Pathophysiology of Pain

Definition of Pain

• Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage.
• Most common symptom that brings patients to see a physician.

Purpose of Pain

• Protective in nature: withdrawal from heat source, limit damage to joints to prevent further injury.
• Leads to learned behaviors: avoidance, behaviors can become dysfunctional.

Anatomy of Pain

• The somatosensory system provides information about: touch, proprioception, temperature, pain, and itching.
• The somatosensory system consists of:
  • Peripheral nervous system
  • Spinal cord
  • Brain (somatosensory cortex, thalamus)

First-Order Neurons

• Cell body located in the dorsal root ganglion and lies in the vertebral foramina at each spinal cord level.
• Each neuron has a single axon that bifurcates:
  • One end travels distal to the periphery.
  • The other end travels into the dorsal horn of the spinal cord.

Axons

• The neuronal process that carries the action potential from the nerve cell body to a target.
• In the somatosensory system, primarily concerned with 3 fibers:
  • A-beta fibers
  • A-delta fibers
  • C fibers
• May or may not be myelinated, which impacts the speed of signal transmission.

Somatic Sensory Receptors

• Diverse in composition:
  • Free nerve endings in the skin
  • Specialized nerve endings (act as amplifiers or filters)
  • Sensory terminals associated with specialized transducing cells
• All somatic sensory receptors fundamentally work the same way:
  • Stimuli applied to the skin deform or otherwise change the nerve ending, which affects the ionic permeability of the receptor membrane.
  • The resulting change in permeability generates a depolarizing current, thereby triggering action potentials.

Mechanoreceptors

• Respond to tactile non-painful stimuli.
• Provide information regarding:
  • Touch
  • Pressure
  • Vibration
  • Tickle
  • Position senses (static position and rate of movement)
• Divided into two functional groups based on their response during stimulation:
  • Rapidly adapting
  • Slowly adapting
• Four major types of mechanoreceptors:
  • Meissner's corpuscles
  • Pacinian corpuscles
  • Merkel's disks
  • Ruffini's corpuscles

Thermoreceptors

• Function to detect changes in temperature using two types of receptor cells:
  • Warm: sense temperatures between 30-45°C
  • Cold: sense temperatures between 17-27°C
• Poor indicators of absolute temperature.
• Sense of temperature comes from the comparison of signals from the two types of receptors.

Nociceptors

• Relatively unspecialized nerve cells with "free endings" that initiate the sensation of pain.
• Conduction along the axons is relatively slow compared to that of mechanoreceptors.
• Split into two pathways:
  • Fast pain: A-delta fibers
  • Slow pain: C fibers

Spinal Cord Anatomy

• Gray matter:
  • Dorsal horn (sensory)
  • Ventral horn (motor)
  • Lateral (autonomic)
• White matter
• Central canal

Rexed's Laminae

• Lamina I:
  • Marginal layer
  • Receives noxious stimuli from cutaneous and deep somatic tissues via both A-delta and C fibers
  • Relays pain, temperature
• Lamina II:
  • Substantia gelatinosa of Rolando
  • Receives noxious stimuli from C fibers and A-delta fibers to a lesser degree
  • Relays pain, temperature, and mechanical (light touch) information
  • Considered major site of action for opioids
• Lamina III/IV:
  • Nucleus proprius
  • Receives input from A-beta and A-delta fibers
  • Relays proprioception, mechanical, pain, and temperature sensations
  • First synapse in the spinothalamic tracts occur here

Ascending Pathways

• Dorsal column pathway:
  • Carries sensory information from the body
  • Axons enter the spinal cord and travel ipsilaterally
  • Decussate at the level of the medulla
  • Axons terminate in the thalamus
• Spinothalamic pathway:
  • Carries sensory information from the body
  • Axons enter the spinal cord and travel contralaterally
  • Decussate at the level of the spinal cord
  • Axons terminate in the thalamus

