Pain (text book based)

Question 1

Is pain a different system to somatosensation?

Answer 1

For the periphery the answer is yes

But for the brain its both Yes and No

Question 2

What are nociceptors?

Answer 2

Relatively unspecialized nerve cell endings that initiate the sensation of pain

Nociceptors transduce a variety of stimuli into receptor potentials, which trigger afferent action potentials.

Arise from cell bodies in dorsal root ganglia that send one axonal process to the periphery and the other into the spinal cord or brainstem

Question 3

What are the periphery specialised axons for pain called?

Answer 3

Aδ (A dellta) mylentated axons 20 m/s
C fibre unmyelinated 2 m/s

both are slow compared to typical axonal transmission- only lightly myelinated or unmyelinated

Question 4

Have studies found that rapidly conducting axons that underlie somatic sensation are involved in the transmission of pain?

Answer 4

No

Peripheral axons responsive to nonpainful mechanical or thermal stimuli do not discharge at a greater rate when painful stimuli are delivered to the same region of the skin surface

Question 5

How can you experimentally demonstrate that nociception involves specialised neurons specific to pain?

Answer 5

The nociceptive axons begin to discharge when the strength of the stimulus reaches high level

At this same stimulus intensity, other thermoreceptors discharge at a rate no different from the maximum rate already achieved within the non-painful temperature range

This indicates the presence of both nociceptive are important for pain and are different from and non-nociceptive thermoreceptors

Question 6

What are the 2 types of pain perception?

Answer 6

1. A sharp FIRST PAIN
2. A more delayed, diffuse, and longer-lasting sensation called SECOND PAIN

Question 7

What causes first pain?

Answer 7

A delta fibres- when levels are raised high enough there is a tingling sensation and if the sensation is intense enough then individuals experience sharp pain (first pain)

Question 8

What causes second pain?

Answer 8

C fibres- Stimulus intensity must keep increasing to activate the smaller C fibres axons and this leads to the sensation of a duller longer lasting pain (secondpain)

Question 9

How do we know which axons/fibres cause each different type of pain?

Answer 9

We can anesthetise C fibres and A delta fibres

These selective blocking experiments can confirm that Aδ fibers are responsible for first pain and C fibers are responsible for the duller, longer-lasting second pain

Question 10

What are the two classes of the A Delta faster conducting fibres?

Answer 10

Type 1- Aδ fibers respond to dangerously intense mechanical and chemical stimulation but have relatively high heat thresholds

Type 2- Aδ fibers have complementary sensitivities—that is, much lower thresholds for heat but very high thresholds for me-chanical stimulation

This differentiation in classes demonstrates that the A delta system has differnt pathways for the transmission of heat and mechanical nociceptive stimuli

Each of the major classes of nociceptive afferents is composed of multiple subtypes with distinct sensitivity profiles

Question 11

Are there different types of C fibres?

Answer 11

C-fiber nociceptors respond to all forms of nociceptive stimuli—thermal, mechanical, and chemical—and are said to be polymodal.

However, C-fiber nociceptors are also heterogeneous, with subsets that respond preferentially to heat or chemical stimulation rather than mechanical stimulation.

Further subtypes of C-fiber nociceptors are especially responsive to chemical irritants, acidic substances, or cold.

Each of the major classes of nociceptive afferents is composed of multiple subtypes with distinct sensitivity profiles

Question 12

What is Capsaicin?

Answer 12

Ingredient/chemical in chilli peppers which is responsible for the tingling or burning sensation produced by spicy foods

Question 13

How does Capsaicin work to create a sensation of heat?

Answer 13

The threshold for percieving a thermal stimulus as noxious is 43 degrees, a pain threshold which corresponds to the sensitivities of A delta and C fibres.

Capsaicin activates responses in a subset of nociceptive C fibers (polymodal nociceptors) by opening ligand-gated ion channels (which are repsonsive to heat) that permit the entry of Na+and Ca2+

Capsaicin binds to Vanilloid receptors (VR1, TRPV1), which are found in both A delta and C fibres, and causes the receptor channel to open.

As this TRPV1 receptor is also sensitive to heat (43 degrees), it is not surprising that people experience the taste of chillis as “hot”

Question 14

Why is Capsaicin difficult to get rid of?

Answer 14

Because it is lipid permeable as well as being water soluable, so it goes through the lipid bi-layer and has a special binding site inside of the cell

Question 15

What is the major pathway for discriminative aspects of pain and temperature sensation?

Answer 15

Spinothalamic tract
Trigeminothalamic tract (pain and temperature for the face)

Question 16

Describe the function of the spinothalamic tract?

