Transcript 03 Nociceptive sensation. Somatic sensory analyzer

Nociceptive sensation.
Somatic sensory analyzer
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:
CGRP
CGRP
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.
Neurotransmitters
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Chemical substances that allow nerve
impulses to move from one neuron to another
Found in synapses
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Norepinephrine
Substance P
Acetylcholine
Enkephalins
Endorphins
Serotonin
Can be either excitatory or inhibitory
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Fast pain (acute)
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occurs rapidly after stimuli (.1 second)
sharp pain like needle puncture or cut
not felt in deeper tissues
larger A nerve fibers
Slow pain (chronic)
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begins more slowly & increases in intensity
in both superficial and deeper tissues
smaller C nerve fibers
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Also different changes in
human organism
followed by pain are
observed: increase of
muscle tone, accelerated
heartbeat, increase of
blood pressure,
intensification of
sweating, dilatation of
pupils and elevation of
glucose and cuprum
level in plasma,
activation of hemostasis.
It considered to cause
the majority of both
visceral and biochemical
reactions by excitation
of sympathetic nervous
system, which is
presented by neurons of
hypothalamus,
hypophisis and cells in
medullar substance of
adrenal glands.
Referred Pain:
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Afferent nociceptive impulses
are collected into central
nervous system by two kinds
of nervous fibers: quick adelta myelinated nerve fibers
and C-fibers without myelin.
The ascending fibers are
included in spinothalamic
tract, which passes through
the spinal cord and reach
medulla oblongata. Here
there are second order
sensory neurons of
spinomesencephalic tract.
Fibers of spinothalamic tract
synapse with third-order
neurons in the thalamus,
which in turn project to the
postcentral gyrus of the
contralateral cerebral
hemisphere.
Sensory pathways: 3 neurons
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1st: enters spinal cord from periphery
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2nd: crosses over (decussates), ascends
in spinal cord to thalamus
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3rd: projects to somatosensory cortex
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
Neuropathic (intractable)
pain:
Pain following peripheral
nerve injury. Greater loss of
small fibers than large diameter
fibers. Axons of surviving Abeta fibers sprout new branches
and make connection to neurons
vacated by the lost C fibers .
Nonpainful stimuli become
painful. Change from innocuous
to noxious sensation is called
allodynia.
Thalamic pain syndrome:
usually following stroke in the
ventral basal thalamus.
Rearrangement of local circuit
leads to excruciating pain.
Phantom limb pain:
A-beta
Pain
Signaling
neurons
C fibers
N
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
Location of pathway
terminations
video
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