Pathyphysiology of Pain MDR, Pain Management in Horses VCNA, Cornell Pain Video

What is chronic pain classified as?

Pain lasting longer than 3 months from the initial stimulus

Transduction

Process by which a nociceptive stimulus is transferred to the dorsal horn of the spinal cord, where it can undergo modulation, prior to traveling to the thalamus for further processing, and to create the perception of pain

A-delta fibers

Myelinated fibers

Allow rapid impulse conduction

Conduct both nociceptive and non-nociceptive impulses

Distributed at high receptor density in the periphery with a very small receptive field

Activation results in sharp, well-localized pain sensations

Activated by changes int he tissue environment

• Have specific receptors that sense mechanical stimulation (“high-threshold” nociceptors), thermal input (heat or cold), and chemical irritation

Map to laminae I and V of the dorsal horn of the spinal cord

A-beta Fibers

Myelinated fibers

Conduct non-nociceptive information under normal circumstances

Important for proprioception

Chemicals that Can Trigger Nociceptive Signals

Increased concentrations of H+ or K+

Histamine

Calcitonin gene-related peptide (CGRP)

PGE2, produced from arachidonic acid by COX

C-Fibers

Unmyelinated so slower transmission rates than A-beta and A-delta fibers

Burning or throbbing pain

Polymodal receptors that respond to changes in temperature (hot or cold), pressure, and pH, and communicate with wide dynamic range neurons

Have a higher activation threshold than A-series fibers

Map to lamina II, also called the substantia gelatinosa (SG)

What mediates visceral pain?

Predominantly C-fiber mediated

Nociception at the Level of the Spinal Cord

Nociception activation triggers the release of neurotransmitters such as glutamate (primarily from A-delta fibers) and substance P (primarily C fibers), and CGRP

• Substance P interacts with the neurokinin1 receptor (NK-1)

• Glutamate has 3 receptors

  • Metabotropic glutamate receptor (mGLuR)

  • a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor

  • n-methyl-d-aspartate (NMDA)

    • Calcium channel

    • Usually inactive due to the presence of a magnesium ion in the channel

    • With excessive (repetitive or high frequency) stimulation, the Mg is released, and the NMDA channel becomes available to transmit signals from released glutamate

Release of neurotransmitters activates second order neurons, which decussate to the contralateral side of the spinal cord and travel to the brain along spinal tracts

Neospinothalamic Tract

Directs impulses to the thalamus, then to the sensory cortex

Carries impulses primarily from A-delta fibers

Paleospinothalamic Tract

Directs impulses to the peri-aqueductal gray, pons, and medulla, in addition to the thalamus

Carries impulses from primarily C fibers

Spinoreticular Fibers

Carry nociceptive information to the reticular formation, which governs arousal and results in the autonomic and motor responses to pain

Where are signals transmitted to the thalamus projected?

Projected to the somatosensory cortex and limbic system, resulting in the recognition of the presence of pain

Where does modulation of pain occur?

Centrally at the cerebral cortex

Also the level of the spinal cord

Endogenous Modulation of Nociceptive Transmission

Can occur through descending inhibitory tracts from the thalamus and higher areas of the brain or by hormones (e.g. oxytocin)

The descending inhibitory tracts that originate in the periaqueductal gray cause the secretion of serotonin and activation of inhibitory interneurons that modulate the transmission of signals at the level of the SG, through release of the endogenous opioids enkephalin and dynorphin

Agonism of the mu opioid receptor on the afferent neuron prevents neurotransmitter release, while agonism on the secondary neuron results in decreased transmission in the spinal tract

• Also a target for exogenously administered opioids

Gate-Control Theory of Pain

Nociceptive input to the dorsal horn decreases activity of inhibitory interneurons, while input from the A-beta fibers (non-painful, proprioceptive sensation) has a stimulatory effect on the inhibitor interneurons (ie. decrease the transmission of nociceptive input through negative interneuron influence)

If the frequency of firing from the A-beta fiber exceeds that of the C-fiber, transmission to the dorsal horn, or to the projection of neurons may be inhibited

Wind-Up

An increased pain sensitivity

Results from prolonged nociceptive stimulation

Wind-Up in the Periphery

A change of the physiologic properties of the nociceptors, such that even non noxious stimuli activate nociceptive input (“peripheral sensitization”)

Wind-Up at the Spinal Cord

Constant release of glutamate results in release of Mg from NMDA receptor ion channels and results in hyperexcitability of dorsal horn neurons (“central sensitization”)

Substance P and calcitonin gene-related peptide (CGRP) release from C-fibers may have an additive effect on NMDA receptor activation

What parts of the pain pathway do nociceptors participate in?

