Physiology of pain

Question 1

pain = protective mechanism:

Answer 1

• ## occurs whenever any tissues are being damaged

Question 2

fast pain VS slow pain:

Answer 2

• fast: felt within about 0.1 second after a pain stimulus is applied (needle is stuck into the skin, when the skin is cut with a knife, or when the skin is acutely
  burned, subjected to electric shock)
  !! Fast-sharp pain is not felt in deeper tissues of the body !!
• slow: begins only after 1 second or more and then increases slowly
  over many seconds and sometimes even minutes, usually associated with tissue destruction, can lead to prolonged, unbearable suffering
  !! can occur both in the skin and in almost any deep tissue or organ !!

Question 3

nociception:

Answer 3

= perception of pain, depends on specifically dedicated receptors and pathways.

Question 4

pain receptors =

Answer 4

• free nerve endings
• They are widespread in the superficial
  layers of the skin + some internal tissues, nevertheless, any
  widespread tissue damage can summate to cause the slow-chronic-aching type of pain in most of these areas

Question 5

nociceptors: (déf)

Answer 5

A stimulus that causes (or is on the verge of causing) tissue damage usually elicits a sensation of pain.
* Receptors for such stimuli are known as nociceptors.

Question 6

nociceptors (description):

Answer 6

• sensitive to both heat and to
  capsaicin, the ingredient in chili peppers that is responsible for the familiar tingling or burning sensation produced by spicy foods

Question 7

types of nociceptors:

Answer 7

• vanilloid receptor (VR- 1 or TRPV1) is
  found in C and Aδ fibres and is activated by moderate heat (45°C) as well as by capsaicin.
• (vanilloid-like receptor, VRL-1 or TRPV2) has a higher threshold response to heat (52°C), is not sensitive to capsaicin, and is found in Aδ fibres.
• (Both are members of the larger family of transient receptor potential (TRP) channels, known to comprise many receptors sensitive to different ranges of heat and cold.)

Question 8

nociceptors response:

Answer 8

• respond to intense mechanical deformation, excessive heat,
  and many chemicals, including neuropeptide transmitters,
  bradykinin, histamine, cytokines, and prostaglandins, several of
  which are released by damaged cells
• These substances les trucs chemical) act by combining with specific ligand-sensitive ion
  channels on the nociceptor plasma membrane

Question 9

chemical substances released by damaged cells:

Answer 9

• Several of these chemicals are secreted by cells of the immune
  system that have moved into the injured area.
• In fact, there is a great deal of interaction between substances
  released from the damaged tissue, cells of the immune system, and nearby afferent pain neurones.
  (the tissue, immune cells, and afferent neurones themselves—release substances that affect the nociceptors and are, in turn, affected by these substances)

Question 10

The 3 types of stimuli:

Answer 10

• mechanical,
• thermal, and
• chemical pain stimuli.

Question 11

chemicals that excite the chemical type of pain:

Answer 11

bradykinin, serotonin, histamine, potassium ions, acids, acetylcholine, and proteolytic enzymes
- (!!prostaglandins and substance P enhance the sensitivity
of pain endings but do not directly excite them!!)

Question 12

chemical substances = important in:

Answer 12

stimulating the slow, suffering type of pain that occurs after tissue injury

Question 13

How is pain initiated ?

Answer 13

Pain is initiated by a noxious or harmful stimulus and perceived by sensory neurones that produce signals that are
delivered to and interpreted by the brain

Question 14

Pain physiology includes three main components:

Answer 14

• Transduction is the conversion of a nociceptive signal into an electrical or chemical signal.
• Transmission of signal through the nociceptive pathway, which encompasses the sensory and postsynaptic neurones.
• Modulation is a phenomenon by which a painful signal is remodelled, either downregulated or upregulated, partially accounting for differences between responses to the same
  signal among individuals. Modulation occurs at all the ‘relays’ in the pathway: the sensory neurone, the dorsal horn and the higher-order brain.

