Pain: Types and Pathways

Pain has accompanied humans since they first existed, first lamented as the curse of
existence and later understood as an adaptive mechanism that ensures survival. Pain
is the most common symptomatic complaint and the main reason why people seek
medical care. Pain symptoms are seen every day, by every physician, in every clinic
and hospital in the world. Understanding pain physiology is the cornerstone to
understanding how to treat it and to providing the individual with their first sigh of
relief as definitive management is undertaken.

Last updated: May 17, 2024

CONTENTS

Overview
Anatomy and Physiology of Pain Pathways
Visceral Pain
Peripheral versus Central Sensitization
The Gate Control Theory of Pain
Clinical Relevance
References

Overview
Definitions
 Pain:
According to the International Association for the Study of Pain (IASP),
pain is “an unpleasant sensory and emotional experience associated
with actual or potential tissue damage, or described in terms of such
damage.”
Mental suffering or distress
Nociception:
Noxious (or toxic) stimulus or stimulus that can become noxious with
prolonged exposure
Process through which peripheral pain receptors transmit information
about current (or potential) tissue damage centrally as pain
Nociceptor: receptor in end organ that detects biochemical changes
associated with current or potential tissue damage
Hyperalgesia: exaggerated response to noxious stimuli
Allodynia: sensation of pain in response to an innocuous stimulus

Types of pain
Physiologic (acute) pain
Pathologic (chronic) pain
Nociceptive:
Pain in response to actual or potentially harmful stimuli
Often described as aching, localized
Aggravated by movement
Neuropathic:
Nerve injury or impairment that is associated with allodynia
Often described as radiating, shooting
Independent of movement
Table: Differences between acute and chronic pain

Physiologic Acute pain Chronic pain

change

Vital signs May vary consistently with No or minimal change

degree of pain severity

Purpose of Useful Inhibits function and not

pain useful

Central Short term; improves with Remains present despite

sensitization healing of injury absence of ongoing injury

Neuropathic Increases likelihood of Common etiology of

pain chronic pain when present in chronic pain
acute phase

Nociceptive Often found during acute pain Commonly presents with

pain state some neuropathic pain
Differences in types of pain and their common etiologies
CRPS: complex regional pain syndrome
Image by Lecturio.

Embryology
7 weeks: development of free nerve endings
18 weeks: hormonal stress responses to pain
23–30 weeks: thalamic projections into the somatosensory cortex
26 weeks: hemodynamic and behavioral reactions to painful stimuli

Function of pain
Adaptive measures to minimize and avoid further tissue damage
Evoked responses:
Withdrawal from noxious stimulus (e.g., spinal reflexes)
Anticipatory movements (e.g., movement of the arms to protect the
eyes and face, bracing before imminent impact)
Anatomy and Physiology of Pain Pathways
Phases
1. Transduction
2. Transmission
3. Modulation
4. Central perception

Nociception process
Thermal, mechanical, or chemical stimuli of noxious intensity comes into
contact with a tissue.
Injured tissue releases inflammatory mediators, including:
Globulin
Protein kinases
Arachidonic acid
Histamine
Nerve growth factor (NGF)
Substance P (SP)
Calcitonin gene–related peptide (CGRP)
These mediators stimulate transducer channels (similar to voltage-gated
channels) → initiation of receptor potentials (transduction)
Receptor potentials evoke action potentials in sensory nerve fibers.
Action potentials are carried as afferent signals via sensory nerve fibers to
the dorsal root ganglia and dorsal horn of the spinal cord (transmission).
From there, the signal is transmitted up the spinal cord to the brain stem
and thalamus, where significant processing (modulation) may occur.
The signal finally reaches the somatosensory cortex (central perception).
The biopsychosocial interpretation of the painful experience also involves:
Amygdala: involved in the emotional and affective response to pain
and pain modulation
Hypothalamus: involved in the neuroendocrine corticotropin response
to pain
Periaqueductal gray matter: key center for pain modulation, involved
in aversive and defensive pain behaviors
Basal ganglia: involved in the cognitive, affective, and discriminative
(ability to localize sensory input) aspects of pain perception
Cerebral cortex: ultimate site of pain perception, potential for
conscious activation of descending pathways for pain modulation
Modulation of pain
Pain signals are modulated (reduced transmission from nociceptive
afferents) by endogenous opioid peptides (e.g., endorphins, dynorphins,
enkephalins) in the:
Spinal cord
Dorsal root ganglia
Midbrain periaqueductal gray (PAG)
This mechanism occurs in the “descending” (“inhibitory”) pathways.
Mechanisms of action of endogenous opioid peptides:
Activation of mu, kappa, and delta opioid receptors → decreased
presynaptic Ca2+ influx → decreased release of glutamate and SP
Increased K+ conductance in dorsal horn neurons
Other modulators include:
Norepinephrine (NE)
Glycine
GABA

Diagram showing the pathway of pain transduction, transmission, modulation, and central
perception
Image by Lecturio.

