PainPain

Significance of PainSignificance of Pain

Pain is adaptiveAlerts us to dangerMotivates escape and avoidance learningMotivates recuperationCongenital insensitivity to painPain is partly subjectiveInfluenced by expectations and emotions

Pain is adaptiveAlerts us to dangerMotivates escape and avoidance learningMotivates recuperationCongenital insensitivity to painPain is partly subjectiveInfluenced by expectations and emotions

IASP Definition of PainIASP Definition of Pain

Pain is a sensory and emotional experience associated with actual tissue damage or described in terms of such damage

pain is a sensory experience associated with activation of nociceptors and pain pathwayspain is an emotional experiencetissue damage is not necessary

Pain ChronicityPain Chronicity

Acute Acute - Transient / Recurrent - Transient / Recurrent - Reversible- Reversible

ChronicChronic - Long lasting/Reversible- Long lasting/Reversible- Persistent / Irreversible- Persistent / Irreversible

Types of Pain

Chemical, mechanical pressure, and extreme heat

All mediated through nociceptors

All go through a common pathway in the brain

Once activated, nociceptors become sensitized (hyperalgesic) for the duration of an injury

Pathological Pain - Chronic Pain Inflammation or nerve damage

ArthritisNeuropathic painBack painMigraineDegenerative diseases (MS)80% of doctor visits70 billion in health care costs and reduced productivity

Current clinical treatments are based on animal research

Using Animal Models to Study PainAcute pain: gradually incremented stimuli applied to tail or paw and determine intensityof stimulation required to elicit a withdrawalor vocalization response.

Chronic pain: unilateral inflammation of thepaw or joint, nerve ligation, etc. Measure guarding of limb, hyperreactivity to heat ormechanical stimulation, or reduced locomotoractivity.

Electrophysiology and histology

Justification for animal modelsJustification for animal models

Pain is a complex biological and psychological process that must be investigated in a living organism.

Animal research has led to advances in understanding pain and its treatment.

Animal rights movement creating barriers to laboratory animal research on pain.

Pain is a complex biological and psychological process that must be investigated in a living organism.

Animal research has led to advances in understanding pain and its treatment.

Animal rights movement creating barriers to laboratory animal research on pain.

Pain Transmission & ModulationPain Transmission & Modulation

Research has clarified that the experience of pain is due to the combined activity of distinct systems that transmit and modulate pain.1) Ascending Pain Transmission: Bottom-up process of pain transmission provides the brain with information about tissue damage.2) Descending Pain Modulation: Top down process of pain modulation regulates pain transmission.

Research has clarified that the experience of pain is due to the combined activity of distinct systems that transmit and modulate pain.1) Ascending Pain Transmission: Bottom-up process of pain transmission provides the brain with information about tissue damage.2) Descending Pain Modulation: Top down process of pain modulation regulates pain transmission.

Ascending PainTransmission Pathway

The ascending neural pain pathway is only a 3 neuron relay

The major convergence point is the ventral posterior lateral nucleus of the thalamus, which relays the signal to limbic and cortical areas

Ascending Pain Pathway (Purves, 2001).

Descending Pain Modulation Pathway

Descending pain pathway (Purves, 2001).

The Descending Pain Pathway – The Periaqueductal Grey (PAG) is the major convergence point.

Pain Transmission PathwayPain Transmission PathwayPrimary afferent nociceptors respond to intense thermal, mechanical, and chemical stimuli. Located in all pain sensitive regions of te body.Activated by chemicals (bradykinin, prostaglandins, histamine, etc.) released during tissue damage and inflammation, causing transmission of action potentials. Axons of these neurons carry the signal into the cord, release neurotransmitters that activate pain transmission neurons in the dorsal horn of the spinal cord.Pain transmission neurons carry this signal to various regions of the brain where it is processed and evaluated.E.g., spinothalamic tract neurons carry the signal from the spinal cord to specific thalamic nuclei, which have reciprocal connections with somatosensory cortex - map of body

Primary afferent nociceptors respond to intense thermal, mechanical, and chemical stimuli. Located in all pain sensitive regions of te body.Activated by chemicals (bradykinin, prostaglandins, histamine, etc.) released during tissue damage and inflammation, causing transmission of action potentials. Axons of these neurons carry the signal into the cord, release neurotransmitters that activate pain transmission neurons in the dorsal horn of the spinal cord.Pain transmission neurons carry this signal to various regions of the brain where it is processed and evaluated.E.g., spinothalamic tract neurons carry the signal from the spinal cord to specific thalamic nuclei, which have reciprocal connections with somatosensory cortex - map of body

Neural Pathways of Pain

Anatomically related to the cutaneous senses

Free nerve endings The sensitive terminals of pain neurons

are not surrounded by special capsules or end organs as are the endings of touch and temperature receptors

Free nerve endings can be found in all body tissues from which pain is sensed, from the skin to the pulp of the teeth.

