Physiology of pain saq mbbs

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Physiology of Pain - MBBS SAQ

Definition

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. It is both a sensation and an emotion - acute pain is accompanied by behavioral arousal, elevated BP, heart rate, pupil dilation, and cortisol release. - Harrison's Principles of Internal Medicine, 22E

Types of Pain

Type	Character	Fiber	Speed
Fast (First) Pain	Sharp, pricking, well-localized	Aδ (thin myelinated)	~15 m/s
Slow (Second) Pain	Dull, burning, aching, poorly localized	C (unmyelinated)	0.5-2 m/s

1. Peripheral Mechanisms - Nociceptors

Nociceptors are free nerve endings (peripheral terminations of sensory neurons) found in skin, connective tissue, blood vessels, periosteum, and most visceral organs.

Components of a typical cutaneous nerve showing Aβ, Aδ, and C fiber types

Fiber types in a peripheral nerve. Aβ: large myelinated (non-pain); Aδ: small myelinated (fast pain); C: unmyelinated (slow pain). - Harrison's Principles of Internal Medicine, 22E

Three categories of nociceptors:

Mechanoreceptors - respond to intense mechanical stimuli; transmitted by Aδ fibers
Thermoreceptors - respond to extreme heat/cold; mainly C fibers
Polymodal nociceptors - respond to mechanical, thermal, and chemical stimuli; C fibers (majority)

Adequate stimuli differ by tissue:

Skin: pricking, cutting, crushing, burning, freezing
Viscera: distension, ischemia, inflammation (NOT cutting)
Muscle: ischemia (e.g., intermittent claudication), spasm
Joints: synovial inflammation, ligament tearing

2. Chemical Mediators of Pain (Peripheral)

When tissue is damaged, proteolytic enzymes release pain-producing substances that excite nociceptor terminals:

Histamine - from mast cells
Prostaglandins (PGs) - sensitize nociceptors
Serotonin (5-HT)
Bradykinin (BK) - one of the most potent algogenic substances
Potassium ions (K+)
Leukotrienes
Substance P - released from C fiber endings; causes vasodilation, edema (mast cell histamine release), and attracts leukocytes -> neurogenic inflammation (axon reflex of Lewis)

3. Sensitization

Peripheral Sensitization

Repeated/prolonged noxious stimuli lower the threshold of nociceptors - they fire more readily and at higher frequency. Caused by BK, PGs, nerve growth factor activating intracellular signaling, increasing membrane insertion of ion channels.

Central Sensitization

Activity generated by peripheral nociceptors enhances excitability of dorsal horn neurons. This leads to:

Hyperalgesia - increased pain from the same noxious stimulus
Allodynia - pain from normally innocuous stimuli (e.g., sunburned skin is painful to gentle touch)

Silent nociceptors - Aδ and C fibers in viscera that are normally insensitive but become active during inflammation; explain why visceral disease causes severe pain.

4. Pain Pathways (Spinal Cord and Ascending Tracts)

First-order neurons (Primary afferents)

Cell bodies in the dorsal root ganglion (DRG)
Aδ and C fibers enter the dorsal horn and synapse in Rexed laminae I, II, and V
- Aδ fibers: mainly laminae I and V
- C fibers: mainly lamina II (substantia gelatinosa)

Neurotransmitters at dorsal horn

Excitatory amino acids (glutamate, aspartate)
Neuropeptides: Substance P, CGRP, CCK

Second-order neurons (Dorsal horn)

Nociceptive-specific (NS) neurons - respond only to noxious input
Wide dynamic range (WDR) neurons - respond to both nociceptive and non-nociceptive stimuli

Axons of most second-order neurons cross in the anterior white commissure and ascend in the anterolateral quadrant as the spinothalamic tract (STT).