Types of afferent nerve fibers

Type A fibers:

Large and myelinated → fast-conducting

A-alpha: primary receptors of the muscle spindle and Golgi tendon organ
A-beta:
Afferent axon with the largest diameter
Secondary receptors of the muscle spindle that contribute to
cutaneous mechanoreceptors.
Perceive light touch and/or moving stimuli
A-delta:
Free nerve endings that conduct stimuli related to pressure and
temperature.
Conduction speed approximately 20 m/sec
A-gamma: motor neurons that control the intrinsic activation of the muscle
spindle.
Type B fibers:

Midsized, thinly myelinated fibers

Responsible for autonomic information
Type C fibers:

Unmyelinated nociceptor slow fibers

Conduction speed approximately 2 m/sec
Respond to combinations of thermal, mechanical, and chemical stimuli

Rexed laminae
Organized somatosensory and motor map laid out in the spinal cord
(primarily the dorsal horn) of each spinal segment
Different types of sensory nerves (and some motor, laminae VI–IX) and the
corresponding information they carry are organized so as to synapse in
specific territories in the dorsal horn known as laminae.
There are 10 laminae, designated I–X:
Lamina I: receives and relays noxious and thermal stimuli
Lamina II: receives and relays noxious and nonnoxious physical stimuli
and is involved in pain modulation
Lamina III: receives and relays physical stimuli related to light touch
and proprioception
Lamina IV: receives and relays nonnoxious physical stimuli
Lamina V: receives and relays noxious stimuli and is involved in pain
modulation
Lamina VI: receives and relays information involved in spinal reflexes
and proprioception
Lamina VII: receives and relays information related to visceral function
and noxious stimuli
Lamina VIII: receives and relays information related to modulation of
voluntary movement
Lamina IX: receives and relays information related to motor control
(gross muscle contraction)
Lamina X: centrally located (central gray commissure); where sensory
and motor neurons cross before ascending/descending and where
some degree of interneuronal cross-talk (modulation) takes place
There are also associated nuclei that are beyond the scope of this
discussion.
Under physiologic conditions, sensory and motor information (and
associated modulation) is transmitted within and among the laminae in a
highly organized and predictable fashion.
Under pathologic conditions (e.g., persistent nociceptive input, neurologic
damage), there can be an abnormal rearrangement of sensory inputs that
contributes to the development of central sensitization and other
manifestations of chronic pain:
Nociceptive neural inputs land in laminae devoted to nonnoxious or
motor stimuli.
Nonnoxious or motor inputs land in laminae devoted to nociceptive
stimuli.
Leads to abnormal pain perception to normally nonnoxious stimuli or
movements:
Allodynia
Hypersensitivity
Hyperalgesia
Paresthesia/dysesthesia
Development of neuropathic pain in an area devoid of nerve
damage
Expansion of the receptive field beyond the normal territory of a
peripheral nerve
Spontaneous pain in the absence of noxious stimuli or tissue
damage
Abnormal interneuronal reflexes may develop:
Muscle activation or joint movement (motor stimuli,
proprioceptive stimuli) triggers painful stimuli.
Painful stimuli may trigger abnormal motor activity (e.g.,
hypertonicity, muscle spasm).
Painful stimuli may trigger autonomic or enteric phenomena and
vice versa. For example:
Nausea in response to painful stimulus
Sweating and/or piloerection in response to painful
stimulus
Vasoconstriction in an area of painful stimulus (i.e., CRPS)
Cross section of the spinal cord showing the rexed laminae (left) and associated nuclei (right)
Image by Lecturio.

Ascending and descending pain pathways

Ascending pathway of pain:
 Nociceptors:
Receptors in the periphery respond to heat, intense cold, mechanical
distortion, changes in pH, and chemical irritants (e.g., ADP, bradykinin,
serotonin, histamine)
Afferent nerve conduction → 1st-order neuron
Neuron cell bodies:
The cell bodies of 1st-order neurons are located in the dorsal horn and
dorsal root ganglia of the spinal gray matter (or trigeminal ganglia)
Glutamate, SP, and CGRP are the main neurotransmitters released by
primary afferents
2nd-order neuron:
After synapsing in the spinal cord, the 1st-order neurons project to
2nd-order neurons
2nd-order neurons cross the midline at the anterior white commissure
These neurons then ascend to the thalamus via the contralateral
spinothalamic tract, carrying both pain and temperature sensations.
Thalamus:
From the thalamus, the stimulus is sent to the somatosensory
cerebral cortex via fibers in the posterior limb of the internal capsule
Other thalamic neurons project to areas of the cortex associated with
emotional responses (e.g., cingulate gyrus, insular cortex)
Descending pathway of pain:

The hypothalamus and cortical regions process painful stimuli and signal for the
release of inhibitory mediators and hormones (e.g., opioid peptides,
norepinephrine, glycine, and GABA) that make pain suppression more effective
→ pain modulation

Visceral Pain
Characteristics
Poorly localized
Unpleasant
Associated with nausea and autonomic symptoms