Transduction of Pain

Tissue Damage and ChemoreceptorsSubstance P, Histamine, Bradykinin, Serotonin, K+ C Fibers (Type 4) with chemoreceptorsAnd the Immune System

Two Types of Peripheral Pain Neurons

A-delta fibers Thick, myelinated, fast conducting

neurons Mediate the feeling of initial fast, sharp,

highly localized pain.

C fibers Very thin, unmyelinated, slow-conducting Mediate slow, dull, more diffuse, often

burning pain.

Central Pain Pathways: Fast PainFast pain and A-delta fibres

A-delta fibers synapse on cells in the spinal cord that lead to an area of the thalamus called the ventrobasal complex

ventrobasal complex also receives neurons that mediate touch

sends its output to the somatosensory cortex allows us to localize where pain originates

Central Pain Pathways: Slow PainSlow pain and C fibres

C fibres synapse on cells in the spinal cord

Relays to a midline nucleus in the thalamus and

to the limbic system responsible for motivational and

emotional aspects of pain Those connections are important for

the interpretation of pain.

Sensitization of Pain TransmissionSensitization of Pain Transmission

Pain transmission system can be sensitized by noxious stimuli.

Explains many chronic pain syndromes where pain perception is distorted

Allodynia - lowering of pain thresholds to normally non-noxious stimuli

Hyperalgesia - lowering of pain thresholds to noxious stimuli

Secondary hyperalgesia - spread of pain and hyperalgesia to uninjured areas

Spontaneous pain - pain in absence of noxious stimulation, “pain memory”

Pain transmission system can be sensitized by noxious stimuli.

Explains many chronic pain syndromes where pain perception is distorted

Allodynia - lowering of pain thresholds to normally non-noxious stimuli

Hyperalgesia - lowering of pain thresholds to noxious stimuli

Secondary hyperalgesia - spread of pain and hyperalgesia to uninjured areas

Spontaneous pain - pain in absence of noxious stimulation, “pain memory”

Multiple Pain MechanismsMultiple Pain Mechanisms

• Nociception

• Peripheral sensitization

• Central sensitization

• Decreased inhibition/

Structural reorganization

Multiple Pain SymptomsMultiple Pain Symptoms

• Spontaneous Pain

Superficial/Deep

Continuous/Intermittent

• Evoked Pain

Thermal/Mechanical

Allodynia

Hyperalgesia

Noxiousstimulus

Transduction Conduction Transmission

primary sensory neuron central neuron

Modulation

NociceptionNociception

“Ouch” Pain

Nociceptor ActivatorsNociceptor Activators

Heat

H+

VR1

ASIC TRPV3

Bradykinin

B1/B2 DRASIC/mDEG

Mechanical

generator potential

action potentials

Nociception – TransductionNociception – Transduction

Cold

CRM1

COX-2 Insensitive

Afferent Central Terminal

Glutamate

Sub P

Activity

NK1

mGluR

NMDA

AMPAAMPA

VGCCGABAA

AdensosineOpiateCB1

Dorsal Horn Neuron

Transmission/ModulationTransmission/Modulation

COX-2Insensitive

Nociception is not COX-2

Sensitive

Nociception is not COX-2

Sensitive

Mechanisms of Neuropathic Pain

Central sensitizationNon painful information is processed as painful

Transmission of painful information is facilitated

Allodynia

Hyperalgesia

Complex Regional Pain Syndrome

Fibromyalgia

Sensitization of pain transmissionSensitization of pain transmissionBoth peripheral and central mechanisms mediate sensitization and contribute to the development and maintenance of pathological pain.

Peripheral: Peptides (bradykinin, histamine, prostaglandin) released at injury site sensitize peripheral nerve endings of primary nociceptors

Central: axons from primary nociceptors release peptides (e.g.,substance P, neurokinin-A, CGRP, CCK) and excitatory amino acids (e.g., glutamate). Peptides act to amplify excitatory effects of glutamate, creating a burst of nociceptor activity causing a long-lasting hyperreactivity of dorsal horn neurons. Mechanism underlies hyperalgesia.

