Transcript Peripheral sensitization to pain

Physiology of analyzers
Characteristic of optical system of eye
Components of eye
Sclera gives shape to eyeball
and protect its inner
structures.
Cornea transmits and refracts
light.
Choroid supplies blood to
eyeball.
Ciliary body supports lens
through suspensory ligament
and determines its thickness;
secretes aqueous humor.
Iris regulates diameter of pupil,
and hence the amount of light
entering the vitreous chamber.
The function of retina is
photoreception; transmits
impulses.
Lens refracts light and focuses
onto fovea centralis.
Circulation of inner eye fluid
Aqueous humor, a clear liquid, is produced
in the ciliary’s body by diffusion and active
transport and flows through the pupil to fill
the anterior chamber of the eye. It is
normally reabsorbed through a network of
trabeculae into the canal of Schlemm, a
venous channel at the junction between
the iris and the cornea – anterior chamber
angle.
Circulation of inner eye fluid
Physical refraction, formation of
representation in reduced eye
• Refraction is a bent of light rays when they pass
from one medium into a medium of a different
density, except when they strike perpendicular to
the interface. Refractive index is a ratio of speed
of light ray in air to corresponding transparent
medium.
• Reducted eye is the model of eye in which all
mediums have one index of bent. It need for
value of bent force of eye. In this case formed
less, overturn and real pictures.
Clinical refraction, their kinds
There are three kinds of refraction: myopia
(nearsightedness), emetropia (norm),
hypermetropia (hyperopia or
farsightedness).
Emetropia
When the
main focus
of eye is
onto retina
and we
have clear
picture we
say about
emetropia.
Myopia
When the ray come together in front of
retina we say about myopia.
Hyperopia
When the ray come together at the back of
retina we say about hyperopia.
Kinds of aberration. Astigmatism
Astigmatism is a common condition in which
the curvature of the cornea is not uniform.
When the curvature in one meridian is
different from that in other, light rays in that
meridian are refracted to a different focus,
so that part of the retinal image is blurred.
Concept of accommodation, its
mechanism and regulation
The process by which the curvature of the lens is
increased is called accommodation. At rest the
lens is held under tension by the lens
ligaments. Because the lens substance is
malleable and the lens capsule has
considerable elasticity, the lens is pulled into a
flattened shape.
When the gaze is directed at a near object, the
ciliary muscle constricting. This decreases the
distance between the edges of the ciliary's body
and relaxes the lens ligaments, so that the lens
springs into a more convex shape. The
relaxation of the lens ligaments produced by
contraction of the ciliary's muscle is due partly to
the sphincter like action of the circular muscle
fibers in the ciliary's body and partly to the
contraction of longitudinal muscle fibers that
attach interiorly, near the corneoscleral junction.
Protective mechanisms of eye
Role of cornea and conjunctive
• Conjunctiva protects the eyeball by
preventing object.
• Pupils reactions
• When light is directed into one eye, the
pupil constricts (pupillary light reflex). The
pupil of the other eye also constrictes
(consensual light reflex).
• Eye tonometry is basis on ability of ocular apple to deformation
under pressure on the outside. The more deformation of eyes by
respective power of pressure- the lower quantity of intraocular
pressure.
• The tonometer of A.M.Maclakov is small cylinder with parts, which
finish grounds with milk glass diameter 10 mm. At first 1-2 gums of
solution of anaesthetic substance (0,5 % solution of dykayn) are
dripped in the eye. Grounds of tonometer is greased by thin layer
of dye-stuff (colargol, methylene blue) after cylinder is free
accommodated on the cornea of research eye such, that it flattens
it its weight approximately during 1 second. In the place of flatten
dye leaves on the cornea, the light spot is replied its on the ground
of tonometer. The imprint of this spot on the slightly moist paper is
named tomogram. The more intraocule pressure- the lesser size of
imprint and conversely.
• The quantity of area of flatten is connected with level of intraocular
pressure by mathematical dependence, that made it possible for
S.S.Golovina worked tables of remitting of diameter of circle of
flatten in tonometric indexes.
• The complete consists of 4 tonometers with mass 5 g; 7,5 g; 10 g;
15 g; that widen range of measuring of intraoular pressure.
• The intraocular pressure is 16-26 mm of mercury post in the norm.