Question 15

locations and fibres of slow VS fast pain:

Answer 15

• Aδ fibers, which release glutamate, are responsible for fast pain
• C fibers, which release a combination of glutamate and substance P, are responsible for the delayed slow pain
• Innocuous cold/cool receptors are on the endings of Aδ and C fibers
• Innocuous warmth receptors are on C fibres.
• Itch and tickle are also related to pain sensation

Question 16

different kinds of nociceptors:

Answer 16

• Nociceptors: sensory neurons with unmyelinated C fibers or finely myelinated Aδ fibers .
• Mechanical nociceptors respond to strong pressure (e.g., from a sharp object).
• Thermal nociceptors are activated by skin temperatures above 42°C or by severe cold.
• Chemically sensitive nociceptors respond to various chemicals such as bradykinin, histamine, high acidity,
  etc.
• Polymodal nociceptors respond to combinations of these stimuli.
  Nociceptor activation is location dependent: e.g. skin responses to cutting, viscera is not.

Question 17

how is pain receptor adaptation?

Answer 17

In contrast to most other sensory receptors of the body, pain receptors
adapt very little and sometimes not at all.

Question 18

how does increase of sensitivity to pain increase?, which is the more painful chemical ?

Answer 18

= hyperalgesia
- it allows the pain to keep the person apprised of a tissue- damaging stimulus as long as it persists
-Extracts from damaged tissue cause intense pain when injected beneath the
normal skin. One chemical that seems to be more painful than others is
bradykinin
- the intensity of the pain felt correlates with the local increase in
potassium ion concentration or the increase in proteolytic enzymes that
directly attack the nerve endings and excite pain by making the nerve
membranes more permeable to ions

Question 19

causes of pain during ischemia:

Answer 19

• Under normal conditions, cells use oxygen to produce energy efficiently. However, when there’s insufficient blood flow during ischemia, oxygen levels drop. As a result, cells switch from aerobic (oxygen-dependent) metabolism to anaerobic metabolism (which doesn’t require oxygen) to produce energy.
• Anaerobic metabolism produces lactic acid as a byproduct. When lactic acid accumulates in the tissues due to ischemia, it lowers the pH (makes the environment more acidic), which can irritate and stimulate pain nerve endings (nociceptors), causing pain.
  (Both the buildup of lactic acid and the release of other chemical agents, such as bradykinin and proteolytic enzymes, directly stimulate the nerve endings responsible for detecting pain. (Along with lactic acid, other chemicals are released as cells are damaged during ischemia: bradykinin + proteolyctic enzymes) This combination contributes to the sensation of pain experienced during ischemia.)

Question 20

when ischemia, how long and why does pain occur?

Answer 20

• When blood flow to a tissue is blocked, the tissue often becomes very
  painful within a few minutes.
• The greater the rate of metabolism of the tissue, the more rapidly the pain
  appears
• In the absence of muscle exercise, the pain may not appear for 3 to 4
  minutes even though the muscle blood flow remains zero

Question 21

Muscle spasm as a cause of pain:

Answer 21

= the basis of many clinical pain syndromes
* This pain probably results partially from the direct effect of muscle spasm in stimulating mechanosensitive pain receptors, but it might also result from the indirect effect of muscle spasm to compress the blood vessels and cause
ischemia.
* spasm increases the rate of metabolism in the muscle tissue, thus
making the relative ischemia even greater, creating ideal conditions for the release of chemical pain-inducing substances

Question 22

Local chemical mediators in peripheral nociceptive sensitization:
Hyperalgesia and allodynia

Answer 22

*Injured cells release K+, substance P,
bradykinin, prostaglandin E2 (a
cyclooxygenase metabolite of
arachidonic acid), which sensitizes
nociceptors.
*Nociceptive terminals release
Substance P and CGRP, which facilitate
histamine release from mast cells and
vasodilation– resulting in inflammatory
response and pain sensitisation
*Immune response:
Macrophages and damaged epithelial
cells secrete growth factors, cytokines
(IL-1b), Bradykinin, ATP, H+, all of which
hypersensitize nociceptive response

Question 23

the 2 pathways for transmitting pain signals:

Answer 23

(even if pain receptors = nerve endings)
The two pathways mainly correspond to the two types of pain-
* a fast-sharp pain pathway: (elicited by either mechanical or thermal pain stimuli, transmitted in the peripheral nerves to the spinal cord by small type Aδ fibres at velocities between 6 and
30 m/sec)
* a slow-chronic pain pathway: elicited mostly by chemical types of pain stimuli but sometimes by persisting
mechanical or thermal stimuli, transmitted to the spinal cord by
unmyelinated type C fibers at velocities between 0.5 and 2 m/sec.

