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3. Pain and Temperature System • Objectives:

1. Understand the difference between nociception and pain. 2. Describe the types of sensory receptors that transmit pain and temperature. 3. Understand how axon diameter relates to transmission of pain and temp information. 4. Describe the basis of the flexion (withdrawal) reflex for pain. 5. Describe the general location of the reticular formation in the brainstem. 6. Describe the names and locations of the cell bodies and axons in the pathways that

transmits fast and slow pain and temp. Describe the cortical areas involved. 7. Describe how information is transmitted from first order to second order neurons in this

pathway and its clinical consequences. 8. Understand the role of the postcentral gyrus in pain perception. 9. Describe the descending pathways that modulate pain (anti-pain). 10. Describe the effects of lesions in the spinal cord, brainstem, and cortex on pain sensation 11. Understand: thalamic pain syndrome, the effects of damage to the postcentral gyrus,

Brown-Sequard Syndrome, Syringomyelia • Concepts of nociception and pain

• nociception is the detection and localization of a stimulated pain receptor (nociceptor) • pain involves the emotional (affective) and arousal aspects of such stimulation. • Pain is a complex and subjective experience; it can arise without nociceptor stimulation. • Subjective nature of pain makes it

difficult to measure. There is NO absolute scale to compare pain. Usually patients are asked to rate their pain on a scale of 1–10. However, a “5” for one person may be a “10” for another. How does this affect treatment?

• A recent NEJM study on pain

imaging showed that brain areas could be reliably distinguished and correlated with the intensity of pain stimuli. Also, social pain (rejection) activated similar areas, but with different activity patterns compared to physical pain.

• Classifications of Pain

• Multiple classifications exist; Helps guide treatment. • Most common classification is: Acute vs Chronic pain, which is also helpful in

understanding pain pathways. Other categories can include cancer pain, chronic noncancer pain, chronic pain syndrome, etc.

• Distinction of Acute vs Chronic was traditionally based on duration, but now involves broader definitions that relate to period of healing/pathology; acute and chronic pain can involve different mechanisms and different treatment strategies.

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• Acute Pain • A current definition: “complex, unpleasant experience with emotional and cognitive, as

well as sensory, features that occur in response to tissue trauma.”2

• Characteristics: related closely to tissue pathology; resolves with tissue healing; source is nociceptor activity.

• Causes: trauma, surgery, labor in pregnancy, acute disease • Purpose: signals the extent of or potential for tissue injury

Duration Source Tissue Injury Sec - hours Nociceptor stim Little/none Acute

Prolonged Days - weeks Nociceptor stim Hypersensitivity

Injury Inflammation

Chronic Months - years Abnormal CNS response Trauma, nerve damage, tumors, disease

• Chronic Pain

• A current definition: Pain that lasts beyond the period of healing and that involves low tissue pathology insufficient to explain the pain.1

• Characteristics: occurs in relative absence of tissue pathology; outlasts period of tissue healing; source is usually neuropathic.

• Causes: trauma, malignancy, chronic disease, non-life threatening disease (arthritis, neuropathy)

• Mechanism: The neurological cause of chronic pain is unknown. Current hypothesis is that it is caused by excess nociceptor activity that outlasts the healing period.

• Purpose: serves no useful biological purpose to patient • Recovery from damage to structures involved in pain pathways can result in chronic

episodes of spontaneous pain. • Examples: headache, back pain, fibromyalgia, neuropathic pain resulting from nerve

injury, Multiple Sclerosis, stroke. • Neuropathic Pain: pain arising as a consequence of a lesion or disorder of the

somatosensory system. Symptoms are constant with burning sensation. • Associated with more complex response to the pain - patients may show problems with

employment, social relationships, psychological well being. • Therapeutics: the pharmacology of chronic pain is complicated by our lack of a

mechanism to explain it. The pathways that transmit and control pain travel through the spinal cord, brainstem and cortex and involve multiple transmitter systems. Pharmacological strategies target these transmitter systems at specific CNS levels in an attempt to reduce transmission of pain information.

