Nociceptors the sensors of the pain pathway
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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.
Notes de l'éditeur
- 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.