Question 24

sharp VS slow pain approach to people:

Answer 24

• sharp pain = apprises the person rapidly of a damaging influence and,
  therefore, plays an important role in making the person react immediately to remove himself or herself from the stimulus
• slow pain = ends to become greater over time. This sensation eventually
  produces the intolerable suffering of long-continued pain and makes the
  person keep trying to relieve the cause of the pain
• On entering the spinal cord from the dorsal spinal roots, the pain fibers
  terminate on relay neurons in the dorsal horns.

Question 25

DUAL PAIN PATHWAYS IN THE CORD AND BRAIN STEM:

Answer 25

through:
(1)the neospinothalamic tract
(2)the paleospinothalamic tract.

Question 26

spinal cord connections (C-fibres, A truc…)

Answer 26

• After Aδ and C-fibers entering
  dorsal horn, their branches enter
  dorsolateral tract of Lissaurer
  for 1-2 spinal segments (both
  ascending/descending).
• C-fiber branches then synapse
  on 2nd order neurons in lamina
  1&2, while Aδ fiber branches
  synapse on 2nd order neurons
  in lamina 1&5.
• Axons of 2nd order neurons in
  the dorsal horn cross the
  midline and ascend in
  ventrolateral tract.

Answer 27

(The neospinothalamic tract is a part of the larger spinothalamic tract in the nervous system, which is responsible for transmitting pain and temperature sensations from the body to the brain.)
* The fast type Aδ pain fibers transmit mainly mechanical and
acute thermal pain.
* They terminate mainly in lamina I (lamina marginalis) of the
dorsal horns.
* There excite second-order neurons of the neospinothalamic
tract.
* These give rise to long fibers that cross immediately to the
opposite side of the cord through the anterior commissure and
then turn upward, passing to the brain in the anterolateral
columns.
(btw: Transmission of pain signals into the brain stem, thalamus, and cerebral
cortex by way of the fast pricking
pain pathway and the slow burning
pain pathway)

Question 28

Termination of the Neospinothalamic Tract in the Brain Stem and Thalamus

Answer 28

• A few fibres of the neospinothalamic tract terminate in the reticular areas of the brain stem, but most pass all the
  way to the thalamus without interruption, terminating in
  the ventrobasal complex

Question 29

path of fibres of neospinothalamic tract:

Answer 29

(The ventrobasal complex (or ventrobasal nuclei) refers to a group of nuclei located in the thalamus, a key structure in the brain responsible for relaying sensory information to the cerebral cortex. It plays a critical role in processing and transmitting sensory signals.)
* A few fibers of the neospinothalamic tract terminate in the reticular areas of the brain stem, but most pass all the
way to the thalamus without interruption, terminating in
the ventrobasal complex.
* From these thalamic areas, the signals are transmitted to the somatosensory cortex.

Question 30

substances of fast pain (Glutamate, Neurotransmitter of the Type Aδ
Fast Pain Fibers), the specific case of glutamate:

Answer 30

• Glutamate is the neurotransmitter substance secreted in
  the spinal cord at the type Aδ pain nerve fiber endings.
• This is one of the most widely used excitatory transmitters
  in the central nervous system, usually having a duration of
  action lasting for only a few milliseconds.