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time

Pain

Inte

nsity

• Characteristics of Nociceptor Activation: • Pain has a FAST and first component that is felt

immediately after stimulation. This is the sensory-discriminative component that is linked to nociceptor activation and allows determination of stimulus location, intensity, onset, and duration.

• Pain has a SLOW and second component that persists after the stimulus has ended. This is the motivational-emotional component influenced by personal experience, emotional framework, culture and cognitive (attention, anxiety) aspects.

• The FAST and SLOW components are due to action potential conduction rates. They have separate, but parallel, pathways through the CNS.

• Pain produces autonomic (blood pressure, heart beat) and motor (withdrawal) reflexes.

1. American Pain Society- http://www.ampainsoc.org/ce/npc/I/c_classification.htm 2. Chapman CR, Nakamura Y. A passion of the Soul: an introduction to pain for consciousness researchers. Conscious Cogn. 8:391-422; 1999.

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time

Pain

Inte

nsity

Aδ

- fast

- slow C

Pain Pathway • Sensory stimuli - pain, temperature; itch – recently shown as a distinct pain modality using a

unique neurotransmitter to send activity along pain pathway. • Sensory Receptors: (free nerve endings)

• Nociceptors –unique in responding to physical AND chemical stimuli, eg. mechano, thermal, and polymodal (respond to mechano/thermal/chemical stimuli)

• Thermal receptors

Nerve Fiber Group Axon Diameter Conduction Velocity Function Group A (myelinated) α 10 – 20 µm 60 - 120 m/sec Mechanoreceptor β 5 – 15 µm 30 – 90 m/sec Mechanoreceptor γ 3 – 10 µm 10 - 50 m/sec Mechanoreceptor δ 1 – 5 µm 6 - 30 m/sec Nociceptor (mechano, thermo)

Thermal r. Group C (unmyelinated) 0.5 – 2 µm 0.5 – 2 m/sec Nociceptor (polymodal)

Thermal r. •Fast component of pain is carried by Aδ fibers; Primarily

from mechanonociceptors that signal a brief, sharp, pricking sensation.

• Slow component of pain is carried by C fibers; Primarily from polymodal nociceptors that signal a secondary, longer lasting, burning sensation.

• Aδ and C fibers use a specific Na channel isoform to conduct action potentials. Mutations (channelopathies) result in syndromes that can increase or decrease pain perception. Goal of pharmacological research is to develop a specific blocker for this Na channel subtype.

•Pain pathways and destinations indicate its complex nature:

• Several pathways transmit pain information: • Spinothalamic tract – for fast pain • Spino reticulo-thalamic tract – for slow pain

• Collectively, these tracts are known as the ALS (anterolateral system - all travel together in the anterolateral region of spinal cord and brainstem). They are also referred to as the spinal lemniscus.

• Pain information is relayed to multiple CNS areas: Reticular Formation in the brainstem, periaqueductal grey, superior colliculus, several thalamic nuclei, hypothalamus, several cortical areas. The complex nature of pain arises from the wide distribution of this information to many regions of the CNS.

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• Reticular formation– in the brainstem, the tracts and nuclei we can identify easily are surrounded by other large areas that appear indistinct. These areas contain axons and cells bodies that are involved in many functional systems. For convenience, we generally refer to these surrounding areas as reticular formation. A shown in the shaded areas below, reticular formation is located in the dorsal half of the brainstem.

Important differences between Pain pathway and Tactile pathway:

Pain Pathway Tactile Pathway Receptor Nociceptor Meissner’s, merkel, pacinian, ruffini Axon Size Small Medium/Large 2° neuron Dorsal horn Caudal medulla Crossing CNS Spinal cord Caudal medulla Destinations for info Reticular formation, periaqueductal

grey, superior colliculus, hypothalamus, thalamus, cortex

Thalamus, cortex

Relay in Thalamus VPL, Intralaminar nuc. VPL Cortical area Somatosensory cortex, insula,

cingulate gyrus, orbitofrontal Somatosensory cortex

Modulation Initiates descending activity from brainstem to spinal cord

Little

1) Lateral Spinothalamic Tract – Fast Pain component via Aδ fibers

Cell Body/Nucleus Axon/Tract First-Order Neuron DRG Spinal Nerve/Dorsolateral Fasc. Second-Order Neuron Marginal Zone, Nuc Proprius Spinothalamic Tract/ALS Third-Order Neuron Ventral Posterior Lateral* Post. Limb Internal Capsule