Two components of the spinothalamic tract:

Tract	Other name	Thalamic nucleus	Cortex	Pain type
Lateral STT	Neospinothalamic	VPL nucleus	Primary sensory cortex (S1)	Fast, well-localized
Medial STT	Paleospinothalamic	Central/laminar nuclei (via PAG, brainstem)	Limbic system, insula	Slow, poorly localized, emotional

Third-order neurons

VPL -> primary somatosensory cortex (S1), parietal operculum
Multiple cortical areas activated: S1, S2, thalamus, PAG, supplementary motor, insular cortex (confirmed by fMRI and PET)

5. Gate Control Theory (Melzack and Wall, 1965)

Gate control theory of pain at the dorsal horn

Gate control theory - Neuroscience: Exploring the Brain, 5th Ed.

Concept: The transmission of pain signals from dorsal horn projection neurons is regulated by the balance of input from large-diameter (Aβ) and small-diameter (Aδ/C) fibers, mediated via inhibitory interneurons.

Mechanism:

Large Aβ fibers (touch) --> excite inhibitory interneurons (I cells) --> close the gate (presynaptic inhibition of T/projection cells) --> pain reduced
Small C fibers (pain) --> inhibit I cells --> open the gate --> pain transmitted

Clinical application:

Rubbing injured skin (activates Aβ) reduces pain
Transcutaneous electrical nerve stimulation (TENS) works on this principle
Descending modulation from brainstem, thalamus, and limbic lobes also controls the gate

6. Descending Pain Modulation (Endogenous Analgesia)

Emotional stress, fear, or strong distraction can suppress pain via a descending inhibitory system:

Periaqueductal gray (PAG) - midbrain; receives input from cortex, hypothalamus, amygdala (emotional signals). Key control center.
PAG --> Raphe nuclei (medulla; serotonergic) and Locus coeruleus (noradrenergic)
These project down to the dorsal horn, inhibiting nociceptive transmission

Endogenous Opioids

The brain produces three families of morphine-like peptides:

Endorphins
Enkephalins
Dynorphins

These bind to opioid receptors (μ, κ, δ) concentrated in PAG, raphe nuclei, and dorsal horn. Their effects:

Suppress release of glutamate from presynaptic terminals
Hyperpolarize postsynaptic neurons
Net result: block transmission of nociceptive signals through the dorsal horn

Naloxone (opioid antagonist) can block these effects, confirming the opioid mechanism. - Neuroscience: Exploring the Brain, 5th Ed.

7. Perception and Threshold

Pain threshold = lowest intensity stimulus perceived as pain; approximately equal in all persons
Inflammation lowers the threshold (sensitization)
Local anesthetics, opioids, and certain CNS lesions raise the threshold
Placebos reduce pain in ~1/3 of patients (endogenous opioid release)
Distraction and suggestion reduce awareness but not the threshold itself

8. Referred Pain

Pain arising from visceral or deep somatic structures is "referred" to a body surface area. Mechanism: visceral and somatic afferents converge on the same second-order (WDR) neurons in the dorsal horn. The brain misidentifies the source as the more familiar somatic structure.

Examples:

Cardiac ischemia -> left arm/jaw pain
Appendicitis -> periumbilical (early), then right iliac fossa (late)
Diaphragmatic irritation -> shoulder tip pain

Summary for SAQ

Pain physiology involves: (1) Peripheral nociceptors (Aδ - fast; C - slow); (2) Chemical mediators (BK, PGs, substance P); (3) Sensitization (peripheral and central); (4) Spinal cord relay (dorsal horn laminae I/II/V -> STT -> thalamus -> cortex); (5) Gate control (Aβ closes, C fibers open the gate); (6) Descending inhibition (PAG -> raphe/locus coeruleus -> dorsal horn, via endorphins/enkephalins).

Sources: Harrison's Principles of Internal Medicine 22E; Adams and Victor's Principles of Neurology, 12th Ed.; Bradley and Daroff's Neurology in Clinical Practice; Neuroscience: Exploring the Brain, 5th Ed.

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