Transduction

What parts of the pain pathway do Ad and C fibers participate in?

Transmission

What parts of the pain pathway does the spinal cord participate in?

Modulation

Projection

What parts of the pain pathway does the brain participate in?

Modulation, perception, localization, affective component, memory

Pain Pathway

Noxious stimuli are recognized by unimodal (recognize a single type of stimulus) or polymodal (recognize multiple types of stimuli) nociceptors located on the terminals of primary afferent neurons (Ad and C) and transduce these stimuli into action potentials

The generated action potentials are transmitted to the dorsal horn of the spinal cord by the primary afferents via the dorsal nerve roots

In the dorsal horn, primary afferents synapse with local excitatory or inhibitory interneurons that modulate the sensory signal and with second-order projection neurons that project the stimulus to the brainstem and thalmus via the spinoreticulothalamic and spinothalamic tracts, respectively

From loci in the brainstem and thalamus, third-order projection neurons relay the signals to the somatosensory cortex, where location and intensity of the stimulus are identified

From the brainstem and amygdala, projection neurons reach the cingulate and insular cortices, which are responsible for the affective/aversive component of the pain experience

Descending pain-moduatory systems exert their modulatory effect predominantly via connections in the dorsal horn through release of neurotransmitters such as serotonin, norepinephrine, and dopamine

The neurotransmitter released and receptor subtype will essentially dictate an antinociceptive or pronociceptive effect

Nociceptive Pain

Produced by activation of high-threshold Ad and C-fiber nociceptors

Peripheral Mechanisms of Nociceptive Pain

Noxious stimuli acts on mechanotransducers, thermotransducers, and chemotransducers

Physicochemical stimuli (pressure, temperature, chemicals) activate ion channels located on sensory nerve endings, creating a transient change in membrane potential that is amplified by sodium channels such as Nav1.8 and Nav 1.9 to form a “regenerative potential”

At this point, endogenous inhibition may occur via activation of potassium channels such as the 2 pore channels TRAAK1 and TREK-1 or further amplified by sodium channels such as Nav1.8 and tetrodotoxin (TTX) - sensitive sodium channels to create an action potential that is propagated toward the CNS where is will be modulated and perceived

Peripheral Mechanisms of Inflammatory Pain

At the site of tissue injury, inflammatory mediators lead to sensitization of nociceptive (A-d and C-fibers) as well as nonnociceptive (A-beta) sensory afferents

Upon injury, inflammatory and noninflammatory cells release a host of signaling molecules

Mediators such as PGE2, bradykinin, ATP, H+, histamine, serotonin (5-HT), nerve growth factor, TNF-a, IL-6, and others activate ligand-gated ion channels and GPRCs, leading to increases in intracellular ion concentration (Na+, Ca2+), activation of calcium-dependent and cAMP-dependent protein kinases (PKC and PKA), which phosphorlyate membrane ion channels and other GPCRs, lowering their activation threshold

Altered protein trafficking and activation of transcription factors (which translocate to the nucleus located in the cell bodies within the dorsal root ganglion) lead to decreased expression of potassium channels (TRAAK, TREDK-1) and increased expression of sodium channels (Nav 1.8/1.9), contributing to lowering the activation threshold of peripheral nociceptors and increasing afferent excitability

With these changes, nerve endings begin to secrete vasoactive and proinflammatory substances, such as calcitonin-gene-related peptide (CGRP), substance P, and others

Central Mechanisms of Inflammatory Pain

Action potentials generated at the site of injury and propagated via primary afferents to the spinal cord dorsal horn, lead to activation of voltage-gated calcium channels (VGCC), calcium-dependent pre-synaptic release of neurotransmitters such as glutamate (Glut), substance P (SP), calcitonin gene-related peptide (CGRP), and brain-derived neurotrophic factor (BNDF) and activation of post-synaptic projection neurons as well as inhibitory interneurons

Glutamate is the primary mediator of excitatory neurotransmission, with modulatory influences from SP, CGRP, and BNDF

Inhibitory neurotransmitters include glycine, GABA, and opioid peptides such as enkephalin released by inhibitory interneurons