Mechanism of vision sensitive
Structure of retina
It is organized in 10 layers and contains the rods
and cones, which are the visual receptors, plus 4
types of neurons: bipolar cells, ganglion cells,
horizontal cells, amacrine cells. Layers: pigment
epithelium, rod and cone (outer and inner
segments), outer nuclear layer, outer plexiform
layer, inner nuclear layer, inner plexiform layer,
ganglion cell layer, optic nerve fibers. In the
center of retina is present fovea centralis, which
has only cones; and blind spot – a place of exit
of optic nerve, where absent visual receptors.
Physiological properties of pigment
layers and photoreceptors of retina
• The light perceived by receptor cells of retina. There are near
120 million of rods and 6 million of cones. The rods are
extremely sensitive to light and are the receptors for night vision
(scotopic vision). The cones are responsible for vision in bright
light (photopic vision) and for color vision. The maximal density
of cones is in fovea centralis, but the fovea contains no rods.
The maximal density of rods is in parafoveal place.
• Each receptor has outer (light-like) segment, where are present
photosensitive pigment, and inner segment, which are rich in
mitochondria. The photosensitive pigments in the rods is called
rhodopsin or visual purple. There are 3 different cone pigments:
iodopsin, photopsin, chlorolab. The photosensitive pigments
have different sensitivity to different length of waves.
• In pigment layer of retina present pigment melanin which take
place in securing the clear vision. Vitamin A takes place in
resynthesis of photosensitive pigments and present in melanin.
Photochemical reaction in retina
receptors
In photoreceptors of retina kvant of light connect with
pigments. For example, rhodopsin has aldegid of vitamin
A (retinals) and protein opsin (scotopsin). Action of light
photon on vision pigment accompany by isomerization of
retinal. That helps to connect retinal with opsin. It
activate calcium ions. That increase to change of
membrane penetration for sodium and rise of receptor
potential (hyperpolarization of receptor cells). In dark
case membrane make way for sodium, that is why it has
very little level of polarization. When there is a big
quantity of light increase amplitude of hyperpolarization.
Conductive and cortex part of
analyzer
• Neural pathways of vision and processing of visual information. Impulses
from the rods and cones pass through bipolar neurons to ganglion neurons.
The 2 optic nerves converge at the optic chiasma. All the fibers arising from
the medial half of each retina cross to the opposite side. The optic tract is a
continuation of optic nerve fibers from the optic chiasma. It is composed of
fibers arising from the retinas of both eyes.
• As the optic tract enters the brain, some of the fibers in the tracts terminate
in the superior colliculi of the midbrain. These fibers and the motor pathways
they activate constitute the tectal system, which is responsible for body-eye
coordination. The tectal system is also insolved in the control of the intrinsic
eye muscles.
• Approximately 70-80 % of the fibers in the optic tracts pass to the lateral
geniculate body of the thalamus. The fibers synapse with neurons whose
axons constitute a pathway called the optic radiation. The optic radiation
transmits impulses to the striate cortex area of the occipital cerebral lobe.
This entire arrangement of visual fibers, known as the geniculostriate
system, is responsible for perception of the visual field.
Recognize of coloring
Theory of coloring perception
• People must determine near 7 mln of colors touch. Each
color has own wave of length (red – 700 nm, green –
546 nm, blue - 435 nm). Mixing of equal quantity of these
colors is white color. Colors have 3 attributes: hue,
intensity and saturation.
• 3-component theory (Yung-Gelmgoltz): there are 3 types
of colors, which have different pigments (for red, green
and violet color). Their combination process in all
nervous centers of central nervous system and cortex.
These process sensitive by our consciousness as
corresponding color.
• Theory of oponent colors (Gering): said that there are 4
main colors which may connect one by one (green-red,
yellow-blue).
Perception of space
Acute of the central vision
• Determination acute of the central vision: Put the table
for the definition of the acute of the central vision on the
well illuminate wall. Investigation has to sit in front of the
table on the distance of 5 meters and close his one eye
with the help of the shield. Show with the pointer letter,
beginning from the upper line, find the lowest line, which
letters investigating person can see clear. Acute of
central vision define with the help of the formula:
• V= d : D, where V – acute of the vision; d – distance from
the eye to the table; D – distance, on which healthy eye
has to see clear this line. Than determine the acute of
vision of another eye. In adult in norm is 1.0.
