CHAPTER 13 PAIN: PATHO AND MGT
The Pain Sensory System
• Pain: An unpleasant sensation localized to a body part.
• Dual nature:
o Sensation – linked to tissue damage or harmful
stimuli.
o Emotion – often described as terrifying,
nauseating, sickening, etc.
Acute Pain Responses
• Behavioral arousal and stress response: FIGURE 13-1 Components of a typical cutaneous nerve. There are two
o ↑ Blood pressure, heart rate, pupil size, cortisol. distinct functional categories of axons: primary afferents with cell bodies
o Local muscle contraction (e.g., limb flexion, in the dorsal root ganglion and sympathetic postganglionic fibers with
abdominal rigidity). cell bodies in the sympathetic ganglion. Primary afferents include those
with large-diameter myelinated (Aβ), small-diameter myelinated (Aδ),
• Accompanied by anxiety and the urge to escape or stop the and unmyelinated (C) axons. All sympathetic postganglionic fibers are
feeling. unmyelinated
Peripheral Mechanisms of Pain
The Primary Afferent Nociceptor Sensitization & Nociceptor-Induced Inflammation
• Peripheral nerve composition:
• Primary sensory afferents Sensitization
• Motor neurons • Lowered threshold + increased firing frequency of nociceptors
• Sympathetic postganglionic neurons after intense, repeated, or prolonged stimulation.
• Cell bodies: • Mediated by inflammatory substances.
• Located in dorsal root ganglia (DRG) within vertebral
foramina. Types
• Axon branches: • Peripheral Sensitization
• Central branch → projects into spinal cord. • Occurs in damaged/inflamed tissues.
• Peripheral branch → innervates tissues (skin, muscle, • Inflammatory mediators activate intracellular signaling in
viscera). nociceptors → ↑ production, transport, and insertion of ion
channels (chemically/voltage gated).
Classification of Primary Afferent Fibers • Result: ↑ excitability of terminals → lower threshold for
Primary sensory afferents are classified by diameter, myelination, mechanical, thermal, and chemical stimuli
and conduction velocity: • Central Sensitization
• A-beta (Aβ) fibers • Occurs in the dorsal horn of the spinal cord.
• Large-diameter, myelinated, fast conduction • Nociceptor activity during inflammation enhances excitability
• Respond to: light touch, vibration, moving stimuli of dorsal horn neurons.
• Normally do NOT produce pain • Leads to:
• A-delta (Aδ) fibers o Allodynia → normally innocuous stimuli produce
pain.
• Small-diameter, thinly myelinated, moderate
conduction speed o Hyperalgesia → exaggerated pain response to
noxious stimuli (e.g., pinprick feels severe).
• Respond to: mechanical and thermal stimuli
• Convey sharp, localized “first pain” Clinical Example = Sunburn: gentle slap or warm shower → severe
• C fibers pain.
• Small-diameter, unmyelinated, slow conduction
• Respond to: mechanical, thermal, chemical stimuli
• Silent Nociceptors
• Convey dull, aching, burning “second pain”
• Normally inactive in healthy tissue (not activated by
mechanical/thermal stimuli).
• Some tissues (e.g., cornea) are innervated only by Aδ and C
• During inflammation, become sensitive to mechanical
stimuli.
fibers, which explains why corneal pain is sharp or burning.
• Important in deep tissue & visceral pain:
• Joints, hollow viscera become exquisitely sensitive when
• Nociceptors = Primary afferent sensory neurons that respond inflamed.
maximally to noxious (painful) stimuli.
• Pain detection depends on Aδ and C fibers → if conduction is • Inflammatory Mediators in Sensitization
blocked, pain sensation is abolished.
