Chapter 2: Pain Transmission and Central Sensitization

second-order neurons

neurons in the spinal cord that receive input from the periphery

primary afferent

neurons with fibers that extend into peripheral tissue on one end, and into the spinal dorsal horn on the other end, with cell bodies residing in the dorsal root ganglia, also called primary sensory neurons

reflex arc

the system in place to mediate reflexive withdrawal responses

when a nociceptor detects a noxious stimuli, this signal is sent to the laminae of the dorsal horn. when signal reaches the horn, interneurons are activated which in turn activate motor neurons which release acetylcholine causing a contraction of muscle and a withdrawal response

decussate

cross over

what happens to the axons of second order neurons in the spinal cord related to nociception?

axons for second order neurons for most nociceptive information will decussate to the opposite side of the spinal cord and following ascending paths to the brain

spinothalamic tract (STT)

the major ascending spinal projection pathway for transmission of nociceptive, crude touch, and thermal information from cutaneous and visceral structures

neurons project from the spinal cord to the thalamus, originate from second order neurons in the spinal dorsal horn

quickly decussate in the ventral white commissure, and ascend to the brain contralateral

electrical stimulation produces pain and lesions of this impair pain sensation

cutaneous

related to the skin or surface tissue

visceral

from the internal organs

thalamus

a major site for integration of sensory information

somatotopically organized

the relationship between input origin and final destination such that areas that are close together on the body send signals to areas that are close together in the somatosensory map in the brain

sacral

fibers from this origin are most lateral

related to lower spine and tailbone

cervical

fibers from this origin are most medial

related to the neck

lateral division of the SST

forms a direct, monosynaptic pathway to the ventral posterolateral (VPL) nucleus within the thalamus

third-order neurons then project to the primary somatosensory cortex

important for coding the sensory-discriminative qualities of a stimulus, such as its intensity, location, and duration

carries axons from wide dynamic range afferent neurons with restricted receptive fields

most cell bodies found in laminae I and V

anterior division of SST

phylogenetically older than the other division

axons ascend a few levels before decussating

project via the anterior funiculus to the more medial, intralaminar thalamus, many of which divide along the way to medullary, pontine, and midbrain regions

ascends parallel to the other tract

axons originate with high threshold, nociceptive-specific neurons with large receptive fields

most cell bodies found in laminae VI-VIII

laminae of the dorsal horn

the layers of cells in the dorsal horn of the spinal cord where different cells from the periphery converge on interneurons and projection cells, often defined by the type of cells terminating and/or present in each area

spinoreticular tract

contains axons of second-order neurons that project from the spinal dorsal horn to the reticular formation of the hindbrain

multisynaptic pathway comprised of axons originating mainly in deeper laminae of the dorsal horn (primarily VII-VIII)

decussate and ascend in the ventrolateral funiculus, forming a major direct projection to the reticular formation

important for arousal, autonomic and behavioral reflexes, emotional aspects of pain, and descending nociceptive regulation

neurons respond to noxious and innocuous cutaneous and visceral mechanical stimuli, noxious heat, and light tactile stimuli, and are thought to have large receptive fields covering broad areas of the body

postsynaptic dorsal column (PSDC) pathway

transmission of noxious sensory information from deep tissues

second-order spinal neurons giving rise to axons are localized primarily to laminae III and IV with another column located in lamina X

which ascending spinal tract sends projections to the reticular formation first?

spinothalamic tract

spinoreticular tract

dorsal column tract

reticulospinal lemniscus tract

spinoreticular tract

interneurons

contribute to early integration of sensory information before its transmission to the brain, and some also relay directly to ventral horn neurons to coordinate reflex behaviors

propriospinal

local neurons in the spinal cord that make connections across multiple segments and are often involved in coordination of sensorimotor reflexes

ascend and descend many segments to connect various levels of the spinal cord

these neurons are important for coordination of motor reflexes between cervical and lumbar spinal regions and for heterosegmental inhibition of nociception

heterosegmental

across multiple sites

supraspinal

above the spine, brain

Amygdala, caudate, Hippocampus, Nucleus Accumbens, putamen, prefrontal cortex

emotion/behavior

emotion, value, motivation

chronic pain; maladaptive pain-related emotion and behavior

prefrontal cortex, anterior cingulate cortex, secondary somatosensory cortex, insular cortex

pain affect/cognitive control

pain affect/ unpleasantness

context-dependent influences

cognitive control of pain

insular cortex, supplementary motor area, primary motor cortex, primary somatosensory cortex, temporal-parietal junction

sensory/motor/multisensory

escape planning and motivation

integration of motor and sensory aspects of pain

encode intensity of pain

receive nociceptive input from spinal cord

multisensory integration

chronic pain: altered higher-level pain process (TPJ)

periacqueductal gray, locus coeruleus, rostral ventral medulla

descending pain modulation

chronic pain: dysfunctional descending control of pain

what are nociceptors to do once terminated in the spinal cord?