Question 31

Paleospinothalamic Pathway for Transmitting Slow-Chronic Pain
(DONC: glutamate is the
neurotransmitter most involved in transmitting fast pain into the central
nervous system, and substance P is concerned with slow-chronic pain)

Answer 31

• The paleospinothalamic pathway is a much older system and transmits
  pain mainly from the peripheral slow-chronic type C pain fibers.
• In this pathway, the peripheral fibers terminate in the spinal cord almost
  entirely in laminae II and III of the dorsal horns, which together are called
  the substantia gelatinosa

Question 32

Glutamate & Substance P, Slow-Chronic Neurotransmitters of Type C
Nerve Endings

Answer 32

• C pain fiber terminals entering the
  spinal cord secrete both glutamate transmitter and substance P transmitter
• The glutamate transmitter acts instantaneously and lasts for only a few
  milliseconds.
• Substance P is released much more slowly, building up in concentration over a period of seconds or even minutes.

Question 33

Projection of the Paleospinothalamic Pathway (Slow-Chronic Pain
Signals) into the Brain Stem and Thalamus:

Answer 33

• The slow-chronic paleospinothalamic pathway terminates widely in the
  brain stem.
• Only one tenth to one fourth of the fibers pass all the way to the thalamus.
• Instead, most terminate in one of three areas:
  (1) the reticular nuclei of the medulla, pons, and mesencephalon; (2) the
  tectal area of the mesencephalon or (3) the periaqueductal gray region
  surrounding the aqueduct of Sylvius.

Question 34

localization of slow chronic pain and why?

Answer 34

• Localization of pain transmitted by way of the paleospinothalamic pathway is poor.
• For instance, slow-chronic pain can usually be localized only to a
  major part of the body, such as to one arm or leg but not to a specific point on the arm or leg.

Question 35

the 3 components of the analegia system:

Answer 35

Periaqueductal Gray (PAG): Located in the midbrain, this region plays a central role in the analgesia system by activating pathways that inhibit pain signals. It releases endogenous opioids (like endorphins) that can suppress pain transmission.

Raphe Nuclei: Found in the medulla, these nuclei receive input from the PAG and release serotonin. Serotonin helps inhibit pain signals traveling up the spinal cord.

(a 2nd signal from raphe magnus nucleus transmitted from dorsolateral column to spinal cord): Dorsal Horn of the Spinal Cord: The final part of the analgesia system, where descending signals from the brainstem modulate the activity of pain pathways before they reach the brain. Neurons in the dorsal horn can inhibit incoming pain signals through the release of neurotransmitters like enkephalins.

Question 36

substances involved in analegia system and what component they come from:

Answer 36

• Analgesia system of the brain and spinal cord, showing (1) inhibition of incoming pain signals at the cord level and (2) presence of enkephalin-secreting neurons that suppress
  pain signals in both the cord and the brain stem.
• Several transmitter substances are
  involved in the analgesia system;
  especially involved are enkephalin and
  serotonin.
• Many nerve fibers derived from the
  periventricular nuclei and from the
  periaqueductal gray area secrete
  enkephalin at their endings.

Question 37

how serotonin and enkephalin work in the analegia system:

Answer 37

• Fibers originating in this area send signals to the dorsal horns of
  the spinal cord to secrete serotonin at their endings.
• The serotonin causes local cord neurons to secrete enkephalin as
  well.
• The enkephalin is believed to cause both presynaptic and
  postsynaptic inhibition of incoming type C and type Aδ pain
  fibers where they synapse in the dorsal horns.
• Thus, the analgesia system can block pain signals at the initial
  entry point to the spinal cord.
  (* This presumably results from
  local lateral inhibition in the spinal
  cord. It explains why such simple
  maneuvers as rubbing the skin
  near painful areas is often effective
  in relieving pain, And it proba bly also explains why liniments are often useful
  for pain relief. This mechanism
  and the simultaneous
  psychogenic excitation of the
  central analgesia system are
  probably also the basis of pain
  relief by acupuncture)

Question 38

Referred pain:

Answer 38

• Often a person feels pain in a part of the body that is fairly remote from the
  tissue causing the pain.
• This is called referred pain. For instance, pain in one of the visceral organs often is referred to an area on the body surface

Question 39

mechanisms of referred pain:

Answer 39

• Branches of visceral pain fibers synapse in the spinal cord on the same
  second- order neurons (1 and 2) that receive pain signals from the
  skin.
• When the visceral pain fibers are stimulated, pain signals from the
  viscera are conducted through at least some of the same neurons that
  conduct pain signals from the skin, and the person has the feeling that
  the sensations originate in the skin itself.