• Bradykinin (BK)
• Nerve growth factor (NGF)
Stimuli Detected by Nociceptors
• Prostaglandins (PGs)
• Thermal: heat, intense cold
• Leukotrienes
• Mechanical: strong pressure, pinch, tissue distortion
• Low pH (acidosis)
• Chemical:
• Acidic pH (low pH) • Nociceptor-Induced (Neurogenic) Inflammation
• Irritants: ATP, serotonin, bradykinin (BK), histamine • Nociceptors are not passive messengers; they actively
contribute to inflammation
Receptors & Ion Channels Involved
• Release polypeptide mediators from peripheral terminals:
• TRPV1 (Transient Receptor Potential Vanilloid 1)
• Substance P
• Also called vanilloid receptor • Potent vasodilator
• Found in nociceptive neurons • Mast cell degranulation
• Activated by: • Leukocyte chemoattractant
o Heat (>43°C) • ↑ release of inflammatory mediators
o Acidic pH • Depletion reduces severity of experimental arthritis
o Endogenous mediators (inflammatory chemicals) • Calcitonin Gene-Related Peptide (CGRP)
o Capsaicin (chili pepper compound) • Cholecystokinin (CCK)
• Role: mediates burning pain from heat, inflammation, and
spicy foods ✅ Key Point: Sensitization is a central mechanism of clinical pain,
explaining tenderness, soreness, and chronic inflammatory pain,
Functional Roles while silent nociceptors explain why inflamed deep tissues and
, FIGURE 13-2 Events leading to • Examples:
activation, sensitization, and spread of
Central Mechanisms of Pain
sensitization • Athletes/soldiers: severe injuries with little pain.
of primary afferent nociceptor terminals.
Spinal Cord & Referred Pain
A. Direct activation by intense pressure
• Placebo effect: expectation of relief → actual analgesia.
Pathway of Pain
and consequent cell Transmission
damage. Cell • Nocebo effect: expectation of worsening → increased pain.
• damage induces lower pH (H+) and
leads to
Primary afferent • Minor injuries may be unbearable if anxiety/fear is high.
nociceptors enter(Kspinal
release of potassium cord via
+) and to
dorsal root
synthesis → terminate
of prostaglandins in dorsal
(PGs) and Descending Pain-Modulating Pathway
horn.
bradykinin
• Origin: circuits involving hypothalamus, midbrain, medulla.
(BK). PGs increase the sensitivity of the
• terminal toRelease
BK and other neurotransmitters:
pain-producing • Action: selectively controls spinal pain-transmission neurons.
• substances. B. Secondary activation.
Glutamate → rapid excitation
Impulses generated in the stimulated • Mechanisms:
of terminal
2nd-order dorsal horn neurons.
o Opioid receptors in these structures.
• propagate not only to the spinal cord but
Substance P & CGRP →
also into other terminal branches where o Endogenous opioid peptides: enkephalins, β-endorphin.
slower, longer-lasting
they induce the release of excitation.
peptides, o Activated by:
including substance P (SP). Substance
Convergence
P causes • Suggestion of pain relief
•
vasodilation and neurogenic edema with
Each primary
further accumulation afferent
of BK. Substance
• Strong emotions (e.g., stress, athletic performance)
contacts
P many spinal neurons. • Placebo effect
•
also causes the release of histamine (H)
from mastEach spinal
cells and neuron
serotonin (5HT) receives • Surgery
inputs
from from multiple afferents. Dual Modulatory Role
•
platelets.
Visceral & deep • Pain Inhibition: suppresses pain → basis for opioid and placebo
musculoskeletal inputs converge with skin inputs on the analgesia.
same spinal neurons. • Pain Facilitation: enhances pain → explains why
suggestion/expectation can worsen pain.
Referred Pain Mechanism
• Key Insight: Pain can be generated/augmented centrally, even
• Spinal neurons are more often activated by skin inputs. without peripheral stimulus.
• Therefore, pain from deep/visceral structures is mislocalized to Clinical Relevance
skin regions innervated by the same spinal segment. • Explains:
Example
• Placebo analgesia
• Central diaphragm afferents → C3–C4 DRG. • Pain during stress or reduced during distraction
• Same DRG also supplies shoulder/lower neck skin. • Chronic pain syndromes (e.g., migraines → overactive
facilitatory circuits).