once terminated in the spinal cord, their job is to transmit the periphery signals they have detected and transduced to the CNS

transmission accomplished through the release of neurotransmitters and co-transmitters into the synaptic cleft between primary afferent (excitatory) and second-order neurons

glutamate

the most abundant excitatory amino acid in the peripheral and CNS

classified as a nonessential amino acid and is synthesized in neurons from local precursors such as glutamine

binds to and activates four unique types of cell surface receptors that include ionotropic (AMPA, NMDA, and kainate receptors) ligand gated changes and a group of metabotropic receptors

glutamate binding to AMPA receptors

a rapid transient EPSP is generated in response to a rise in intracellular sodium entering through the receptor

sets the baseline response of dorsal horn neurons to noxious stimulation

NMDA receptors

dependent upon the degree of postsynaptic depolarization

at resting potentials, blocked by the presence of a magnesium ion

only with high intensity, or sustained transmission, that postsynaptic depolarization is of sufficient amplitude or duration to expel the magnesium ion from the channel, allowing synaptic transmission

wind-up

a neural phenomenon whereby postsynaptic responses increase to repetitive stimuli of fixed intensity, occurs as result of NMDA receptor priming

consequence of dual excitatory amino acid (EAA) and neuropeptide release, acting at postsynaptic NMDA and tachykinin recepotrs

central sensitization

changes to the central nervous system in response to painful input, resulting in increased sensitivity to nociceptive input

metabotropic glutamate receptors (mGluRs)

a family of G-protein-coupled receptors responsible for slower glutamatergic neurotransmission

g-protein-coupling among the groups differs

whether inhibit or enhance pain depends on their location

group 1 receptors

(mGlu1 and mGlu5)

receptors potentiate NMDA receptor function, phosphorylate extracellular signal-related kinases and decrease voltage-gated potassium currents, thus contributing to enhanced pain, in the dorsal horn

in peripheral terminals of primary afferents and in supraspinal sites, effects are pro-nociceptive and antinociceptive, respectively

Group II receptors

(mGlu2 and mGlu3)

expressed primarily in presynaptic neurons where they regulate neurotransmitter release, and are antinociceptive regardless of their site of action

group III

(mGlu4, mGlu6, mGlu7, and mGlu8)

evidence that they presynaptically modulate neurotransmitter release and alter nociceptive transmission in a site- and state-dependent fashion

which receptor type is likely to allow for fast responses?

ionotropic

metabotropic

g-protein coupled

opioid

ionotropic - because activation of ionotropic receptors opens an ion channel in the pore, they are fast responders

substance p

neuropeptide that is highly expressed in dorsal root ganglia and in the dorsal, but not ventral, grey matter of the spinal cord - supportive evidence for the involvement in neurotransmission between primary afferent and second-order neurons

CGRP

poorly defined role in pain-related neurotransmission on the basis of depletion, augmentation, and antagonism studies

clearest role in nociceptive transmission relates to its peripheral effects, which play a prominent role in migraine associated pain

ATP

plays a role in neurotransmission and neuromodulation in nociceptive pathways

activates two distinct families of receptors that include the ligand-gated, purinergic P2X family of ion channels and metabotropic, G-protein couples P2Y receptors

facilitates GABA and glycine-mediated inhibitory neurotransmission involving spinal interneurons

purinergic receptors

expressed by both primary afferent neurons and second-order neurons in the dorsal horn

through theses receptors that ATP modulates neurotransmission in the spinal cord

GABA and glycine

inhibitory amino acids responsible for fast inhibitory neurotransmission in the CNS of mammals

occur primarily in the response to activation of ionotropic receptors that, when open, allow for rapid flow of negatively charged chloride ions across the cell membrane

GABAA

activation of these receptors in presynaptic primary afferent terminals results in a reduction in neurotransmitter release to second-order neurons

in postsynaptic spinal cord neurons, directly reduces neuronal excitability, limiting the possibility of sending a pain signal to the brain

subject to changes in intracellular chloride concentration, largely determined by chloride cotransporters - signal switches from excitatory to inhibitory during maturation of the central nervous system

GABAB

slower mechanism of action that promotes an outward (inhibitory) current in second-order spinal neurons

actions on motoneurons effectively decrease muscle tone and spasticity also exhibit direct analgesic properties

inhibitory amino acids GABA and glycine are responsible for fast inhibitory response. What type of receptor would these molecules activate?

ionotropic

metabotropic

g-protein coupled

opioid

ionotropic - because activation of these receptors opens an ion channel in the pore, they are fast responders

opioids

major component of pain inhibitory systems

three peptide families: b-endorphin, enkephalins, and dynorphins that bind to three G-protein coupled receptors (mu, delta, and kappa)

arise from large precursor molecules that are broken down into receptor-specific peptide ligands

modulation of many ion channels by these reduces neurotransmission in seconds to minutes, through suppression of excitatory neurotransmitter release and reduced neuronal excitability

exogenously

these opioid agonists that bind to mu receptor (which may act directly at spinal sights, or may involve supraspinal actions that produce spinal effects through descending mechanisms involving serotonin and norepinephrine) are the cornerstone of analgesic therapy for severe pain

kappa receptors

endogenous dynorphins and exogenous agonists that bind to this produce analgesia when administered peripherally, but are neurotoxic when administered at high doses