Answer 16

Pain and temperature from the body is detected from nociceptors in the skin

Signals pass trough the dorsal root ganglion and enter the spinal cord

Ascend or descend one or two vertebral levels via Lissauer’s tract and then synapse with secondary neurons in the grey matter before decussating to the other side of the spinal cord

Axons travel up the length of the spinal cord into the brainstem and then synapse with 3-order neurons in the thalamus. From here, it signals to the primary somatosensory cortex

Question 17

What is the difference between the spinothalamic tract and the dorsal medial lemniscus pathway?

Answer 17

The spinothalamic tract ascends contralaterally- it decussates at the spinal cord and then ascends

The dorsal medial leminscus tract ascends in the ipsilateral dorsal column- it does not decussate until the medulla where they synapse on neurons in the dorsal column nuclei then cross the midline and ascend up to the thalamus

Question 18

How can we localise a spinal cord lesion?

Answer 18

The dorsal medial lemniscus pathway travels ipsilateral up the spinal cord and the spinothalamic tract travels contralaterally, whihc means you can tell where the lesion is depending on the type of symptoms

A unilateral spinal cord lesion results in dorsal column–medial lemniscal symptoms (loss of sensation of touch, pressure, vibration and proprioception) on the side of the body ipsilateral to the lesion

Anterolateral symptoms (deficits of pain and temperature perception) occur on contralateral side of the body. They are due to interruption of fibres ascending from lower levels of the spinal cord, so deficits include all regions on the body that are innvervated by spinal cord segments that lie below the level of the lesion

This is referred to as dissociated sensory loss (contralateral pain and temp and ipsilateral touch and pressure) and can be used to define the level of the lesion

Question 19

What is referred pain?

Answer 19

Few if any neurons in the dorsal horn of the spinal cord are specialised solely for the transmission of visceral (internal) pain

It is conveyed centrally via dorsal horn neurons that may also convey cutaneous pain

Therefore the disorder of an internal organ mat be perceived as cutaneous pain

A patient may present to a physician with complaints of pain at a site other than its actual source - this is called referred pain

Question 20

What is visceral pain?

Answer 20

Pain related to the internal organs of the body

Question 21

What is the pathway for visceral pain?

Answer 21

From organs to consciousness via a component of the dorsal column–medial lemniscal pathway that conveys visceral nociception

->not viewed as a pathway involved in pain perception but compelling evidence has implicated its role in relaying visceral nociceptive information

Primary visceral afferents from the pelvic and abdominal viscera enter the spinal cord and synapse on second-order neurons in the dorsal horn of the lumbar–sacral spinal cord.
Some of these second-order neurons are cells that give rise to the anterolateral system and contribute to referred visceral pain patterns.
However, other neurons that give rise to nociceptive signals synapse on neurons in the intermediate gray region ofthe spinal cord near the central canal.
These neurons send their axons through the dorsal columns in a position near the midline.
Similarly, second-order neurons in the thoracic spinal cord that convey nociceptive signals from thoracic viscera send their axons through the dorsal columns along the dorsal intermediate septum, near the division of the gracile and cuneate tracts.
These second-order axons then synapse on the dorsal column nuclei of the caudal medulla, where neurons give rise to arcuate fibers that form the contralateral medial lemniscus and eventually synapse on thalamocortical projection neurons in the ventral posterior thalamus.
This dorsal column visceral sensory projection now appears to be the principal pathway by which painful sensations arising in the viscera are detected and discriminated.

Question 22

What evidence supports the idea that the dorsal column visceral sensory projection is the principal pathway by which painful sensations in the viscera are detected?

Answer 22

(1) neurons in the ventral posterior lateral nucleus, gracile nucleus, and near the central canal of the spinal cord all respond to noxious visceral stimulation

AND

(2) Are greatly reduced by spinal lesions of the dorsal columns, but not by lesions of the anterolateral white matter

(3) infusion of drugs that block nociceptive synaptic transmission into the intermediate gray regionof the sacral spinal cord blocks the responses of neurons in the gracile nucleus to noxious visceral stimulation, but not to innocuous cutaneous stimulation.

Question 23

What is midline myelotomy?

Answer 23

A surgical transection of the axons that run in the medial part of the dorsal columns

This surgery generates relief from debilitating pain caused by visceral cancers in the abdomen and pelvis

Question 24

What is affective-motivational pain?

Answer 24

the unpleasant feeling, the fear and anxiety, and the autonomic activation that accompany exposure to a noxious stimulus (the classic fight-or-flight response)

Medial thalamic nuclei receive input from anterolateral system axons, and play an important role in transmitting nociceptive signals to both the anterior cingulate cortex and to the insula.
Together with the amygdala and hypothalamus, these limbic forebrain structures elaborate affective-motivational aspects of pain

Question 25

What are the targets on affective-motivational projections?