• Decrease pre-synaptic neurotranmitter release and post-synaptic neuronal excitability by activating chloride (Cl-) influx (GABA, glycine), by inhibiting adenylyl cyclase (AC) and thus preventing activation of cAMP-dependent protein kinase (PKA)

• Activate G protein-coupled inwardly rectifying potassium (GIRK) channels (enkephalin and other opioids)

Glutamate transporters located on inhibitory interneurons control synaptic concentrations of glutamate

Glutamate released during persistent nociceptive activity activates NMDA (normally blocked by magnesium, Mg2+)and metabotropic glutamate receptors (mGlut), resulting in intracellular calcium responses with subsequent activation of calcium-dependent protein kinase (PKC) as well as activation of transcription factors (TF)

PKC phosphorylates and changes the function properties of ion channels and receptors

• Phosphorylation of excitatory receptors (NMDA, mGlut) decreases their activation threshold and increases excitability

• Phosphorylation of inhibitory receptors (GABA, glycine, OR) leads to lack of responsiveness to respective ligands and decreased inhibition

Activation of transcription factors induce the synthesis of proteins such as nitric oxide synthase (NOS) and COX-2, with production of NO and PGE2

• NO and PGE2 act presynaptically to potentiate neurotransmitter release

• PGE2 also acts post-synaptically at different prostanoid receptors to activate PKA and PKC-dependent signaling mechanisms which will contribute to excitability of projection neurons

Excessive uptake of glutamate leads to death of inhibitory interneurons, further contributing to disinhibition

Microglial release of several inflammatory mediators, including TNF-a, lead to transcription changes in pre- and post-synaptic neurons that contribute to increased excitability and long-term potentiation of pain circuits

Unidimensional Pain Scoring Systems

Relatively simple, focusing primarily on pain intesnity without much regard to sensory and emotional qualities of pain

Multidimensional Pain Scoring Systems

More complex, examining the intensity as well as the sensory and affective (emotional) qualities of pain, to provide a more comprehensive assessment of aptient’s pain

Preemptive Pain Scoring (PPS) Pain Scale

Relates the expected level of pain with the invasiveness of the procedure

A degree of pain (none, mild, moderate, severe) is assigned based on this criterion

Simpile and useful for planning perioperative analgesic strategies

Does not take into account individual variation

Not useful in assessing response to therapy

Reliability of Preemptive Pain Scoring (PPS) in Horses

Not tested for reliability but useful for planning perioperative analgesic protocol

Simple Descriptive Scales (SDS) Pain Scale

The most basic pain scale

Usually includes 4 or 5 descriptors from which observers chose level (no pain, mild pain, moderate pain, severe pain, very severe pain)

Simple to use but extremely subjective and discontinuous

Heavily evaluator-dependent

Does not detect small changes in pain behavior

Reliability of Simple Descriptive Scales (SDS) in Horses

Not tested for reliability

Numerical Rating Scales (NRS) Pain Scale

These can include simple descriptive scales with numbers assigned to each pain level for ease of tabulation and analyses (0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain, 4 = very severe pain) or it may constitute numbers from 0 (no pain) to 10 (worse pain possible) placed at equal distances along a horizontal line

• This implies equal difference or weighting between numbers, which is often not the case, and they are discontinuous scales

Reliability of Numerical Rating Scales (NRS) in Horses

Not tested for reliability

Visual Analog Scale (VAS) Pain Scale

Created in an attempt to improve on discontinuous scales

This scale has been widely used in veterinary medicine

Consists of a continuous line (usually 100 mm) anchored at either end with a description of the limits of the scale (no pain at one end and severe pain at the other end)

The observer places a mark on this line corresponding to the perceived degree of pain in the horse under observation

THe pain score is the distance (in mm) from zero to the mark

Visual Analog Scale (VAS) Reliability in Horses

Tested for reliability in laminitis, colic, and synovitis

In general, it has fair (synovitis) to good (colic) to very good (laminitis) interobserver reliability

Dynamic and Interactive Visual Analog Scale (DIVAS) Pain Scale

An extension of the VAS

Horses are first observed for normal/abnormal behaviors (ie, expression, demeanor, posture, stance and mobility) from a distance undisturbed

They are then approached, handled, and encouraged to walk by offering food/treats or using a lead rope

The painful site and surrounding area are then palpated, and a final overall assessment of pain is made, usually using a 100-mm line as in the VAS