• This pathway carries information about the location and intensity of a pain stimulus. It is the first of several pain signals to arrive at the cortex. It enables you to distinguish WHERE a painful stimulus arises on the body. • Pain also evokes a fast flexion/withdrawal reflex. This involves multisynaptic connections of 1° pain fibers with interneurons and motor neurons at multiple spinal cord levels (why?). This is a local response in the spinal cord and it does not involve the brain.

*Different neurons from those used for tactile sensation

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medulla

midbrain

pons

medulla

Spinal cord

Ventral root

Dorsal root

Flexion reflex: • multisynaptic and multilevel in spinal cord • contract flexors and inhibit extensors on 1 side • opposite effect in other leg for postural compensation • Why is this important: 1) indicates complexity of even

“simple”reflexes, 2) shows “wired-in” nature of some actions, 3) for this system indicates a more distributed connectivity.

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• How is information transferred from 1st order to 2nd order neuron: 1° axons enter the spinal cord at the Dorsolateral fasciculus. Axons then enter the dorsal horn where they synapse

on 2° cell bodies. 2° axons travel rostrally as they cross the midline. Information entering the cord at one level enters the ALS on opposite side 2 levels above.

• The targets of neuron #1 are: Laminae I (Marginal zone) and III-V (Nucleus Proprius). Cell bodies of neuron #2, which have long axons that travel to the thalamus, are located in Marginal zone and Nucleus Proprius.

• Pathway termination: postcentral gyrus; conveys information about location/intensity of

pain stimulus. Stimulation of postcentral gyrus does not elicit painful sensation!

•Somatotopic Orientation in spinal cord:

Anterior white commissure

Aδ fibers Aδ fibers

External masses press here first

L1

L3 L3 L2

L4 L4

L1 L2

ALS  

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2) Spino-reticular-thalamic tract: • Slow pain component transmitted via C fibers • Carries information about unpleasant qualities of pain: burning, long-lasting. • This is not a 3-neuron sensory pathway! Multisynaptic pathway via reticular

formation in medulla and pons to intralaminar nuclei in thalamus to cortex. Travels parallel to Lateral Spinothalamic Tract.

Cell Body/Nucleus Axon/Tract First-Order Neuron DRG Spinal Nerve/Dorsolateral Fasc. 2°- and 3°- Order Neurons

Marg. Zone, Substantia Gelatinosa ALS- spinoreticular fibers

4°, 5°… Neuron Reticular Formation Reticular Formation Last Neuron Intralaminar Thalamic Nuclei Post. Limb Internal Capsule

• Intralaminar nuclei project to several cortical areas associated with emotion and attention aspects of pain:

Insula, and Cingulate Gyrus

Substantia Gelatinosa (II) neurons are interneurons, which do not send axons into the ALS. It provides the opportunity for more connections and thus more modulation of pain signals.

C fibers

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• ALS also relays information to the midbrain - Periaqueductal Gray (PAG) and Superior

Colliculus.

• PAG is a pain modulatory center that is part of the anti-pain pathway. Superior

Colliculus is a visual reflex center that mediates head and eye turning toward pain stimuli.

•Descending anti-Pain Pathway:

• This pathway relays information from the PAG in the midbrain to the reticular formation in the medulla and then to spinal cord to terminate in the dorsal horn where it inhibits transmission of pain signals from 1° to 2° pain neurons.

• This descending pathway is activated by: 1) ascending pain (Spinoreticular) fibers and 2) cortex.