• Inflammation of diaphragm → pain perceived in shoulder (referred
pain). ✅ Key Point: Pain is shaped not only by peripheral input but also by
descending brain circuits that can suppress or amplify pain
✅ Key Point: Referred pain = spatial displacement of pain sensation, signals, strongly influenced by psychological factors.
due to convergence of visceral + somatic inputs on the same
spinal neurons.
Ascending Pain Pathways
Spinothalamic Tract
• Main pathway for pain & temperature. Neuropathic Pain
• Formed by axons of spinal neurons contacted by primary • Pain caused by damage or dysfunction of peripheral or central
afferent nociceptors. nociceptive pathways.
• Crosses to contralateral side → ascends in anterolateral white • Paradoxical: lesions may cause loss of sensation but also
matter of spinal cord, medulla, pons, and midbrain. chronic pain.
• Lesion → permanent loss of pain & temperature • Often severe, persistent, and resistant to standard analgesics.
discrimination. Causes
• Peripheral nerve damage: e.g., diabetic neuropathy, herpes
Thalamic Projections zoster (postherpetic neuralgia).
1. Somatosensory Cortex
• Central nervous system damage: trauma or vascular injury to
o Sensory–discriminative aspects of pain: spinal cord, brainstem, thalamus.
§ Location
§ Intensity Clinical Features
§ Quality • Quality: burning, tingling, electric shock-like.
2. Cingulate Cortex & Insular Cortex
• Occurrence: spontaneous (without stimulus) or triggered by light
o Affective–emotional aspects of pain: touch.
§ Produces suffering • Sensory deficit: in the same area as pain.
§ Drives fear and behavior modification
3. Frontal Cortex • Hyperpathia: exaggerated response to mild/repeated stimuli.
o Emotional dimension of pain. • Allodynia: pain from normally non-painful stimuli (e.g., light
o Lesions here → diminish emotional suffering, but pain touch).
perception (intensity, quality) remains intact. • Example: postherpetic neuralgia → responds to topical 5%
The Pain Sensory System
• Pain: An unpleasant sensation localized to a body part.
• Dual nature:
o Sensation – linked to tissue damage or harmful
stimuli.
o Emotion – often described as terrifying,
nauseating, sickening, etc.
Acute Pain Responses
• Behavioral arousal and stress response: FIGURE 13-1 Components of a typical cutaneous nerve. There are two
o ↑ Blood pressure, heart rate, pupil size, cortisol. distinct functional categories of axons: primary afferents with cell bodies
o Local muscle contraction (e.g., limb flexion, in the dorsal root ganglion and sympathetic postganglionic fibers with
abdominal rigidity). cell bodies in the sympathetic ganglion. Primary afferents include those
with large-diameter myelinated (Aβ), small-diameter myelinated (Aδ),
• Accompanied by anxiety and the urge to escape or stop the and unmyelinated (C) axons. All sympathetic postganglionic fibers are
feeling. unmyelinated
Peripheral Mechanisms of Pain
The Primary Afferent Nociceptor Sensitization & Nociceptor-Induced Inflammation
• Peripheral nerve composition:
• Primary sensory afferents Sensitization
• Motor neurons • Lowered threshold + increased firing frequency of nociceptors
• Sympathetic postganglionic neurons after intense, repeated, or prolonged stimulation.
• Cell bodies: • Mediated by inflammatory substances.
• Located in dorsal root ganglia (DRG) within vertebral
foramina. Types
• Axon branches: • Peripheral Sensitization
• Central branch → projects into spinal cord. • Occurs in damaged/inflamed tissues.
• Peripheral branch → innervates tissues (skin, muscle, • Inflammatory mediators activate intracellular signaling in
viscera). nociceptors → ↑ production, transport, and insertion of ion
channels (chemically/voltage gated).
Classification of Primary Afferent Fibers • Result: ↑ excitability of terminals → lower threshold for
Primary sensory afferents are classified by diameter, myelination, mechanical, thermal, and chemical stimuli
and conduction velocity: • Central Sensitization
• A-beta (Aβ) fibers • Occurs in the dorsal horn of the spinal cord.
