Nociceptors are sensory neurons that detect potentially damaging stimuli and mediate the pain response. The document discusses the anatomy and physiology of nociception, including:
1) Nociceptors express receptors that detect noxious heat, cold, and mechanical stimuli.
2) Nociceptor activation leads to action potentials that are conducted to the spinal cord and brain.
3) Central modulation and sensitization can lower pain thresholds and lead to hyperalgesia and allodynia.
4) While specific nociceptor populations respond to different stimuli, their roles in transmitting specific pain modalities require further study.
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Nociceptors the sensors of the pain pathway
1. NOCICEPTORS: THE SENSORS OF THE PAIN
PATHWAY
Realised by :
Federica Pilotto (Turin University)
Asmae Lguensat (Cady ayyad
University)
2. OUTLINES:
Introduction
1- Anatomy and physiology of cutaneous nociception
2-The response of nociceptors to noxious stimuli
Transduction of noxious heat
Transduction of noxious cold
Transduction of noxious mechanical stimuli
3-Conduction
4-Central modulation
5-Adaptive and maladaptive shifts in pain threshold
6-Do labeled lines transmit noxious stimulus information?
Future challenges
3. INTRODUCTION
Pain definition
Pain has been defined as a complex costellation of unpleasant sensory,
emotional and cognitive experiences provoked by real or perceived tissue
damage and manifested by certain autonomic, psychological and behavioral
reactions.
Pain have different qualities and temporal featuares
First pain: lancinating, stabbing
Second pain: more pervasive and includes burning, throbbing
Pain is highly individual and subjective
4. 1-ANATOMY AND PHYSIOLOGY OF CUTANEOUS
NOCICEPTION
Nociceptors
Nociceptors, a peripherally localized neuron preferentially sensitive to a noxius
stimulus.
They respond to different stimuli:
- Thermal
- Mechanical
- Chemical
• Cutaneous nociceptors are housed in peripheral sensory ganglia
• Nociceptors are generally electrically silent and transmit all or none action
potentials only when stimulated
5. The speed of transmission correlated
to the diameter of axon of sensory neurons
and wheter or not they are myelinated
C-fibers axons unmyelinated and small
diameter (velocity: 0.4-1.4 m/s)
Their peripheral afferent innervates the
skin and central process projects to
superficial lamin I and II of the dorsal horn
A-fibers axons myelinated (velocity: 5-30
m/s)
A-fiber nociceptors project to superficial
laminae I and V
6. The relay neurons project to
medulla, mesencephalon and
thalamus, which in turn project
to somatosensory and anterior
cingulate cortices to drive
sensory-discriminative and
affective-cognitive aspects of
pain, respectively.
Green: diffuse inhibitory controls
induced by nociceptive stimuli
Violet: segmental controls of
non-pain peripheral origin
7. 2-THE RESPONSE OF NOCICEPTORS TO NOXIOUS
STIMULI
Generalities :
Activation of nociceptors requires :
Depolarization of peripheral terminals with
sufficient amplitude and duration
stimulus intensity will be encoded in the
resulting train of impulses
Painful
Stimuli
8. TRANSDUCTION OF NOXIOUS HEAT
5 classes of nociceptors
increase their activity
dependent on the
intensity of the heat
stimulus beyond the
threshold for pain
perception (~40°C–45°C).
Under normal conditions,
the activity in only a
subset of heat-responsive
fibers correlates to the
degree of pain perceived.
Ion channels that transduce heat
9. Fibers implicated in heat transmission and
associated receptors :
A-fibers
C-fibers
Responding to
temperatures cooler than the
perceptual pain threshold for
heat
Rapidly activate, adapt
during prolonged heat
stimulation
Sensitive to capsaicin
TRPV2 receptor
Human C-MH polymodal
nociceptors are activated in
a temperature range (39°C–
51°C)
Heat induced C-MH fiber
activity correlates with pain
perception in the absence of
injury
Transiently activated by
capsaicin
TRPV1 receptor
10. TRANSDUCTION OF NOXIOUS COLD
The intensity of cold increases
with stimulus intensity
between about 20°C and 0°C.