•Visceral Pain Pathways

• visceral pain is transmitted by sympathetic nerve fibers (mixed sensory/motor nerves) • visceral pain is poorly localized due to low nociceptor density and pathway convergence

Cell Body Axon 1° Dorsal Root Ganglia (T1-L2) splanchnic nerve to spinal nerve

2° dorsal horn; central grey ALS 3° VPL Int. Capsule

• What does visceral pain feel like? – 1) a deep body sensation, eg stomach ache or 2) pain from a body dermatome different in location from the visceral organ where the pain originates (known as referred pain), eg left arm for heart attack.

Pain Source Dermatome referred to Diaphragm C3-C4

Heart Lt T1-T4 Stomach Lt T6-T9 Appendix Rt T10

Kidney L1-L2

Superior Colliculus

PAG

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• What accounts for the difference in how visceral pain is experienced? • The general pathway is similar in both cases. However: 1. Pain felt as a deep body sensation – pain info is transmitted with fidelity to the cortex where it terminates in the visceral area of the postcentral gyrus located ventrally within the lateral sulcus. It is perceived as a deep body sensation.

2. Referred Pain – some 1° sympathetic pain fibers converge onto 2° somatic ALS neurons in segments T1-L2, causing visceral pain information to merge with body dermatome information. The ALS carries this information to the cortex (postcentral gyrus), where it is interpreted as originating in the associated dermatome.

• Alternate Pathways Too!

• Visceral pain from the pelvic region also is carried by a group of axons in the dorsal midline between fasciculus gracilis. A surgical treatment known as Limited Midline Myelotomy, creating a lesion in this area, significantly reduces chronic pelvic pain.

From Principles of Neural Science, Kandel, Schwartz, and Jessell, 1991

Referred pain

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• Summary of Pain Pathways •Clinical Implications of Lesions:

• Peripheral Nerve damage: can cause neuropathic pain (episodes of unpleasant pain that are not associated with nociceptor stimulation). An example of this is Phantom Limb Pain that is experienced after limb amputation.

• Spinal cord/brainstem damage: ALS lesions cause loss of pain on contralateral body. • VPL damage: complete damage causes a pure sensory loss of tactile and pain sensation. If recovery occurs, thalamic pain syndrome can result - pain episodes involving all or part of the contralateral body with burning, unpleasant quality, triggered spontaneously or by touch.

• Postcentral gyrus damage: impairs ability to localize source of pain, but pain is still experienced due to other cortical areas that receive pain info.

• Syringomyelia – formation of a cavity around central canal of the spinal cord. Due to its position, crossing spinothalamic fibers are affected. Commonly occurs at cervical levels. Can be caused by developmental abnormalities (Chiari malformation), trauma, spinal cord tumors.

• Brown-Sequard (pronounced secar) Syndrome – produced by spinal cord damage; results in loss of tactile sensation on one side of body and loss of pain/temperature sensation on opposite side. These are key symptoms characteristic of damage to the spinal cord due to the pathways these sensory stimuli travel in the CNS.

P/T ALS

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Syringomyelia You examine a 40 year-old man who has burned both hands, but he says he never felt it. Pin prick sensation is absent on hands, arms, and shoulders of both sides, but normal elsewhere. Tactile sensation is intact. How can we explain this?

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• Conclusion to Opening Case: A 24-year-old man was brought to the emergency room after he was shot during an argument outside a bar. On exam, he had the following symptoms: there was loss of touch and vibration sense in his left lower limb beginning at L2 (top of thigh). He could not tell the position of his left leg when it was passively moved by his physician. Tactile, vibration and position sense were normal in his right lower limb. Pinprick sensation was absent in his right lower limb starting at L4 (below the knee), but normal in his left lower limb and elsewhere.

Questions: • Which sensory systems were affected; where on body? • Why did he lose some sensation on his right side but other sensation on left. • Is there a single location where damage (Lesion) causes these symptoms.

• Approach to Solving:

1. Determine whether symptoms are specific to a particular CNS level (eg cortex: astereognosis, inability to locate pain while still feeling it, etc), brainstem, or spinal cord.

2. If not specific to a level, draw pathways of systems involved. Determine where pathways are adjacent to each other (same side of CNS, same area). This is the most likely place damage would affect these pathways and produce the symptoms. Structures near one another would most likely be involved together. The type of lesion influences how large a territory is affected.

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