• Large-diameter, myelinated, fast conduction • Nociceptor activity during inflammation enhances excitability
• Respond to: light touch, vibration, moving stimuli of dorsal horn neurons.
• Normally do NOT produce pain • Leads to:
• A-delta (Aδ) fibers o Allodynia → normally innocuous stimuli produce
pain.
• Small-diameter, thinly myelinated, moderate
conduction speed o Hyperalgesia → exaggerated pain response to
noxious stimuli (e.g., pinprick feels severe).
• Respond to: mechanical and thermal stimuli
• Convey sharp, localized “first pain” Clinical Example = Sunburn: gentle slap or warm shower → severe
• C fibers pain.
• Small-diameter, unmyelinated, slow conduction
• Respond to: mechanical, thermal, chemical stimuli
• Silent Nociceptors
• Convey dull, aching, burning “second pain”
• Normally inactive in healthy tissue (not activated by
mechanical/thermal stimuli).
• Some tissues (e.g., cornea) are innervated only by Aδ and C
• During inflammation, become sensitive to mechanical
stimuli.
fibers, which explains why corneal pain is sharp or burning.
• Important in deep tissue & visceral pain:
• Joints, hollow viscera become exquisitely sensitive when
• Nociceptors = Primary afferent sensory neurons that respond inflamed.
maximally to noxious (painful) stimuli.
• Pain detection depends on Aδ and C fibers → if conduction is • Inflammatory Mediators in Sensitization
blocked, pain sensation is abolished.
• Bradykinin (BK)
• Nerve growth factor (NGF)
Stimuli Detected by Nociceptors
• Prostaglandins (PGs)
• Thermal: heat, intense cold
• Leukotrienes
• Mechanical: strong pressure, pinch, tissue distortion
• Low pH (acidosis)
• Chemical:
• Acidic pH (low pH) • Nociceptor-Induced (Neurogenic) Inflammation
• Irritants: ATP, serotonin, bradykinin (BK), histamine • Nociceptors are not passive messengers; they actively
contribute to inflammation
Receptors & Ion Channels Involved
• Release polypeptide mediators from peripheral terminals:
• TRPV1 (Transient Receptor Potential Vanilloid 1)
• Substance P
• Also called vanilloid receptor • Potent vasodilator
• Found in nociceptive neurons • Mast cell degranulation
• Activated by: • Leukocyte chemoattractant
o Heat (>43°C) • ↑ release of inflammatory mediators
o Acidic pH • Depletion reduces severity of experimental arthritis
o Endogenous mediators (inflammatory chemicals) • Calcitonin Gene-Related Peptide (CGRP)
o Capsaicin (chili pepper compound) • Cholecystokinin (CCK)
• Role: mediates burning pain from heat, inflammation, and
spicy foods ✅ Key Point: Sensitization is a central mechanism of clinical pain,
explaining tenderness, soreness, and chronic inflammatory pain,
Functional Roles while silent nociceptors explain why inflamed deep tissues and
, FIGURE 13-2 Events leading to • Examples:
activation, sensitization, and spread of
Central Mechanisms of Pain
sensitization • Athletes/soldiers: severe injuries with little pain.
of primary afferent nociceptor terminals.
Spinal Cord & Referred Pain
A. Direct activation by intense pressure
• Placebo effect: expectation of relief → actual analgesia.
Pathway of Pain
and consequent cell Transmission
damage. Cell • Nocebo effect: expectation of worsening → increased pain.
• damage induces lower pH (H+) and
leads to
Primary afferent • Minor injuries may be unbearable if anxiety/fear is high.
nociceptors enter(Kspinal
release of potassium cord via
+) and to
dorsal root
synthesis → terminate
of prostaglandins in dorsal
(PGs) and Descending Pain-Modulating Pathway
horn.
bradykinin
• Origin: circuits involving hypothalamus, midbrain, medulla.