Answer 25

Includes several subdivisions of the reticular formation, the periaqueductal gray, the deep layers of the superior colliculus, and the parabrachial nucleus
The parabrachial nucleus processes and relays second pain signals to the amygdala, hypothalamus, and the medial thalamic nuclei

Question 26

What are the two distinct aspects of the experience of pain?

Answer 26

1. Those that are responsbile for the sensory discrimination of pain
   - the location, intensity and quality of the noxious stimulation- these aspects of pain are thought to depend on information relayed through the ventral posterior lateral nucleus
   -> electrophysiological recordings from nociceptive neurons in the primary somatosensory cortex (SI) show that these neurons have small, localized receptive fields—properties corrresponding with behavioral measures of pain localization.
2. Those that are responsible for the affective and motivational responses to pain
   -unpleasant feeling, the fear and anxiety, and the autonomic activation that accompany exposure to a noxious stimulus
   -> Electrophysiological recordings in human patients show that cingulate neurons respond to noxious stimuli, and support the role of the anterior cingulate cortex in the perception of pain.
   ->Moreover, patients who have undergone cingulotomies report an attenuation of the unpleasantness that accompanies pain.

Question 27

What is hyperalgesia?

Answer 27

Following a painful stimulus associated with tissue damage (e.g., cuts, scrapes, bruises, and burns), stimuli in the area of the injury and the surrounding region that would ordinarily be perceived as slightly painful are perceived as significantly more so=hyperalgesia.

E.g. the increased sensitivity to temperature that occurs after sunburn.

This effect is due to changes in neuronal sensitivity that occur at the level of peripheral receptors as well as their central target

Question 28

What is peripheral sensitsation?

Answer 28

Peripheral sensitization results from the interaction of nociceptors with the “inflammatory soup” of substances released when tissue is damaged.

These substances arise from activated nociceptors or from non-neuronal cells that reside within, or migrate to, the injured area.

Question 29

How does peripheral sensitisation work?

Answer 29

Nociceptors release peptides and neurotransmitters such as substance P, calcitonin gene-related peptide (CGRP), and ATP, all of which contribute to the inflammatory response.

Non-neuronal cells that contribute to this “inflammatory soup” include mast cells, platelets, basophils, macrophages, neutro-phils, endothelial cells, keratinocytes, and fibroblasts.

These cells are responsible for releasing extracellular protons, arachidonic acid and other lipid metabolites, bradykinin, histamine, serotonin, prostaglandins, nu-cleotides, nerve growth factor (NGF), and numerouscytokines, chief among them interleukin-1β (IL-1β) andtumor necrosis factor α (TNF-α).

Most of these substances interact directly with receptors or ion channels of nociceptive fibers, augmenting their response.

The prostaglandins are thought to contribute to peripheral sensitization by binding to G-protein-coupled receptors that increase levels of cyclic AMP within nociceptors.
Prostaglandins also reduce the threshold depolarization required for generating action potentials via phosphorylation of a specific class of TTX-resistant sodium channels that are expressed in nociceptors.

Cytokines can directly increase sodium channel activity, via activation of the MAP kinase signaling pathway, and can also potentiate the inflammatory response via increased production of prostaglandins, NGF, bradykinin, and extracellular protons.

=Substances released by damaged tissues augment the response of nociceptive fibers. In addition, electrical activation of nociceptors causes the release of peptides and neurotransmitters that further contribute to the inflammatory response

Purpose of complex chemical signaling cascade arising from local damage is not only to protect the injured area, but also to promote healing and guard against infection by means of local effects such as increased blood flow and the migration of white blood cells to the site, and by the production of factors that reduce inflammation and resolve pain

Question 30

How is phantom limb linked to central sensitisation?

Answer 30

If a limb is amputated or removed we may still experience pain even though it no longer exists, may be due to a central sensitisation, so the pain representation in the brain has been ramped up and it still remains when the limb isnt there

Question 31

What is central sensitisation?

Answer 31

Central sensitization refers to a rapid onset, activity-dependent increase in the excitability of neurons in the dorsal horn of the spinal cord following high levels of activity in the nociceptive afferents.

As a result, activity levels in nociceptive afferents that were subthreshold prior to the sensi-tizing event become sufficient to generate action potentials in dorsal horn neurons, contributing to an increase in pain sensitivity.

Although central sensitization is triggered indorsal horn neurons by activity in nociceptors, the effects generalize to other inputs that arise from low-threshold mechanoreceptors.