b) Factors, which are determine acute of
central vision
c) Peripheral vision
d) Binocular (stereoscopic) vision (Vision by
both eyes)
4. Aged peculiarities of vision function
a) Acute of vision, space vision
b) Aged peculiarities of light sensitivity and
color vision
c) Prevent work in the case of breach vision
in children and teenagers
Hearing
Anatomy of the Ear Region
• External ear collects sounds
• Middle ear cavity separated from
external ear by eardrum and from
internal ear by oval & round
window
• 3 ear ossicles connected by
synovial joints
• Auditory tube leads to
nasopharynx
• helps to equalize pressure on both
sides of eardrum
• Membranous labyrinth contains
organs of hearing and equilibrium
Inner Ear-Membranous Labyrinth
• Membranous
labyrinth
– membranous
tubes filled with
endolymph
• contain sensory
receptors for
hearing and
equilibrium
Physiology of Hearing
• Auricle collects sound waves
• Eardrum vibrates
• Ossicles vibrate and push on
oval window
– Amplify signal
• produces pressure waves in
scala vestibuli and scala
tympani
– Causes pressure fluctuations
inside cochlear duct which
move hair cells against
tectorial membrane
• Microvilli are bent
producing receptor
potentials
Hair Cell Physiology
•
Hair cells convert mechanical
deformation into electrical
signals
•
As microvilli bend
mechanically-gated channels
open in membrane
– Causes depolarisation
•
Depolarisation opens
voltage-gated Ca2+ channels
at base of the cell
– Triggers release of
neurotransmitter onto the
first order neuron
Pitch and volume
• Sounds at different frequencies vibrate different portions of
the basilar membrane
– high pitched sounds vibrate the stiffer more basal portion of
the cochlea
– low pitched sounds vibrate the upper cochlea which is wider
and more flexible
• Loud sounds vibrate cause a greater vibration of the basilar
membrane & stimulate more hair cells which our brain
interprets as “louder”
Auditory Pathway
• Auditory signals propagate to nuclei within
medulla oblongata
– differences in the arrival of impulses from both
ears, allows us to locate the source of a sound
• Fibres ascend to
– thalamus
– primary auditory cortex
Equilibrium
• Two types of
equilibrium
– Static
• maintenance of
position of body
(mainly head) relative
to gravity
– Dynamic
• maintenance of body
position (mainly head)
during movement
• Vestibular apparatus
located in inner ear
Equilibrium
• Sense organs of static
equilibrium are Otolithic organs
– Saccule and utricle
• Both contain maculae
– Perpendicular to each other
• Gravity moves otolithic
membrane which bends hair
bundles
– opens and closes ion
channels
» Depolarises and
repolarises hair cells
which release
neurotransmitter
» Neurotransmitter
depolarises first
order sensory
neuron
• Saccule and utricle also
involved in detecting linear
acceleration in dynamic
equilibrium
Equilibrium
• Sense organs of
dynamic
equilibrium
– cristae of
semicircular
canals
• Located on 3
axes
Equilibrium
• Bending of hairs
of cristae as
endolymph flows
generates
receptor potentials
Equilibrium pathways
• Most fibres in vestibular nerve enter brain
stem and terminate in vestibular nuclei in
Medulla Oblongata and Pons
– Axons from vestibular nuclei synapse with nuclei
of cranial nerves controlling:
• eye movement
• head and neck movement
• Rest synapse with cerebellum
– Cerebellum co-ordinates sensory and motor
information (i.e. via motor cortex) to ensure
appropriate activation of skeletal muscles to
maintain balance
PAIN:
-definition of pain: an unpleasant sensory or emotional experience
-perception of pain is a product of brain’s abstraction and elaboration of sensory input.
-perception of pain varies with individuals and circumstances (soldier injured)
-activation of nociceptors does not necessarily lead to experience of pain (asymbolia for pain;
patient under morphine)
-pain can be perceived without activation of nociceptors (phantom limb pain, thalamic pain
syndrome)
-important for survival, protect from damage: congenital and acquired insensitivity (diabetic
neuropathy, neurosyphilis) to pain can lead to permanent damage
-pain reflexes can be stopped if not appropriate (step on nail near precipice, burn hands while
holding a baby. Pain can be suppressed if not needed for survival (soldier…).
In general 2 clinical states of pain:
Physiological (nociceptive) pain  direct stimulation of nociceptors.
Neuropathic (intractable) pain  result from injury to the peripheral or central
nervous system that causes permanent changes in circuit sensitivity and CNS
connections.