Central Sensitization, a form of LTP that depends on the concurrent activation of NMDA receptors (glutamate) and NK-1 tachykinin receptors by neurokinin A and substance P.

Both peripheral and central mechanisms mediate sensitization and contribute to the development and maintenance of pathological pain.

Peripheral: Peptides (bradykinin, histamine, prostaglandin) released at injury site sensitize peripheral nerve endings of primary nociceptors

Central: axons from primary nociceptors release peptides (e.g.,substance P, neurokinin-A, CGRP, CCK) and excitatory amino acids (e.g., glutamate). Peptides act to amplify excitatory effects of glutamate, creating a burst of nociceptor activity causing a long-lasting hyperreactivity of dorsal horn neurons. Mechanism underlies hyperalgesia.

Central Sensitization, a form of LTP that depends on the concurrent activation of NMDA receptors (glutamate) and NK-1 tachykinin receptors by neurokinin A and substance P.

Neuropathic PainNeuropathic PainPain caused by damage to nervous systemInvolves peripheral and central sensitizatione.g., peripheral nerve cut, crushed, partial denervation and inflammatione.g., MVA, diabetes, MS, herpes zoster Nerve damage causes spontaneous shooting, stabbing, or burning pain over time. Local pain and then spreads. Allodynia to touch.Central sensitization occurs in spinal cord, brainstem, thalamus, and cortex, where neurons exhibit spontaneous activity, lowered thresholds, receptive field expansion. Paralleled by anatomical reorganization at each level of the pathway. E.g., phenotypic switching in cord, somatosensory map

Pain caused by damage to nervous systemInvolves peripheral and central sensitizatione.g., peripheral nerve cut, crushed, partial denervation and inflammatione.g., MVA, diabetes, MS, herpes zoster Nerve damage causes spontaneous shooting, stabbing, or burning pain over time. Local pain and then spreads. Allodynia to touch.Central sensitization occurs in spinal cord, brainstem, thalamus, and cortex, where neurons exhibit spontaneous activity, lowered thresholds, receptive field expansion. Paralleled by anatomical reorganization at each level of the pathway. E.g., phenotypic switching in cord, somatosensory map

Phantom Limb PainPhantom Limb Pain

Pain originating from the absent limbPain memories of pre-amputation painAnimal models of injury prior to deafferentation increase autonomy behaviorPreemptive analgesia blocks it by blocking the afferent barrage that leads to central sensitizationReorganization of somatosensory cortex after deafferentation painTop down effects

Pain originating from the absent limbPain memories of pre-amputation painAnimal models of injury prior to deafferentation increase autonomy behaviorPreemptive analgesia blocks it by blocking the afferent barrage that leads to central sensitizationReorganization of somatosensory cortex after deafferentation painTop down effects

Pain Mechanism

Etiological Factorsinflammation/tissue damage/nerve lesions

Pain Syndromespost-operative/arthritic/back pain/neuropathic

Inflammatory and Neuropathic Pain

Chemical mediators are released from damaged tissue and inflammatory cells. Some inflammatory mediators directly activate nociceptors, while others act together to sensitize the pain pathway.

Neuropathic pain

Innocuous/Noxiousstimulus

Reduced Transduction Threshold

primary sensory neuron central neuron

Peripheral SensitizationPeripheral Sensitization

Primary hyperalgesiaPrimary heat allodynia

Inflammation

There are prostanoid and non-prostanoid sensitizers

Peripheral SensitizationPeripheral Sensitization

PKC

PKA

(SNS/SNS2)

VR1

Ca2+

PG

EP/IP

AACox-2PGS

Primary sensory neuronperipheral terminal

Tissue Tissue damagedamage

MacrophageMacrophage

Mast Mast cellcell

IL1, IL6TNF

H+ COX-2Sensitive

Nai

ve 12h6h

Skin

Noxiousstimulus

Increased Pain Responsiveness

primary sensory neuron central neuron

Central SensitizationCentral Sensitization

Secondary hyperalgesiaTactile allodynia

IrritantsTissue damageInflammation

Brush-Evoked Mechanical Allodynia

Weak synapseinnocuous

stimulusnon-painful sensation

innocuous stimulus

painful sensation

Increased synaptic strength

AA fibre mechanoreceptor fibre mechanoreceptor

Central Sensitization – Central Pain Hypersensitivity

Central Sensitization – Central Pain Hypersensitivity

Relevance to human painRelevance to human pain

Cutaneous Hyperalgesia - e.g, burn pain - primary hyperalgesia at site of burn, secondary hyperalgesia in surrounding skin. allodynia - touch sensitivityPrimary hyperalgesia linked to prolonged changes in excitability of peripheral nociceptors and central neurons.Secondary hyperalgesia due to sensitization of dorsal horn neurons and expansion of their receptive fields