Neurotransmitters

• Pain initiators:
  • Glutamate
  • Substance P
  • Calcitonin gene-related peptide
  • Asparate
  • Bradykinin
  • Prostaglandins
• Pain inhibitors:
  • GABA
  • Serotonin
  • Endorphins
  • Enkephalins
  • Dynorphin
  • Glycine
  • Adenosine
  • Norepinephrine
  • Acetylcholine
  • ATP### Third-Order Neurons
• Cell body located in the thalamic relay nuclei
• Axons synapse in the thalamus with second-order neurons (specifically in the ventro-posterior thalamus)
• Axons terminate on the somatosensory cortex (Area I in the postcentral gyrus of the parietal cortex and Area II in the superior wall of the Sylvian fissure)
• Send fibers to areas of the postcentral gyrus of the parietal cortex and superior wall of the Sylvian fissure

Somatosensory Cortex

• Receives sensory aspects of pain
• Interacts with anterior cingulate cortex, which is associated with emotional distress related to pain
• Linked to limbic cortex and insular cortex, which are associated with emotion and addiction

Descending Pain Pathway

• Responsible for pain inhibition
• Descending neurons originate in the periventricular and periaqueductal gray
• Transmit through the nucleus raphe magnus to the substantia gelatinosa via the descending dorsolateral funiculus
• Upon reaching Rexed's lamina II, synapse with interneurons

Periaqueductal Gray Matter

• Located around the cerebral aqueduct within the tegmentum of the midbrain
• Initiates pathway for pain inhibition
• Releases both enkephalin and GABA

Nucleus Raphe Magnus

• Thin midline nucleus located in the pons and upper medulla
• Transmits second-order signals via the dorsolateral columns in the spinal cord to the dorsal horns of the spinal cord
• Releases 5-HT (serotonin) which descends to the dorsal horn of the spinal cord and forms excitatory connections with inhibitory interneurons located in lamina II

Key Inhibitory Neurotransmitters

• Enkephalin: released by periaqueductal gray matter, inhibits pain
• Serotonin: released by nucleus raphe magnus, inhibits pain
• GABA: released by periaqueductal gray matter, inhibits pain

Pain Pathways

• Dorsal column system: responsible for transmission of sensory information from mechanoreceptors, thermoreceptors, and nociceptors
• Descending pain pathway: responsible for pain inhibition
• Ascending pain pathway: transmits pain information from the spinal cord to the thalamus and somatosensory cortex

Theories of Pain

• Descartes' Theory of Pain: describes pain as a perception that exists in the brain and makes a distinction between the neural phenomenon of sensory transduction and the perceptual experience of pain
• Specificity Theory of Pain: proposes that each modality has a specific receptor and associated sensory fiber that is sensitive to one specific stimulus
• Intensity Theory of Pain: defines pain as an emotion that occurs when a stimulus is stronger than usual
• Pattern Theory of Pain: proposes that sensory impulses are coded according to the number of receptors stimulated and the rate of their discharge
• Gate Control Theory of Pain: proposes that the "gate" in the spinal cord is the substantia gelatinosa, which modulates the transmission of sensory information from primary afferent neurons to transmission cells in the spinal cord

Mechanoreceptors

• Divided into two functional groups: rapidly adapting (respond at the onset/offset of the stimulus) and slow adapting (respond throughout the duration of the stimulus)
• Four major types: Meissner's corpuscles (rapidly adapting), Pacinian corpuscles (rapidly adapting), Merkel's disks (slow adapting), and Ruffini's corpuscles (slow adapting)

Thermoreceptors

• Function to detect changes in temperature using two types of receptor cells: warm (sense temps between 30-45°C) and cold (sense temps between 17-27°C)
• Poor indicators of absolute temperature, sense of temperature comes from the comparison of signals from the two types of receptors