The threshold for pain
perception to cold : about
15°C
Cooling the skin to 4°C
activates A- and C-fibers
sensitive to innocuous cooling
and cold-sensitive nociceptors
Ion channels that transduce cold
11. Channels implicated in cold transmission:
TRPM8 channel TRPA1 channel
Noxious cold stimuli
activate NSC currents and
calcium influx and decrease
K+ channel activity and
Na+/K+-ATPase function
the analgesic effects of
cold temperature (17°C) were
lost in mice lacking TRPM8
TRPA1 contributes to
variation in cold-pain
sensitivity
May respond to cold
indirectly through cold-
induced intracellular calcium
release
Can be activated by a slow
temperature ramps in
excised patches in the
absence of calcium
12. TRANSDUCTION OF NOXIOUS MECHANICAL
STIMULI
Transduction in soma membranes
suggests direct gating by
pressure of ion channels with
NSC and possibly Na+
permeability
the identification of proteins
involved in sensing innocuous
touch has been done, but their
genetic deletion in mouse does
not compromise behavioral
responses to noxious pressure
Ion channels that transduce mechanical
stimuli
13. 3-CONDUCTION
Nociceptors express a wide variety of voltage gated channel.
For instance: nociceptors responsive to noxius cold require the expression of
the tetradotoxin-resistant (TTX-resistant) Nav 1.8 channel at the periferal
terminal.
Peripheral CGRP release by inflammatory mediators is unaffected by TTX,
suggesting an important role of TTX-resistant Nav in regulated pain thresholds.
14. 4-CENTRAL MODULATION
Nociceptors release a variety of substances from their central
terminals that have the potential of exciting second-order neurons
through multiple mechanisms.
Fast and slow synaptic transmission are mediated in large part by
glutamate and peptides
Anterograde transmission of action potentials from the spinal cord to the
periphery results in release of peptides and other inflammatory
mediators in the skin and exacerbates nociceptor excitability and pain
It is at the spinal level that non nociceptive neurons are recruited by strong
nociceptor activation through functional modulation of local circuits
15. 5-ADAPTATIVE AND MALADAPTATIVE SHIFTS IN PAIN
THRESHOLD
• Allodynia: pain evoked by a
normally innocuous stimulus.
• Hyperalgesia: an increase in
the perception of pain elicited
by a noxius stimulus.
16. What are the cellular mechanisms mediating
hyperalgesia?
Plasma extravasation
Electrical stimulation of the majority of C-polymodal fiber
Centrally propagating impulses can invade
peripheral arborizations innervating other areas
Release of peptides (CGRP,somatostain) in the interstitial tissue
Arteriolar vasodilatation
Liberated enzymes and blood cells further contribute to the
accumulation of inflammatory mediators and neurogenic inflammation
A large variety of substances feed back onto
nociceptors innervating the injured region
17. Decrease thermal and
chemical thresholds in the
primary area are due in part to
sensitization of TRPV1 and
TRPA1
Hyperalgesic
priming:
evoked by cytokine
and neurotrophin
induced recruiment of
Gi/o-PKCε signaling in
nociceptors can
produced prolonged
sensitization and
mechanical
hyperalgesia and may
contribute to chronic
pain.
18. 6-DO LABELED LINES TRANSMIT NOXIOUS
STIMULUS INFORMATION?
Pharmacologic and hereditary
genetic ablations have
defined the role of nociceptors
in pain
Genetically encoded tracers
have enabled visualization of
specific subpopulations of
sensory neurons
The sensitivity of C-MH fibers
innervating hairy skin to cold, heat,
and mechanical stimuli is reduced
in mice constitutively lacking
MrgprD-expressing cells reported
to be TRPV1 and peptide negative.
An additive loss of both mechanical
and heat-induced nocifensive
behaviors was achieved after
further pharmacologic ablation of
central TRPV1+ terminals
Mice expressing diphtheria toxin
under the Nav1.8 promoter reveal
significant loss of sensory neurons
19. FUTURE CHALLENGES
our knowledge concerning mammalian nociception and
pain
far from complete
Using genetics and pharmacological approaches to
understanding the contributions of molecules, signaling
pathways, and cell populations to nocifensive behaviors to
particular stimulus modalities in normal and pathophysiological
states in rodents will inspire hypotheses that ultimately must
be tested in humans.
Editor's Notes
The intensity of these global reactions underscores the importance of avoiding damaging situations for survival and maintaining homeostasis.
Local inhibitory and excitatory interneurons in the dorsal horn as well as descending inhibitory and facilitatory pathways originating in the brain modulate the transmission of nociceptive signals, thus contributing to the prioritization of pain perception relative to other competing behavioral needs and homeostatic demands.
The stimulus intensity ensures that despite any attenuation and slowing of the receptor potential by passive propagation between the sites of transduction and action potential generation
A-MH type I–fibers require longer exposures to noxious temperatures to achieve maximal firing rates
Topological model of vanilloid receptor-like transient receptor potential (TRPV) channel structure. The channel is proposed to have 6 transmembrane domains (TM1–TM6), a pore loop (PL), and a long NH2 terminal and COOH terminal, both cytoplasmic. The NH2 terminal has 2–5 ankyrin repeat domains (ARD), with 3 ARDs being typical.