Dynamic and Interactive Visual Analog Scale (DIVAS) Reliability in Horses

Not tested for reliability but presumably at least as reliable as VAS

Used to assess laminitis pain

Composite Pain Scales (CPS)

Further development of the simple descriptive and numerical rating systems

Certain behavior categories are chosen (ie, pawing, kicking at abdomen, appetite, appearance, sweating, posture, and assigned a value according to descriptors of intensity/frequency

Composite Pain Scales (CPS) Reliability in Horses

Many uses

Has been reliably used for assessing abdominal and musculoskeletal pain

Horse Grimace Scale/Pain Face

Focuses on changes in facial expression described as low or asymmetrical ears, angle appearance of the eyes, withdrawn or tense stare, mediolaterally dilated nostrils, and tension of lips, chin, and certain facial muscles

Horse Grimace Scale/Pain Face Reliability in Horses

Used to assess postcastration pain, in 2 experimental models of acute pain (mechanical and chemical), and in horses with acute laminitis

Appears to be effective and reliable for assessing acute pain, but not yet formally validated

Therapies that Target Nociceptors (Transduction)

Local anesthetics

Morphine

Ketamine

Cryotherapy

COX inhibitors

sEH inhibitors

Surgical technique

Acupuncture

Therapies that Target Ad and C Fibers (Transmission)

Local anesthetics

Alchohol

Buprenorphine

Ketamine

Xylazine

Therapies that Target the Spinal Cord (Modulation, Projection)

Opioids

Alpha-2 agonists

Ketamine

COX inhibitors

sEH inhibitors

Tramadol

Benzodiazepines

Gabapentin

Acupuncture

Therapies that Target the Brain (Modulation, Perception, Localization, Affective Component, Memory)

General anesthetics

Opioids

Alpha-2 Agonists

Treatment Options for Nociceptive Pain

Local or general anesthetics

Opioids

Alpha-2 agonists

Acupuncture

Treatment Options for Inflammatory Pain

COX inhibitors

Soluble epoxide hydrolase inhibitors

Local anesthetics

Acupuncture

Opioids

Fish oil

Cryotherapy

Tiludronate

Polyphenols (ie reservatrol)

Weight management

Treatment Options for Neuropathic Pain

Tramadol

Ketamine

Soluble epoxide hydrolase inhibitors

Gabapentin

Local anesthetics

Fish oil

Cyproheptadine

Tiludronte

Polyphenols (ie, resveratrol)

Acupuncture

Cytotoxicity of Local Anesthetics from Least to Most

Ropivacaine, mepivacaine, lidocaine, bupivacaine

Definition of Pain

An unpleasant sensory and emotional experience associated with actual or potential tissue damage

Acute Pain

Occurs immediately after a stimulus is received

Severity can vary

Responds well to treatment

Subsides once stimulus is removed

Chronic Pain

Persists past initial stimulus (3-6 months)

Severity can vary

May or may not respond well to treatment; may require a “multi-modal” approach

Can result in allodynia, hyperalgesia, and opioid tolerance

Nociception

Stimulation of sensory nerve cells called nociceptors, which produce a signal that travels along a chain of nerve fibers via the spinal cord to the brain

First Neuron in the Nociceptive Pathway

Primary afferent neuron

Transduction of noxious stimuli and conduction of signals from the peripheral tissues to neurons in the dorsal horn of the spinal cord

Second Neuron in the Nociceptive Pathway

The projection neuron

Receives input from the primary afferent neurons and projects to neurons in the medulla, pons, midbrain, thalamus, and hypothalamus

Third Neuron in the Nociceptive Pathway

Supraspinal neurons

Integrate signals from the spinal neurons and project to the subcortical and cortical areas where pain is finally perceived

Where are visceral nociceptors located?

Organs and linings of body cavities

Characteristics of Pain from Visceral Nociceptors

Poorly localized, diffuse, deep, cramping or splitting

Sources of Acute Pain from Visceral Nociceptors

Chest tubes, abdominal drains, bladder, and intestinal distension

Sources of Chronic Pain from Visceral Nociceptors

Pancreatitis, liver metastases, colitis

Where are somatic nociceptors located?

