along the axon towards the SPC

5. entry into the SPC 

Receptors – Chemical Stimulation

what is chemical stimulus exposure?

Endogenous chemicals are released during tissue injury or inflammation

what is Activation of Nociceptors in the Skin

C-fibers

what is generates action potential ?

Chemical binding opens ion channels → influx of Na⁺ and Ca²⁺ → depolarization

what is Signal Propagation Along the Axon towards spinal cord?

C fibers: Slow conduction

what is entry into the SPC?

Fibers enter via the dorsal root into the dorsal horn

– H+ ions, ATP, Serotonin, Substance P- Open Ion Channels
– Bradykinins, Histamines, prostaglandins, Nerve Growth Factors - Increase Nerve Sensitivity

Mast Cells, Macrophages, neutrophiles, T-Cells

what is immune response ?

Release of cytokines and macrophages

• chemical release after injury 

• amplification of pain signals 

• protective but problematic

Peripheral Sensitization

Chemical Release After Injury

– When tissue is damaged, it releases prostaglandins, bradykinin, histamine, and substance P
– chemicals bind to receptors on nociceptors, lowering their activation threshold

Amplification of Pain Signals:

– nociceptors become hypersensitive
– leads to primary hyperalgesia (increased pain at the site of injury)

Protective but Problematic:

– Initially protective as it encourages rest and healing
– can lead to chronic pain, where nervous system remains in a heightened state of alert

• Injuries don’t occur in isolation—they happen within environments
• Environmental factors can amplify or reduce the pain experience

Input Mechanisms - Environment

environment Influences include:

– Stress, anxiety
– Financial concerns
– Beliefs and fears
– Social and cultural context
– Conditioned response

what is negative environmental influences

what is positive environmental influences

• High-stress environments increase risk of persistent pain
– Car accidents, stressful jobs

• Boeing study

what is Boeing study?

– Job satisfaction was the strongest predictor of back pain—not physical workload

what is positive environmental influences?

• Early contact sports may reduce risk of chronic pain

• Demolition derby drivers: <5% develop chronic whiplash vs. 33% in general population

• Cultural stoicism
  – Less expressive cultures report less pain

• Pain is shaped by biological, psychological, and social factors

•  Consider the patient’s environment when assessing and treating pain

Clinical Implications – Environment

what should be asked about for clinical implications-environment?

• Stress levels
• Job satisfaction
• Cultural background
• Beliefs about pain

Various biological and physiological processes of the  __ are important in the development of a pain experience

peripheral nervous system

what are 4 key processes of peripheral neurogenic?

– Ion channel expression
– Nerve compression
– Blood supply
– Dorsal root ganglion (DRG)

None of these processes occur in isolation

Peripheral Neurogenic - Ion Channels

• Ion channels are gateways for ions across nerve membranes
• Crucial for action potential generation and nerve sensitivity
• Targeting ion channels
– Influences the actional potential and sensitivity of the nervous system
• Pharmaceuticals and Therapies can modulate ion channel activity

Ion Channels & Pain – Why They Matter

• Proteins forming passages in nerve membranes

• Types of ion channels depend on genetic instructions

  • – Short Half Life (48 hours)

• Can open/close to change membrane voltage → depolarization → action potential

Ion Channel Basics

Ion Channel Basics Found in areas of no myelin

– Nodes of Ranvier
– Dorsal Root Ganglia (DRG)

what are types of ion channels?

• voltage gated 

• chemical gated 

• temperature gated 

• mechanical gated

• immune gated 

• hydrogen gated 

• light gated

what is voltage gated?

respond to electrical changes

what is chemical gated

activated by substances like adrenaline

what is temperature gated?

response to heat/cold

what is mechanical gated?

activated by pressure / tension

what is immune gated ?

respond to cytokines 

what is hydrogen gated?

sensitive to pH changes

what is light gated?

respond to light exposure

what is myelin loss?

• Mechanical injury (e.g., ankle sprain)
• Immune conditions (e.g., MS, HIV)
• Chemical damage (e.g., inflammation, chemotherapy)
• Create Abnormal Impulse Generating Site (AIGS)

Axons can generate their own impulses when ion channel concentrations are abnormal

Abnormal Impulse Generating Sites (AIGS)

Abnormal Impulse Generating Sites (AIGS) Can be triggered by:

• Stress (adrenaline, fear, anxiety)
• Movement or pressure
• Temperature changes

• Therapy can modulate ion channel activity

  • Pain Neuroscience Education (PNE)

  • Therapeutic alliance

  • Mindfulness

• These reduce stress chemicals (catecholamines) → lower ion channel expression → reduced sensitivity

Clinical Implications - Therapy

• Mechanical compression of nerves typically causes:

• Radiculopathy Insight:

• Pathophysiological Cascade:

Peripheral Neurogenic - Nerve Compression

Mechanical compression of nerves typically causes:

• Numbness
• Weakness
• Pins & needles
• Not pain directly

Radiculopathy Insight:

Pain in extremities often due to chemical activation of

Pathophysiological Cascade:

1. Compression → altered blood flow/nutrition → pain
2. Neurogenic inflammation → macrophages & T-lymphocytes
3. Demyelination → ion channel influx -> AIGS

Peripheral sensitization

• Nervous system = 2–3% of body mass

• Consumes ~25% of circulating oxygen

  •  6–8% stretch → slowed blood flow

  • 15% stretch → blood flow stops

  • 20% stretch → cell death & demyelination

Peripheral Neurogenic - Blood Flow

blood flow clinical implications:

• Reduced blood flow → peripheral sensitization
• Increased blood flow → desensitization

• Cluster of sensory neuron cell bodies
• Located outside the spinal cord
• Non-myelinated → high concentration of ion channels

Peripheral Neurogenic - Dorsal Root Ganglion (DRG)

what are key features:

• Highly mechanosensitive
• Sensitive to stress chemicals
• Referred to as "the most sensitive structure in the human body"

• Sympathetic fibers form a basket weave around the DRG

  • Releases adrenaline → triggers action potentials fires bi- directionally

• Antidromically → target tissues → release of substance P, histamine → redness, swelling, spreading pain → peripheral sensitization

• Orthodromically → CNS → central sensitization

Clinical Implications - DRG

Pain processing is complex at each spinal level due to:

• Convergence from adjacent spinal segments
• Sympathetic nervous system input
• Immune system activity
• Motor neuron feedback
• Contralateral (opposite side) input

Gating mechanisms ensure accurate transmission of

• Location (e.g., dermatome)

• Type of stimulus (e.g., light touch vs. danger)

• Side of the body

what is complex process?

• “feature exact”

  • indicated health nervous system

• Receives nociceptive input from peripheral tissues via
  nociceptive fibers

• Incoming signals are processed by interneurons

  • inhibit 

  • facilitate to second order neurons

Processing Mechanisms - Dorsal Horn

transmit nociceptive information to the brain for interpretation and response

Processing Mechanisms - Second Order Neurons

Two key types of second-order neurons:

• Wide Dynamic Range (WDR) neurons: respond to a range of stimuli; involved in everyday sensory processing

• Nociceptive Specific (NS) neurons: respond only to high-threshold, noxious stimuli; activated in severe threat scenarios

A-beta fibers transmit non-noxious sensory information (e.g., light touch).

Processing Mechanisms – Spinal Cord

A-beta fibers transmit non-noxious sensory information (e.g., light touch).

Processing Mechanisms – Spinal Cord

pants brushing the medial knee sends signals via L3 dorsal horn

Processing Mechanisms – Spinal Cord example

These signals are often blocked at the spinal cord level by interneurons, preventing cortical awareness

– Neurotransmitters involved

• GABA and glycine – inhibitory
• Glutamate– excitatory

1. Periaqueductal Gray (PAG)

2. Relay through Brainstem Nuclei

3. Neurotransmitter Release

4. Endogenous opiod release 

5. opioid receptor activation 

6. pain signal inhibition 

Pain Modulation - Descending Pathway

what is PAG?

• – Located in the midbrain

• – Receives input from the cortex and limbic system (e.g., amygdala, hypothalamus)

what is relay through brainstem Nuclei?

Locus Coeruleus (LC) – releases norepinephrine (noradrenaline)

what is Neurotransmitter Release?

– Serotonin and norepinephrine descend to the spinal cord
– Modulate pain by acting on interneurons in the dorsal horn

what is endogenous opiod release?

Includes endorphins, enkephalins, dynorphins

what is Opioid Receptor Activation?

– Located presynaptically (on nociceptor terminals) and postsynaptically (on second-order neurons)
– Inhibits release of substance P and glutamate
– Reduces excitability of pain-transmitting neurons

what is Pain Signal Inhibition?

– Centrally: Inhibits transmission in the spinal cord
– Peripherally: Reduces nociceptor sensitivity

• Repeated stimulation of dorsal root afferents (especially C fibers) causes action potential windup

• Windup = progressive increase in neuron firing due to temporal summation

• Persistent input leads to neuroplastic changes in spinal cord and brain → central sensitization

  • – Chronic C fiber input can cause interneuron death

  • – Loss of interneurons reduces inhibitory control, increasing nociceptive signal transmission to the second order neuron

Clinical Implications – Central Sensitization

• Persistent nociceptive input causes reorganization of dorsal horn laminae

• C fibers retract, and A-beta fibers grow into nociceptive layers, allowing light touch to activate pain pathways → light touch allodynia

Neuroplastic Changes in the Dorsal Horn

Central Sensitization

• With fewer interneurons

• Brain receives more signals, but with less precision

• Results in increased threat perception and reduced descending inhibition

Clinical Implications - Feature Loss

With fewer interneurons

– removes gating mechanism
– allows input from multiple sources (other spinal levels, opposite side of body, A-beta fibers) to reach second-order neurons
– brain receives mixed signals (e.g., pain and touch)