Cutaneous Hyperalgesia - e.g, burn pain - primary hyperalgesia at site of burn, secondary hyperalgesia in surrounding skin. allodynia - touch sensitivityPrimary hyperalgesia linked to prolonged changes in excitability of peripheral nociceptors and central neurons.Secondary hyperalgesia due to sensitization of dorsal horn neurons and expansion of their receptive fields

Central Terminal

Glutamate

Sub P

PKC

Activity

PKA

NK1

mGluR

NMDA TyrS/T

S/T

IP3

Ca2+

AMPAAMPA

pERKsrc

Central Sensitization - Acute PhaseCentral Sensitization - Acute Phase

COX-2Insensitive

tRN

AN

aïve

1 H

r2

Hrs

4 H

rs6

Hrs

24 H

rs

12 H

rs

48 H

rs

COX-2

-actin

COX-2 Induction in the Spinal Cord - InflammationCOX-2 Induction in the Spinal Cord - Inflammation

Cox-2 is not induced in the

Spinal Cord by Peripheral Nerve Injury

Cox-2 is not induced in the

Spinal Cord by Peripheral Nerve Injury

Cox2

Actin

Sham

12 h

24 h

72 h

7 d

100112

11597 88Cox2 band

intensity

Primary sensory neuroncentral terminal

PGE2

EP

EP/IP

COX-2

Nociceptive dorsalhorn neuron

Inhibitoryinterneuron EP

Glycine receptor

++

++

++

––

Central Sensitization Late Phase (Inflammation)Central Sensitization Late Phase (Inflammation)

COX-2Sensitive

There are COX-2 sensitive peripheral andcentral components of inflammatory pain

Cox-2 inhibitors can only act when COX-2is induced - time lag for induction

There are non-prostanoid contributors toinflammatory pain - ceiling effect

Peripheral nerve injury may not be sensitiveto COX-2 inhibitors

A B C

1 2 3

Etiology

Mechanism

Symptom

A B C

1 2 3

Etiology

Mechanism

Symptom

Need to differentiate Analgesicand Anti-hypersensitivity drugs

Temporal and Intensity characteristicsof pain do not reflect mechanisms and may not be useful predictors of analgesic action

Pain Mechanisms and Drug Mechanismsmay provide the most useful input fordetermining Indication and Efficacy

Need mechanism sensitive/specificoutcome measures in additionto global pain scores

Need clinical trials that validatemechanistic hypotheses

Need to consider labeling claims in lightof action of a drug with specificpain mechanism(s) as well as empiricalclinical data on efficacy

Are there global analgesics?

Descending Pain ModulationDescending Pain Modulation

The brain and higher psychological processes can alter the activity of the pain transmission system. The brain can amplify or inhibit incoming pain signals through descending modulatory pathways.

The brain and higher psychological processes can alter the activity of the pain transmission system. The brain can amplify or inhibit incoming pain signals through descending modulatory pathways.

Gate control theory•Ronald Melzack and Patrick Wall (1965, 1982) For pain to be experienced, input from •peripheral pain neurons must pass through a gate located at the point where •they enters the spinal cord and lower brain stem.

Descending Pain Control

Cingulate Cortex & Amygdala Emotional states

Periaqueductal Gray Opioid Receptors Projects to Raphe Nuclei

Raphe Nuclei Project down to dorsal horn

and Spinal 5 Nucleus Serotonin (5-HT) Inhibits Ascending Systems

Substance P release by Primary Afferents

Locus Coeruleus Norepinephrine

Stress-Induced Analgesia

Descending Pain Modulation Pathway

Descending pain pathway (Purves, 2001).

The Descending Pain Pathway – The Periaqueductal Grey is the major convergence point.