Thus, stimuli that under normal conditions would be innocuous (such as brushing the surface ofthe skin) activate second-order neurons in the dorsal horn that receive nociceptive inputs, giving rise to a sensation of pain. The induction of pain by a normally innocuous stim-ulus is referred to asallodynia.

Question 32

How do analgesics work?

Answer 32

Identifying the components of the inflammatory soup and their mechanisms of action is a fertile area of exploration in the search for potential analgesics (compounds that reduce pain’s intensity).

For example, NSAIDs (nonsteroidal anti-inflammatory drugs), which include aspirin and ibuprofen, act by inhibiting cyclooxygenase (COX), an enzyme important in the biosynthesis of prostaglandins.

Interfering with neurotrophin or cytokine signaling has become a major strategy for controlling inflammatory disease and the resulting pain.

Blocking the action of TNF-α with a neutralizing antibody has been significantly effective in the treatment of autoimmune diseases, including rheumatoid arthritis and Crohn’s disease, leading to dramatic reduction in both tissue destruction and the accompanying hyperalgesia.

Likewise, anti-NGF antibodies have been shown to prevent and to reverse the behavioral signs of hyperalgesia in animal models.

In terms of placebos:
Imaging studies show that the administration of a placebo with the expectation that it represents ananalgesic agent is associated with activation of endogeneous opioid receptors in cortical and subcortical brain regions that are part of the pain matrix, including the anterior cingulate and insular regions of cortex and the amygdala

Question 33

What are the descending systems that modulate the transmission of ascending pain signals? 3 cards

-This explicates how a placebo could work, priming the cortex so the information projects back down the spinal cord

Answer 33

Studies of descending pathways to the spinal cord that regulate the transmission of nociceptive information have shown that they arise from several brainstem sites, including the parabrachial nucleus, dorsal raphe, locus coeruleus, and medullary reticular formation.

The analgesic effects of stimulating the periaqueductal gray are mediated through these brainstem sites.

These centers employ a wealth of different neurotransmitters (e.g., noradrenaline, serotonin, dopamine, histamine,acetylcholine) and can exert both facilitatory and inhibitory effects on the activity of neurons in the dorsal horn.

Descending projections can exert their effects on a variety of sites within the dorsal horn, including the synaptic terminals of nociceptive afferents, excitatory and inhibitory interneurons, and the synaptic terminals of the other descending pathways, as well as by contacting the projection neurons themselves.

Although these descending projections were originally viewed as a mechanism that served primarily to inhibit the transmission of nociceptive signals, it is now evident that these projections provide a balance of facilitatory and inhibitory influences that ultimately determines the efficacy of nociceptive transmission

Question 34

How do endogenous opioids, such as enkephalin, modulate ascending pain signals?

Answer 34

A variety of brain regions are susceptible to the action of opioid drugs, particularly the periaqueductal gray matter and other sources of descending projections.

Hence, the areas that produce analgesia when stimulated are also responsive to exogenously administered opioids

Several categories of endogenous opioids have been isolated from the brain and intensively studied. These agents are found in the same regions involved in the modulation of nociceptive afferents.
All three of the major groups (enkephalins, endorphins, and dynorphins) are present in the periaqueductal gray matter.
Enkephalins and dynorphinshave also been found in the rostral ventral medulla and in those spinal cord regions involved in pain modulation

A class of enkephalin-containing local circuit neurons within the dorsal horn synapses with the axon terminals of nociceptive afferents, which synapse with dorsal horn projection neurons. The release of enkephalin onto the nociceptive terminals inhibits their release of neurotransmitter onto the projection neuron, reducing the level ofactivity that is passed on to higher centers.
Enkephalin-containing local circuit neurons are themselves the targets of descending projections, providing a powerful mechanism by which higher centers can decrease the activity relayed by nociceptive afferents.

Question 35

How do endocannaboids modulate ascending pain signals?

Answer 35

Exogenously administered cannabinoids are known to suppress nociceptive neurons in the dor-sal horn of the spinal cord without altering the activity ofnon-nociceptive neurons.

We now know that endogenous cannabinoids in the CNS act as neurotransmitters; they are released from depolarized neurons and travel to pre-synaptic terminals, where they activate cannabinoid re-ceptors (CB1) through a retrograde signaling mechanism.

The actions of endocannabinoids are thought to decrease the release of neurotransmitters such as GABA and glutamate, thus modulating neuronal excitability.

Evidence fora direct effect of endocannabinoids on the transmissionof nociceptive signals comes from studies showing that analgesic effects induced by electrical stimulation of the periaqueductal gray can be blocked if CB1antagonists are administered.

In addition, it appears that exposure to noxious stimuli increases the level of endocannabinoids in the periaqueductal gray matter, a finding that supports a major role for these molecules in the descending control of pain transmission