Nociceptors

• Relatively unspecialized nerve cells with "free endings" that initiate the sensation of pain
• Conduction along the axons is relatively slow compared to that of mechanoreceptors
• Split into two pathways: fast pain (A-delta fibers) and slow pain (C fibers)
• Present in both somatic and visceral tissues, with three major classes: A-delta mechanosensitive nociceptors, A-delta mechanothermal nociceptors, and polymodal nociceptors

Somatic Sensory Receptors

• Receptor type, location, function, and associated axon:
  • Meissner's corpuscles: glabrous skin, touch and vibration, A-beta fibers
  • Pacinian corpuscles: subcutaneous tissue, interosseous membranes, and viscera, vibration, A-beta fibers
  • Merkel's disks: all skin, hair follicles, continuous touch, A-beta fibers
  • Ruffini's corpuscles: all skin, continuous heavy touch and pressure, A-beta fibers
  • Thermoreceptors: skin, temperature, A-delta fibers (cold receptors) and C fibers (warmth receptors)
  • Free nerve endings: skin, organs, pain, itch, touch, and pressure, A-delta fibers and C fibers

Definition of Pain

• International Association for the Study of Pain: an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage
• Most common symptom that brings patients to see a physician

Purpose of Pain

• Protective in nature, leading to withdrawal from heat sources and limiting damage to joints to prevent further injury
• Leads to learned behaviors, including avoidance and dysfunctional behaviors

Anatomy of Pain

• The somatic senses are the nervous mechanisms that collect sensory information from all over the body
• The somatosensory system provides information about touch, proprioception, temperature, pain, and itching
• The somatosensory system consists of the peripheral nervous system, spinal cord, and brain
• Afferent neurons and A-delta and C fibers are involved in the transmission of pain signals

First-Order Neurons

• Cell body located in the dorsal root ganglion and lies in the vertebral foramina at each spinal cord level
• Each neuron has a single axon that bifurcates, with one end traveling distal to the periphery and the other end traveling into the dorsal horn of the spinal cord

Axons

• The neuronal process that carries the action potential from the nerve cell body to a target
• Fasciculus gracilis (axons from lower body/legs) and fasciculus cuneatus (axons from upper body/arms) are involved in the transmission of pain signals

Dorsal Column Pathway

• First-order axons in the dorsal column rapidly travel ipsilaterally and terminate in the medulla where they synapse with second-order neurons
• Axons in this pathway mediate sensation and proprioception
• Axons decussate the midline of the medulla and ascend the brainstem as a bundle called the medial lemniscus
• Second-order neurons terminate in the thalamus and synapse with a third-order neuron

Trigeminal Pathway

• Carries sensory information from the face, head, mouth, and nasal cavity
• Axons enter the brain stem at the level of the pons or the mesencephalic nuclei in the midbrain
• Axons carry information similar to that of the dorsal column pathway (touch/pressure/vibration/proprioception)

Alternative Pain Pathways

• Spinoreticular tract: mediates arousal and autonomic responses to pain
• Spinomesencephalic tract: may activate antinociceptive pathways
• Spinohypothalmic and spinotelencephalic tracts: evoke emotional behavior
• Spinocervical tract: alternative pathway for pain
• Fibers in the dorsal columns: responsible for light touch and proprioception

Second-Order Neurons

• Cell body location varies based on ascending pathway
• Location that the axon decussates is dependent upon the ascending pathway the particular neuron is located in
• Two types of second-order neurons: wide dynamic range and narrow dynamic range
• Wide dynamic range neurons are primarily responsible for touch, pressure, vibration, and proprioception
• Narrow dynamic range neurons are primarily responsible for pain and temperature sensations

Gate Control Theory of Pain

• Proposed that the "gate" in the spinal cord is the substantia gelatinosa in the dorsal horn
• The gating mechanism is controlled by the activity of the large and small fibers
• Small fibers (pain sensations) facilitate/open the gate
• Large fibers (non-pain sensations) inhibit/close the gate