Nociceptors (Free nerve ending)
Mechanical nociceptors: activated by strong stimuli such as pinch,
and sharp objects that penetrate, squeeze, pinch the
skin.  sharp or pricking pain, via A-delta fibers.
Thermal nociceptors: activated by noxious heat (temp. above
45°C), noxious cold (temp. below 5°C), and strong
mechanical stimuli.  via A-delta fibers.
Polymodal nociceptors: activated by noxious mechanical stimuli,
noxious heat, noxious cold, irritant chemicals.
 slow dull burning pain or aching pain, via nonmyelinated C fibers. Persists long after the stimulus is
removed.
Research for a transduction protein: capsaicin (from chili peppers)
bind to capsaicin receptor on nociceptor endingstransducer for noxious
thermal and chemical stimuliburning sensation associated with spicy
food. Knockout mouse lacking capsaicin receptor drinks solution of
capsaicin, has reduced thermal hyperalgesia
Mechanisms associated with
peripheral sensitization to
pain
Agents that Activate or Sensitize Nociceptors:
Cell injury  arachidonic acid  prostaglandins   vasc. permeability
(cyclo-oxygenase)
 sensitizes nociceptor
Cell injury  arachidonic acid  leukotrienes   vasc. permeability
(lipoxygenase)
 sensitizes nociceptor
Cell injury   tissue acidity   kallikrein   bradykinin   vasc. permeability
 activates nociceptors
  synthesis & release of prostaglandins
Substance P (released by free nerve endings)  sensitize nociceptors
  vasc. perm., plasma extravasation
(neurogenic inflammation)
 releases histamine (from mast cells)
Calcitonin gene related peptide (free nerve endings)  dilation of peripheral capillaries
Serotonin (released from platelets & damaged endothelial cells)  activates nociceptors
Cell injury  potassium  activates nociceptors
Peripheral
sensitization
to pain:
Some definitions:
Hyperalgesia increased
sensitivity to an already painful stimulus
Allodynia normally non painful
stimuli are felt as painful (i.e .light touch of a
sun-burned skin)
Peripheral sensitization to pain:
CGRP
CGRP
To summarize peripheral sensitization to pain:
-Sensitization results from the release of various chemicals by the
damaged cells and tissues (bradykinin, prostaglandins, leukotrienes…).
These chemicals alter the type and number of membrane receptors on
free nerve endings, lowering the threshold for nociceptive stimuli.
-The depolarized nociceptive sensory endings release substance P and
CGRP along their branches (axon reflex), thus contributing to the spread
of edema by producing vasodilation, increase in vascular permeability
and plasma transvasation, and the spread of hyperalgesia by leading to
the release of histamine from mast cells.
-Aspirin and NSAID block the formation of prostaglandins by inhibiting
the enzyme cyclooxygenase.
-Local anesthetic preferentially blocks C fiber conduction, cold decreases
firing of C fibers, ischemia blocks first the large myelinated fibers.
Pain input to the spinal cord:
-Projecting neurons in lamina I receive A-delta and C fibers info.
-Neurons in lamina II receive input from C fibers and relay it to other laminae.
-Projecting neurons in lamina V (wide-dynamic range neurons) receive A-delta, C and A-beta
(low threshold mechanoceptors) fibers information.
How is pain info sent to the brain: hypotheses  pain is signaled by lamina I and V
neurons acting together. If lamina I cells are not active, the info about type and
location of a stimulus provided by lamina V neurons is interpreted as innocuous. If
lamina I cells are active then it is pain.
Thus: lamina V cells details about the
stimulus, and lamina I cells whether it
is painful or not
-A-delta and C fibers release glutamate
and peptides on dorsal horn neurons.
-Substance P (SP) is co-released with
glutamate and enhances and prolongs the
actions of glutamate.
-Glutamate action is confined to nearby
neurons but SP can diffuse and affect
other populations of neurons because
there is no specific reuptake.
Mechanisms of early-onset
central sensitization:
Winduphomosynaptic activity-dependent
plasticity characterized by a progressive
increase in firing from dorsal horn neurons
during a train of repeated low-frequency Cfiber or nociceptor stimulation.
During stimulation, glutamate + substance P
+ CGRP elicit slow synaptic potentials
lasting several-hundred milliseconds.