pain

multidimensional experience that is the net result of many dynamic processes

once physical stimulus is transduced into a neural signal, that signal is subject to alteration at peripheral, spinal, and supraspinal levels

peripheral sensitization

refers to the reduced threshold and increased magnitude of responsiveness of nociceptive neurons in the periphery to stimulation of their respective fields

commonly occurs after tissue injury, when endogenous chemicals, inflammatory mediators, are released at the site of damage

does not account for other temporal, spatial, and threshold changes commonly observed with clinical pain

hyperalgesia

increased pain that occurs within the damaged tissue during the healing period (think sunburn)

sources of inflammatory mediators

including immune cells, epithelial cells, fibroblasts, platelets, and even neurons themselves

central sensitization

manifestations: pain arising spontaneously, evoked by normal non-painful stimuli, and that extends beyond the site of injury to non-injured tissues

drugs that reduce primary hyperalgesia are not effective in attenuating centrally mediated types of pain suggesting differences in underlying mechanisms

results from long-lasting increases in membrane excitability and synaptic efficacy, and reduced inhibition of CNS neurons

hallmark feature is the conversion of incoming signals that would normally faily to generate postsynaptic AP to pain-producing activity because this perception of pain results from changes in CNS neurons, pain is no longer coupled to the presence, intensity, or duration of noxious peripheral

calcium entry through NMDA receptor activation is a prominent component in its initiation although AMPA and metabotropic glutamate receptors may contribute

central sensitization vs wind-up

central sensitization is sustained well beyond the cessation of the input that initiates it unlike wind-up

why is central sensitization thought of as “pain memory”

because the same cellular mechanisms responsible for memory are at work in the spinal cord

how is nociceptive input modulated?

beyond the interneurons, input into the dorsal horn is also modulated by descending inhibitory and facilitatory influences from supraspinal sites

descending modulation

provides a basis for the integration of cognitive and motivational influences on sensory input from the periphery before it reaches the brain

important sites for descending modulatory influences on spinal nociceptive processing

midbrain periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) of the brainstem comprise a well-characterized, reciprocally connected pathway that is activated by ascending nociceptive input

stimulation produced analgesia (SPA)

electrical stimulation of the PAG was first show long ago to reduce spinal neuronal responses and behavioral responses to noxious stimulation

effects comparable to that produced by a high dose of morphine, with a rapid onset and variable duration (seconds to hours)

cross-tolerance

in pharmacology, tolerance to a substance due to previous exposure to a similar substance

Rostral ventromedial medulla (RVM)

a collection of brainstem nuclei situated between the PAG and spinal cord, rich source of serotonergic neurons

within this, the nucleus raphe magnus (NRM) receives strong projections from the PAG and its stimulation produces effects similar to SPA

“ON” cells

activity of these cells increases during nociceptive input to enhance nociceptive signaling

studies demonstrate that the projections from PAG to these cells tend to be GABAergic

“OFF” cells

normally active and turn off during nociceptive input, studies demonstrate that the projections from PAG to these cells tend to be glutamergic

PAG activation effects

this causes the release of endogenous opioids, which leads to opioid receptors inhibiting GABAergic interneurons in the PAG, allowing the glutamatergic projection to “OFF” cells to fire, reducing pain
within RVM the “ON” cells are thought to have opioid receptors on their cell bodies such that endogenous opioids inhibit these cells to further reduce pain transmission

noradrenergic A6 cell group and adjacent locus coeruleus

extensive axonal projections to the spinal cord, descending modulation arising from these neurons can be either inhibitory or facilitatory

if you enhanced the firing of “ON” cells in the RVM, what effect would this have on pain?

none

increase

decrease

there are no “ON” cells in the RVM

increase

neurons from the periaqueductal gray project to what specific region in the descending pain modulation circuit?

RVM

Thalamus

Ventral Horn

DRG

RVM - The PAG projects to the RVM as the final common pathway for descending modulation of pain.

the primary monoamine systems (DA, NE, 5-HT) all project to what area to modulate pain transmission?

PAG

RVM

Dorsal Horn

DRG

Dorsal Horn - the primary monoamine systems project to the dorsal horn to modulate the pain signal

What is the term for enhanced pain sensation during repeated stimulation?

central sensitization

peripheral sensitization

wind-up

facilitation of proprioception

wind-up - the process whereby repeated stimulation can result in greater sensation

when the patellar tendon is struck, causing a rapid “kicking” motion, what is this an example of?

descending modulation

ascending modulation

gate control theory

reflex arc

reflex arc - stricking the patellar tendon sends a signal to the spinal cord that, in turn sends a signal to the motor neurons to cause a reflexive withdrawal as part of the reflex arc

what phenomenon is thought to underlie a number of chronic pain conditions in which hypersensitivity to peripheral stimuli are a major issue?

wind-up

peripheral sensitization

central sensitization

descending modulation

central sensitization - the enhanced response to non-noxious stimuli that may develop over time as a result of changes to NMDA/AMPA receptors in the spinal cord are primary mechanisms underlying central sensitization