Question 40

Visceral pain:

Answer 40

• Any stimulus that excites pain nerve
  endings in diffuse areas of the viscera can cause visceral pain
• include ischemia of visceral
  tissue, chemical damage to the surfaces of the viscera, spasm of the smooth muscle of a hollow viscus, excess distention of a hollow viscus, and stretching of the connective tissue surrounding or within the viscus
• !! all visceral pain that originates in
  the thoracic and abdominal cavities is
  transmitted through small type C pain fibres and, therefore, can transmit only the chronic-aching-suffering type of pain !!

Question 41

visceral pain process:

Answer 41

• Less sharp and poorly localized, and
  frequently are accompanied by
  nauseating, sweating and changes in blood pressure
• Common causes: ischemia, chemical
  stimuli, spasm or overdistention of hollow viscus
• Afferent fibers from visceral structures reach the CNS via sympathetic and parasympathetic nerves
• Often radiates or is referred to other
  areas, causing referred pain

Question 42

Neuropathic pain:

Answer 42

doesn’t need to convert a non-electrical signal = direct nerve stimulation

Question 42

insensitive viscera:

Answer 42

These include the
* Parenchyma of the liver
* Alveoli of the lungs
* Brain

Question 42

Parallel pain pathways:

Answer 42

A.Discriminative Aspects of Pain:
Ventrolateral (Spinothalamic) tract to the ventral
posterior lateral nucleus (VPL) of the thalamus and then
to the primary somatosensory cortex (S1,S2).
B. Affective-motivational Aspects of Pain Ventrolateral (Spinothalamic) tract, then branches to midbrain reticular formation, superior colliculus, periaqueductal grey, hypothalamus, and amygdala, and additionally through midline thalamic nuclei then to
anterior cingulate cortex & insular cortex

Question 43

Types of phantom sensation:

Answer 43

• Kinetic phantom sensations are perceived movements of the
  amputated body part (i.e., feeling your toes flex).
• Kinesthetic phantom sensations are related to the size, shape,
  or position of the amputated body part (i.e., feeling as if your
  hand is in a twisted position).
• Exteroceptive phantom sensations are related to sensations
  perceived to be felt by the amputated body part (i.e., feelings of
  touch, pressure, tingling, temperature, itch, and vibrations).

Question 44

Gating theory for tactile somatosensory modulation of ascending pain signals:

Answer 44

• A(beta) fiber inhibits transmission from C fiber to 2nd order neuron via activation
  of inhibitory interneurons
• Transcutaneous electrical nerve
  stimulation (TENS) of Aβ fibres for pain
  relief.

Question 45

Descending pathway regulation of pain: (analgesia pathway)

Answer 45

• PAG contains endorphin neurons
  and is responsive to opioids
• PAG neurones project to the nucleus
  raphe magnus and the rostral
  ventromedial medulla
• Serotoninergic and
  catecholaminergic descending
  pathways modulate nociception
  transmission, partially by stimulating
  dorsal horn enkephalin-containing
  interneurons
• Enkephalin inhibits nociceptive
  transmission in the dorsal horn.

Question 46

Effects of opioids/Enkephalin at the level of DRG and spinal cord dorsal horn region:

Answer 46

• Decreases Ca2+ influx in DRG neuron
  leading to a decrease in the
  duration of the invoked action
  potential and a reduction in
  transmitter release from 1st order
  nociceptive neuron.
• Hyperpolarizes the membrane of
  dorsal horn 2nd order neuron by
  activation of a K+ conductance.
• Decreases the amplitude of the
  excitatory postsynaptic potential
  (EPSP) produced by stimulation of
  nociceptors.