Windup results from the summation of these
slow synaptic potentials. This produces a
cumulative depolarization that leads to
removal of the voltage-dependent Mg2+
channel blockade in NMDA receptors and
entry of Ca2+. Increasing glutamate action
progressively increases the firing-response
to each individual stimulus (behavioral
correlate: repeated mechanical or noxious
heat are perceived as more and more painful
even if the stimulus intensity does not
change.
Centrally mediated hyperalgesia:
Under conditions of persistent injury, C fibers fire repetitively and the response of
dorsal horn neurons increase progressively (“wind-up” phenomenon). This is due to
activation of the N-methyl-D-aspartate (NMDA)-type glutamate receptor and diffusion
of substance P that sensitizes adjacent neurons. Blocking NMDA receptors can block
the wind-up.
Noxious stimulation can produce these long-term changes in dorsal neurons
excitability (central sensitization) which constitute a memory of the C fiber input. Can
lead to spontaneous pain and decreases in the threshold for the production of pain.
Carpal tunnel syndrome: median nerve frequently injured at the flexor retinaculum.
Pain ends up affecting the entire arm. (rat model  partial ligature of sciatic nerve or
nerve wrapped with irritant solution)
Gate Control Theory of Pain:
Gate Control Hypothesis:
Wall & Melzack 1965
Hypothesized interneurons
activated by A-beta fibers act
as a gate, controlling primarily
the transmission of pain
stimuli conveyed by C fibers
to higher centers.
i.e. rubbing the skin near the
site of injury to feel better.
i.e. Transcutaneous
electrical nerve stimulation
(TENS).
i.e. dorsal column stim.
i.e. Acupuncture
Referred Pain:
Ascending Pathways:
->localization, intensity,
type of pain stimulus
->arousal, emotion; involves limbic system,
amygdala, insula, cingulate cortex, hypothalamus.
Mediate descending control of pain (feedback loop)
New pathway for visceral pain:
selective lesion of fibers in the ventral
part of the fasciculus gracilis reduces
dramatically the perception of pain from
the viscera.
General problems with surgery:
Rhizotomy (cutting dorsal root)
Anterolateral cordotomy (cutting
ALS)
In both cases, pain come back,
excruciating.
Thalamus: lesion VPL, VPM 
thalamic syndrome. Intralaminar nuclei
 (arousal + limbic)
Cortex: S1 cortex  localization,
quality and intensity of pain stimuli.
Lesion of cingulate gyrus and insular
cortex  asymbolia for pain
Descending pathways regulating the
transmission of pain information:
intensity of pain varies among individuals
and depends on circumstances (i.e. soldier
wounded, athlete injured, during stress).
Stimulation of PAG causes analgesia so
profound that surgery can be performed.
PAG stimulation can ameliorate intractable
pain. PAG receives pain information via the
spinomesencephalic tract and inputs from
cortex and hypothalamus related to
behavioral states and to whether to activate
the pain control system. PAG acts on raphe &
locus ceruleus to inhibit dorsal horn neurons
via interneurons and morphine receptors.
Application: Intrathecal morphine pumps
Analgesics:
1)
May act at the site of injury and decrease the pain associated with an inflammatory reaction
(e.g. non-steroidal anti-inflammatory drugs (NSAID) such as: aspirin, ibuprofen,
diclofenac). Believed to act through inhibition of cyclo-oxygenase (COX). COX-2 is
induced at sites of inflammation. Inhibition of COX-1 causes the unwanted effects of
NSAID, i.e. gastrointestinal bleeding and nephrotoxicity. Selective COX-2 inhibitor are now
used.
2)
May alter nerve conduction (e.g. local anesthetics): block action potentials by blocking Na
channels. Used for surface anesthesia, infiltration, spinal or epidural anesthesia. Used in
combination to steroid to reduce local swelling (injection near nerve root). Local anesthetic
preferentially blocks C fiber conduction, cold decreases firing of C fibers, ischemia blocks
first the large myelinated fibers.
3)
May modify transmission in the dorsal horn (e.g. opioids: endorphin, enkephalin,
dynorphin…). Opioids act on G-protein coupled receptors: Mu, Delta and Kappa. Opioid
agonists reduce neuronal excitability (by increasing potassium conductance) and inhibit
neurotransmitter release (by decreasing presynaptic calcium influx)
4)
May affect the central component and the emotional aspects of pain (e.g. opioids,
antidepressant). Problems of tolerance and dependence