Cool-sensitive non nociceptive afferents are spontaneously active at normal skin temperature and their excitability increases with decreasing temperature
The effective range for TRPM8-mediated cold coding extends from just below skin temperature into the noxious range (10°C–15°C and below;ref. 10).
Schematic diagram of Ca2+-dependent modulation of TRPM8 channels. Ca2+ entry through TRPM8 channels or other sources can activate CaM, which leads to a switch of TRPM8 channels from a high to a low activity state, thereby causing acute desensitization at the macroscopic current level. CaM binding sites may be located at NH2 terminus of TRPM8 channels. CaM-mediated acute desensitization may not be observed if TRPM8 channels are already at low activity state because of other regulatory mechanisms. One of the other regulatory mechanisms is PIP2 hydrolysis following the activation of Ca2+-dependent PLC, which also results in a switch of TRPM8 channels from a high to a low activity state. However, because there are multiple steps that are involved in PIP2 hydrolysis following Ca2+ entry and also because PIP2 on membranes is abundant, the consumption of PIP2 is likely to be a slower process compared with CaM activation by Ca2+. Therefore, the switch of TRPM8 channels from a high to a low activity state following PIP2 hydrolysis is also likely to be a slower process or tachyphylaxis at the macroscopic current level. TRPM8 channels may be dephosphorylated directly by protein phosphatase 1,2A or indirectly after PKC activation, which may lower the affinity between TRPM8 channels and PIP2, thereby affecting the activity state of TRPM8 channels. DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate.
TRPA1 channel : Is established as a general sensor for noxious irritating electrophilic compounds, these electrophilic agonists open an integral channel pore by covalent binding to the intracellular N terminus of the channel protein
Structural model for TRPA1 protein. Four identical TRPA1 subunits are believed to be combined in the formation a functional channel. Each subunit spanning the plasma membrane six times (transmembrane domains S1–S6) has a long cytoplasmic N-terminal domain. Ovals indicate ankyrin repeats, while filled circles indicate cysteine residues identified as crucial sites for covalent modification of TRPA1 (Hinman et al., 2006; Macpherson et al., 2007; Trevisani et al., 2007; Bessac et al., 2008; Maher et al., 2008; Takahashi et al., 2008; Taylor-Clark et al., 2009).
mechanical stimulation of C-MH and rapidly adapting A-HTM fibers may not.
The perception of pinprick pain intensity is related to activity in capsaicin insensitive A-fiber nociceptors
There are 9 known Nav, 10 Cav, and 40 Kv genes in mammals, many of which have multiple splice variants with different functional characteristics.
Cell excitability and firing behavior depend on the complement of these channels as well as those contributing to frequency modulation.
Of particular importance to pain perception is the plasticity in synaptic strength between primary afferents and the relay and interneurons they drive, presynaptic and postsynaptic modulation by descending facilitatory and inhibitory pathways in the spinal cord, and the efferent aspects of nociceptor function activated by strong GABAergic/glycinergic depolarization of presynaptic terminals leading to the dorsal root reflex
Cellular mechanisms underlying this complicated response involve both peripheral and central processes (14, 38, 105, 107) and require nociceptor input, particularly A-MH and C-MH fibers. After a burn, A-MH fibers (most likely type I) mediate primary heat hyperalgesia in glabrous skin.
Prolonged pain perception observed in inflammatory pain models is generally believed to be produced by ongoing nociceptor activity; formalin, for instance, produces nocifensive behaviors through its activation of TRPA1. Secondary hyperalgesia to punctate pinprick stimuli is mediated at least in part by capsaicin-insensitive A-fiber nociceptors by central sensitization processes.
Psychophysical studies on spinal cord injury patients suffering from partial or complete loss of thermal sensitivity support a model in which both pain-specific pathways and non nociceptive pathways are integrated
Significant cross talk between these pathways exists at multiple levels including stimulus transduction peripheral terminals during neurogenic inflammation, and central connections during central sensitization and may underlie paradoxical temperature sensation
A focus on mechanisms underlying thermal nociception and hyperalgesia is in large part due to the identification of the TRP family of channels.
The future identification of elusive mechanotransducers in somatosensory neurons will likewise thrust the direction of research toward a cellular/molecular understanding of mechanical hyperalgesia and allodynia. The application of genetic technologies and pharmacological approaches to understanding the contributions of molecules, signaling pathways, and cell populations to nocifensive behaviors to particular stimulus modalities in normal and pathophysiological states in rodents will inspire hypotheses that ultimately must be tested in humans.