Nociception process
Nociceptors in the walls of the viscera are sensitive to distention and
inflammation of the organ → receptor and action potentials are evoked:
Pain shifts in intensity when produced in peristaltic structures (e.g.,
intestines).
Pain may be sharp upon contraction and dull upon relaxation.
The action potentials are carried by afferent fibers via sympathetic and
parasympathetic nerves of the myenteric plexus.
The signal is transmitted to the neural bodies in the dorsal (and cranial)
nerve ganglia → signal continues to the dorsal horn of the spinal cord.
Convergence-projection theory: visceral afferent fibers converge with
somatic afferent fibers on the same neural bodies in the dorsal horn → the
signal is sent through the spinal cord to the thalamus and the
somatosensory cortex.
Pain is perceived to come from the somatic structure corresponding to the
somatic fibers that converged with the visceral fibers (referred pain).
For example:
Pain in MI is referred to the left upper limb.
Pain due to ureteral distention is referred to the corresponding
testicle in men.
There may also be motor/sudomotor manifestations in somatic
structures related to the corresponding spinal segment mediated by
spinal interneurons.
In the osteopathic literature, this manifestation is referred to as
facilitation or a viscerosomatic reflex.
Example: muscle spasm, fascial restriction in the paraspinal
musculature at a spinal level corresponding to visceral
dysfunction
Diagram illustrating the convergence-projection theory of visceral pain
Image by Lecturio.
Peripheral versus Central Sensitization
Peripheral sensitization
Results from persistent or repetitive peripheral nociception (traditional
inflammation) or nerve injury
Hyperstimulation or damage to the 1st-order neuron alters the electrical
traits and elaboration of neurotransmitters (e.g., SP, CGRP, NGF).
The inflammation and the initial injury combine to create an enhanced pain
sensation and perpetuates the pain response:
Neuropathic pain may develop in an area devoid of nerve injury.
May manifest with hypersensitivity, hyperalgesia, allodynia.

Central sensitization
Phenomenon thought to occur centrally, perhaps at the level of the rexed
laminae
Generally a progression from peripheral sensitization but may also be
produced without any known peripheral stimulus or a CNS insult.
Segmental central sensitization: neuroplastic changes that occur in
response to a physical injury that cause constant activation of the pain
pathway (i.e., progression from central sensitization)
Suprasegmental central sensitization: neuroplastic changes in brain
sites of the pain pathway with or without known injuries (from CNS
injury).
Often occurs in the setting of CNS insults (e.g., stroke, spinal cord injury)
Often associated with psychiatric conditions:
Anxiety disorders
Mood disorders (e.g., depression)
Sleep disorders
Somatization disorder
May occur as a primary disorder (e.g., fibromyalgia)
Mechanisms of peripheral and central pain sensitization
Image by Lecturio.

The Gate Control Theory of Pain

 A physiologic sensory “gate” exists at the level of the dorsal horn in any
given spinal segment (or cranial nerve nucleus).
Only so much sensory information can get through the gate at any
given time.
Preferential passage through the gate is granted to incoming sensory
signals conducted by larger, more heavily myelinated, faster-
conducting nerve fibers.
An open gate is a dorsal horn receiving isolated noxious (painful)
stimulus.
A closed gate is a dorsal horn receiving simultaneous physical
(nonnoxious) physical stimuli.
Incoming pain signals are largely conducted by A-delta (relatively slow-
conducting) and type C (slow-conducting) fibers, while A-alpha and A-beta
(fast-conducting) fibers carry nonnoxious physical stimuli (e.g., movement,
vibration, pressure, temperature, electrical stimulation).
This distinction becomes very important when painful (noxious) and
other physical stimuli (nonnoxious) are simultaneously applied in the
receptive field of a peripheral nerve.
Nonnoxious physical stimuli (conducted by faster, larger, more heavily
myelinated fibers) are given preferential passage through the gate,
lessening or eliminating the incoming pain (noxious) stimulus.
Humans unknowingly apply this concept on a daily basis to relieve trivial
noxious insults. For example:
Scratching (nonnoxious physical stimulus) a mosquito bite (noxious
chemical stimulus) to relieve the itch (pain)
Rubbing (nonnoxious physical stimulus) the elbow (“funny bone”) after
bumping it on a door frame (noxious physical stimulus) to relieve the
pain
The “pain team” purposefully applies this concept to treat pain
nonpharmacologically:
Massage
Physiotherapy
Peripheral nerve stimulation
Spinal cord stimulation

Clinical Relevance
 Chronic pain: pain that extends beyond the expected period of healing (> 3
months), with an underlying pathology that is insufficient to explain the
presence or extent of the pain. Chronic pain can disrupt sleep, daily
activities, and psychosocial function. Chronic pain is commonly seen in
individuals with malignancies and requires a very personalized
management approach.
Pain management: Today, medical professionals have myriad—both
pharmacologic and nonpharmacologic—options to alleviate pain. The
specific management strategy followed depends on the type of pain and
the individual's circumstances, perspective, and underlying condition.
Complex regional pain syndrome (CRPS): condition characterized by
excruciating pain that is out of proportion to the inciting event and is
accompanied by allodynia, temperature abnormalities, skin discoloration,
and edema, among other findings. This syndrome affects women more
often than men and is often incited by trauma. Diagnosis is clinical,
supported by the Budapest Consensus. Complex regional pain syndrome is
closely related to litigation of work-related issues, requiring special care by
the physician.

References
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