Cutaneous: skin and subq tissues

Deep somatic: blood vessels, muscle, connective tissue

Characteristics of Pain from Somatic Nociceptors

Well-localized, constant, itchy

Sources of Acute Pain from Somatic Nociceptors

Incisions, insertion site of tubes and drains, wound complications, orthopedic procedures, skeletal muscle spasms

Sources of Chronic Pain from Somatic Nociceptors

Bony metastases, arthritis, low-back pain

Where are non-nociceptor or neuropathic receptors located?

Nerve fibers, spinal cord, CNS

Characteristics of Pain from Non-Nociceptor of Neuropathic Receptors

Generalized along distribution of damaged nervous structures

Sources of Acute Pain from Non-Nociceptor or Neuropathic Receptors

Poorly localized, shooting, burning, fiery, shock-like, sharp, painful numbness

Sources of Chronic Pain from Non-Nociceptor or Neuropathic Receptors

Nervous tissue injury due to diabetes, chemotherapy, neuropathies, post-therapeutic neuralgia, trauma, surgery

What are the 4 phases of nociceptive pain?

Transduction

Transmission

Perception

Modulation

Transduction

Substances are released by damaged tissues and lead to the generation of an action potential

• Chemical stimuli

• Thermal stimuli

• Mechanical stimuli

What is the main difference between cytokines and chemokines?

Cytokines - protein that are important for cell signaling, released from the cell

Chemokines - type of cytokine, just there to induce chemotaxis, will attract other types of inflammatory cells

Transmission

Action potential continues from the site of damage to the spinal cord, then ascends up the spinal cord to the higher centers in the brain

What are the peripheral afferent nociceptors?

First order neurons

A-B fibers

A-d fibers

C fibers

What is the ascending pathway for pain and temperature stimuli?

Spinothalamic tract

What is the ascending pathway for touch and proprioception stimuli?

Dorsal column system

What activates A-B nociceptors?

Light touch and/or moving stimuli

Mostly sensory

A-B Nociceptor Conduction Speed

Fast - myelinated

Where are A-B fibers located?

Primarily in skin, normally don’t produce pain

What activates A-d nociceptors?

Mechanical and thermal stimuli

A-d Nociceptor Conduction

Fast - myelinated

What type of pain do A-d fibers produce?

Short-lasting, pricking-type pain

What activates C fibers?

Mechanical, chemical, and thermal stimuli

C Fibers Conduction

Slow - unmyelinated

What type of pain do C fibers produce?

Dull, poorly localized, burning type pain

What are the 2 classes of C nociceptors?

Petidergeric

Nonpetidergic

Peptidergic C Nociceptors

Expresses neuropeptides

• Substance P

• Calcitonin gene related peptide (CGRP)

• Neurokinin A

• Expresses receptors

Nonpeptidergic C Nociceptors

Expresses several receptors for neurotrophic factors and ion channels

Ascending Pathways of the Pain Pathway

Nociceptive fibers synapse with second order neuron at the dorsal root ganglion in the dorsal horn of the spinal cord

First order neuron from the nociceptors goes to the dorsal horn and the rexed laminae

Information travels to the contralateral ventral horn (decussation) and then up the spinothalamic tract

Pain is sent through the spinothalamic tract to the thalamus and through the spinomesencephalic tract to the periaqueductal grey (PAG)

2nd order neuron synapses with the 3rd order neuron and information is sent to the somatosensory cortex

3rd order neuron then sends information to the appropriate area of the homunculus of the primary somatosensory cortex

Rexed Lamina I

Located in the marginal layer

Respond to thermal and nociceptive input from Ad and C fibers

Rexed Lamina II

Located in the substantia gelatinosa

Respond to noxious stimuli and thermal stimuli from Ad and nonpetidergic C fibers

Rexed Lamina III and IV

Located in the nucleus proprius

In the deep dorsal horn, receive low threshold sensory information, not pain, mostly from AB fibers

Rexed Lamina V

Wide range of dynamic neurons

Second Order Neuron from Laminae II, IV, and V Path

Synapses with the reticular activating system (RAS) in the brainstem relaying information about:

• Touch, vibration, and limb proprioception

RAS has projections to the medial thalamus and limbic system:

• Mediates motor, autonomic, endocrine, and emotional response to pain

Second Order Neuron from Laminae I and V Path

Synapses with pons, medulla, midbrain, periaqueductal gray (PAG) and thalamus

Perception

Conscious awareness of pain

What are the components of the limbic system?

Cingulate gyrus

Amygdala

Hippocampus

Hypothalamus

Locus ceruleus

What does the cingulate gyrus deal with?

Behavior and emotion