(BK). PGs increase the sensitivity of the
• terminal toRelease
BK and other neurotransmitters:
pain-producing • Action: selectively controls spinal pain-transmission neurons.
• substances. B. Secondary activation.
Glutamate → rapid excitation
Impulses generated in the stimulated • Mechanisms:
of terminal
2nd-order dorsal horn neurons.
o Opioid receptors in these structures.
• propagate not only to the spinal cord but
Substance P & CGRP →
also into other terminal branches where o Endogenous opioid peptides: enkephalins, β-endorphin.
slower, longer-lasting
they induce the release of excitation.
peptides, o Activated by:
including substance P (SP). Substance
Convergence
P causes • Suggestion of pain relief
•
vasodilation and neurogenic edema with
Each primary
further accumulation afferent
of BK. Substance
• Strong emotions (e.g., stress, athletic performance)
contacts
P many spinal neurons. • Placebo effect
•
also causes the release of histamine (H)
from mastEach spinal
cells and neuron
serotonin (5HT) receives • Surgery
inputs
from from multiple afferents. Dual Modulatory Role
•
platelets.
Visceral & deep • Pain Inhibition: suppresses pain → basis for opioid and placebo
musculoskeletal inputs converge with skin inputs on the analgesia.
same spinal neurons. • Pain Facilitation: enhances pain → explains why
suggestion/expectation can worsen pain.
Referred Pain Mechanism
• Key Insight: Pain can be generated/augmented centrally, even
• Spinal neurons are more often activated by skin inputs. without peripheral stimulus.
• Therefore, pain from deep/visceral structures is mislocalized to Clinical Relevance
skin regions innervated by the same spinal segment. • Explains:
Example
• Placebo analgesia
• Central diaphragm afferents → C3–C4 DRG. • Pain during stress or reduced during distraction
• Same DRG also supplies shoulder/lower neck skin. • Chronic pain syndromes (e.g., migraines → overactive
facilitatory circuits).
• Inflammation of diaphragm → pain perceived in shoulder (referred
pain). ✅ Key Point: Pain is shaped not only by peripheral input but also by
descending brain circuits that can suppress or amplify pain
✅ Key Point: Referred pain = spatial displacement of pain sensation, signals, strongly influenced by psychological factors.
due to convergence of visceral + somatic inputs on the same
spinal neurons.
Ascending Pain Pathways
Spinothalamic Tract
• Main pathway for pain & temperature. Neuropathic Pain
• Formed by axons of spinal neurons contacted by primary • Pain caused by damage or dysfunction of peripheral or central
afferent nociceptors. nociceptive pathways.
• Crosses to contralateral side → ascends in anterolateral white • Paradoxical: lesions may cause loss of sensation but also
matter of spinal cord, medulla, pons, and midbrain. chronic pain.
• Lesion → permanent loss of pain & temperature • Often severe, persistent, and resistant to standard analgesics.
discrimination. Causes
• Peripheral nerve damage: e.g., diabetic neuropathy, herpes
Thalamic Projections zoster (postherpetic neuralgia).
1. Somatosensory Cortex
• Central nervous system damage: trauma or vascular injury to
o Sensory–discriminative aspects of pain: spinal cord, brainstem, thalamus.
§ Location
§ Intensity Clinical Features
§ Quality • Quality: burning, tingling, electric shock-like.
2. Cingulate Cortex & Insular Cortex
• Occurrence: spontaneous (without stimulus) or triggered by light
o Affective–emotional aspects of pain: touch.
§ Produces suffering • Sensory deficit: in the same area as pain.
§ Drives fear and behavior modification
3. Frontal Cortex • Hyperpathia: exaggerated response to mild/repeated stimuli.
o Emotional dimension of pain. • Allodynia: pain from normally non-painful stimuli (e.g., light
o Lesions here → diminish emotional suffering, but pain touch).
perception (intensity, quality) remains intact. • Example: postherpetic neuralgia → responds to topical 5%