•Periaqueductal gray (PAG)–PAG neurons have excitatory connections with inhibitory interneurons in the spinal cord–These inhibitory interneurons prevent ascending neurons to relay pain messages to the brain–Stimulation produced analgesia

•Endorphins or endogenous opioids-Receptors for exogenous opioids-Microinjection of opioids - PAG, intrathecal-Endogenous opioids - POMC-endorphins, enkephalins, dynorphin–The spinal cord inhibitory interneurons release endorphins–Endorphins are inhibitory neurotransmiters–Opiate epidurals inhibit ascending pain signal

Pain-inhibiting System

Periagueductalgray matter

Opiatereceptor Noxious

stimulus

Afferent pain fiberSubstance P

No perception of painTo thalamus

Transmissionof painimpulses tobrain blocked

Nociceptor

Reticularformation

Endogenous opiate

Inhibition of ascending pain pathways

Important anatomical connections between descending brain regions and the dorsal horn of the spinal cord.

There are a number of opioids that exist naturally in the brain that can reduce pain.

Electrical stimulation or pharmacological administration in the PAG produces profound analgesia.

Descending Regulation

Endorphins exert multiple effects that include suppressing the release of glutamate from presynaptic terminals and inhibiting neurons by hyperpolaring their postsynaptic membranes.

Targets of Pain Therapies

Gottschalk et al., 2001

Alternative methodsAcupuncture

Physical Therapy

Chiropractics

Surgery

PharmacotherapyNon-opioid analgesics

Opioid analgesics

Nerve Blocks

Adjuvant analgesics (neuropathic, musculoskeletal)

Electrical StimulationTranscutaneous electrical nerve stimulation (TENS)

Percutaneous electrical nerve stimulation (PENS)

Nonopioid neurotransmitters involved in pain modulationNonopioid neurotransmitters involved in pain modulation

Serotonin (5-HT), Norepinephrine (NE)5-HT containing neurons in rostral ventral medulla (RVM) and NE containing neurons in the pons send projections to the spinal cord which modulate pain transmissionNeurochemical lesions of these systems attenuates morphine analgesia, intrathecal injections of 5-ht and NE induce analgesiaAntidepressant drugs increase 5-HT and NE, used in arthritis, migraine, herpes zoster pain

Serotonin (5-HT), Norepinephrine (NE)5-HT containing neurons in rostral ventral medulla (RVM) and NE containing neurons in the pons send projections to the spinal cord which modulate pain transmissionNeurochemical lesions of these systems attenuates morphine analgesia, intrathecal injections of 5-ht and NE induce analgesiaAntidepressant drugs increase 5-HT and NE, used in arthritis, migraine, herpes zoster pain

Descending Inhibition and FacilitationDescending Inhibition and Facilitation

Cells in brainstem nuclei can inhibit and facilitate pain transmission (Fields, 1992)

Off Cells - inhibit transmission and firing rate increased by opioids

On Cells - enhance transmission, show increased firing rates before withdrawal responses and associated with enhanced pain during opioid abstinence

Conclude: pain modulation is bi-directional

Cells in brainstem nuclei can inhibit and facilitate pain transmission (Fields, 1992)

Off Cells - inhibit transmission and firing rate increased by opioids

On Cells - enhance transmission, show increased firing rates before withdrawal responses and associated with enhanced pain during opioid abstinence

Conclude: pain modulation is bi-directional

Influence on pathological pain?Influence on pathological pain?

A decrease in tonic descending inhibition contributes to chronic pain.Increased on-cell activity may generate pain in the absence of pain.Activity of these cells may mediate the effects of psychological states on pain perception, e.g., anxiety and attention which increase pain in animals and humans

A decrease in tonic descending inhibition contributes to chronic pain.Increased on-cell activity may generate pain in the absence of pain.Activity of these cells may mediate the effects of psychological states on pain perception, e.g., anxiety and attention which increase pain in animals and humans

Activation of Pain Inhibitory SystemsActivation of Pain Inhibitory Systems

Intense sensory stimulation - counterirritation - rubbing, acupuncture, vibration, TENS, Gate Control TheoryStressful or Frightening Stimuli - potentially threatening stimuli and cues that predict their occurrence.

Cat exposure Context conditioning

CS (place)-->US (shock)CR (analgesia) UR

(analgesia)

Intense sensory stimulation - counterirritation - rubbing, acupuncture, vibration, TENS, Gate Control TheoryStressful or Frightening Stimuli - potentially threatening stimuli and cues that predict their occurrence.

Cat exposure Context conditioning

CS (place)-->US (shock)CR (analgesia) UR

(analgesia)

Memorial Processes Memorial Processes

Shock induced hypoalgesia Distractor study in animals Distractor study in humans

Scopolamine study

Placebo analgesia - a form of conditioned analgesia

Shock induced hypoalgesia Distractor study in animals Distractor study in humans

Scopolamine study

Placebo analgesia - a form of conditioned analgesia

Afferent Regulation