Pain Pathways and Perception

Lecture Objectives

• The lecture covers topics of central transduction pathways, phases and types of pain
• Sensitization mechanisms
• Pain pharmacology & analgesia
• The placebo effect

Spinothalamic Tract

• The spinothalamic tract is a sensory pathway originating from the skin and leading to the thalamus
• Sensory data moves upward from the ventral posterolateral nucleus in the thalamus, to the somatosensory cortex of the postcentral gyrus wherein pain is felt
• The spinothalamic tract has two adjacent pathways: anterior and lateral
• The anterior spinothalamic tract relays crude touch data
• The lateral spinothalamic tract conveys pain and temperature information

Brain Areas Active in Processing Pain

• Imaging studies show consistent brain activity in areas which process and regulate pain
• Cognition, mood, injury type, nerve activation, stimulus duration, genetics and endocrine factors all play a role

Control of Pain Perception

• There is a difference between objective injuries and the subjective pain from them
• People may feel different pain levels from similar injuries
• Context dictates whether or not pain is felt, like battlefield injuries during sports competition
• There is a physiological mechanism that controls transmission of nociceptive signals to the brain or that may alter pain interpretation
• Pain controlling systems could possibly explain the placebo effect

Substantia Gelatinosa

• Primary afferent Aδ- or C-fibers carry nociceptive information

Gate Control Theory (GCT) of Pain

• A paper was presented in 1965 by Patrick Wall and Ronald Melzack defining gate control theory of pain
• Nociceptive and non-nociceptive signals are summed in the spinal cord
• Large nerves conduct non-nociceptive information, while smaller fibers conduct nociceptive information
• Pain signals propagate when nociceptive signals outweigh non-nociceptive signals
• Descending afferent fibers adjust pain signals inside the spinal cord
• A gating mechanism controls input within the dorsal horn of the spinal cord
• Inhibitory neurons block projection neurons from signaling the brain if there is no input, keeping the gate closed
• More large-fiber stimulation means normal somatosensory input
• Both projection and inhibitory neurons are stimulated, but the inhibitory neuron stops the signal transmission, and the gate remains closed
• Nociception (or pain reception) occurs with more small-fiber stimulation
• Inhibitory neurons are deactivated and projection neurons send signals, informing the brain of pain, opening the gate

Descending Pain Modulation Pathways

• Nerve signals travel from the somatic sensory cortex and hypothalamus to the periaqueductal gray matter (PAG)
• PAG relays signals to the parabrachial nucleus, medullary reticular formation, locus coeruleus, and Raphe neulei.
• These control transmission of nociceptive signals between the spinal cord and the brain
• This process involves different neurotransmitters

Phases of Pain

• According to Cervero and Laird, pain can be viewed in three phases:
• The phases aren't exclusive, as several mechanisms may happen in the same individual simultaneously

Three Phases of Pain

• Acute pain occurs with a transient noxious stimulus, propagated predominantly by Aδ fibres
• Chronic nociceptive pain arises from prolonged noxious stimulation, creating a substrate
• Nociceptive spinal cord neurons respond by modifying their responses, and become more excitable, causing stimulation of injured area and pain from uninjured surrounding area
• Neuropathic pain is a result of injury or damage where correlations happen with the neural tissue

Chronic Pain States

• Increased response (or increased pain) to a stimulus that is normally painful is hyperalgesia
• Pain evoked by a stimulus that does not normally produce pain is allodynia
• Sensitization is an enhancement of the response of nociceptive pathways after prolonged input of stimuli of certain intensity

Allodynia and Hyperalgesia

• Primary hyperalgesia is the result of events and mechanisms occurring in the periphery
• This happens at the primary afferent nociceptive fibers
• Secondary hyperalgesia is mediated by central mechanisms

Peripheral Mechanisms of Sensitization

• Cutaneous tissue damage/inflammation that can cause two zones of pain
• Punctate Hyperalgesia
• Brush Hyperalgesia
• Capsaicin Injection
• Flare
• Mechanical Stimulation
• Area of primary hyperalgesia is located over the original tissue damage itself
• It has spontaneous pain with increased sensitivity to mechanical, thermal, and chemical stimuli
• Area of secondary hyperalgesia has greater sensitivity to mechanical, but not thermal stimuli in undamaged region near the first zon
• the increase in pain above normal levels perceived to mechanical stimulation produced by a small contact diameter probe such as a von Frey hair is Punctate hyperalgesia
• Alloknesis is pruriceptive sensation (or itch) that can cause scratching behavior evoked in response to a non-pruriceptive stimulus

Central Mechanisms of Sensitization

• Sensitization includes greater spinal cord responsiveness after intense/prolonged nociceptive input
• This includes the dorsal horn neurons, nerve relays and ventral horn neurons
• The thalamus, cortex, and other brain regions undergo relevant changes
• Reduced stimulus intensity can lead to a higher response from stimuli owing to central sensitization

Peripheral vs Central Mechanisms of Sensitization

• Pain threshold lowers in primary afferent neurons
• Protein kinases A and C are phosphorylated, and activation of TRPV1 receptors
• Upregulation occurs of voltage-gated sodium channels and TRPV1 receptors in DRG
• Substance P and CGRP production increases in the periphery and spinal cord
• The spinothalamic tract terminates in the thalamus for somatosensory discrimination
• The mid/anterior insula, anterior cingular cortex, and prefrontal cortex all play a role in pain's affective/motivational components
• PAG and RVM have fight-or-flight responses related to stress-induced analgesia, reticular formation controls descending pathways
• The hypothalamus and amygdala are part of the spinoparabrachial pathway and have autonomic and sensory coordination

Nociceptive, Inflammatory and Pathological Pain

• Nociceptive pain has noxious stimuli which result pain with autonomic response
• In inflammatory pain Peripheral inflammation can cause tenderness that promotes repair
• In Pathological pain, neuropathic pain causes Maladaptive reactions and stroke
• Dysfunctional pain has altered tissue but abnormal central processing that leads to "Nociplastic pain"

Inflammatory Cocktail and Sensitization

• Phosphorylation of receptors and secondary messengers plays a role
• Receptor trafficking and regulation of gene expression influence pain

Dorsal Horn Sensitization

• Both central and peripheral mechanisms are contributing factors
• Long-term potentiation (LTP) occurs in the hippocampus with memory and learning