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Group C nerve fiber
C fiber not labeled, but substantia gelatinosa of Rolando is Rexed lamina II, labeled at upper left. The Rexed laminae comprise a system of ten layers of Grey matter (I-X identified in the early 1950s by Bror Rexed to label portions of the Spinal cord
Dorlands/Elsevier f_05/12360696

Contents

Structure and Anatomy

Location

C fibers are found in the peripheral nerves of the somatic sensory system. Elsevier, the world's largest Publisher of Medical and Scientific literature, forms part of the Reed Elsevier group The peripheral nervous system ( PNS) resides or extends outside the Central nervous system (CNS which consists of the Brain and Spinal cord. [1] They are unique because unlike most other nerves in the nervous system, they are unmyelinated. A nerve is an enclosed cable-like bundle of peripheral Axons (the long slender projections of Neurons. Myelin is an electrically-insulating Dielectric Phospholipid layer that surrounds only the Axons of many Neurons It is an outgrowth [1] This lack of myelination is the cause of their slow conduction velocity, which is on the order of no more than 2 m/s. A nerve conduction study (NCS is a test commonly used to evaluate the function especially the ability of Electrical conduction, of the motor and Sensory nerves [1] C fibers are on average . 2-1. 5 μm in diameter. [1]

Structure

C fibers are a type of axon that classifies its attached free nerve endings, which are pain-sensing nociceptors. An axon or nerve fiber is a long slender projectionof a nerve cell or Neuron, that conducts electrical impulses away from the neuron's Cell A free nerve ending ( FNE) is an unspecialized Afferent nerve ending meaning it brings information from the body's periphery to the brain Pain, in the sense of physical pain, is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm A nociceptor is a Sensory receptor that sends signals that cause the perception of Pain in response to a potentially damaging stimulus [1] The other main classification of nociceptors is Aδ fibers. [1] These fibers have axons that are larger (1-5 μm), in diameter, are thinly myelinated, and have a higher conduction velocity, which is on the order of about 20 m/s. [1]

Remak bundles

C fiber axons are grouped together into what is known as Remak bundles. [2] These occur when an unmyelinated Schwann cell bundles the axons close together by surrounding them. Named after the German physiologist Theodor Schwann, Schwann cells (also referred to as neurolemmocytes) are a variety of Glial cell that mainly [3] The Schwann cell keeps them from touching each other by squeezing its cytoplasm between the axons. The cytoplasm is the contents of a cell that is enclosed within the Plasma membrane. [3] The condition of Remak bundles varies with age. [3] The number of C fiber axons in each Remak bundle varies with location. [2] For example in a rat model, large bundles of greater than 20 axons are found exiting the L5 dorsal root ganglion, while smaller bundles of average 3 axons are found in distal nerve segments. In Anatomy and Neurology, the dorsal root Ganglion (or spinal ganglion) is a nodule on a Dorsal root that contains cell bodies of [2] Multiple neurons contribute axons to the Remak bundle with an average ratio of about 2 axons contributed per bundle. [2] The cross sectional area of a Remak bundle is proportional to the number of axons found inside it. [2] Remak bundles in the distal peripheral nerve are clustered with other Remak bundles. [2] The Remak Schwann cells have been shown to be electrochemically responsive to action potentials of the axons contained within them. In Neurophysiology, the action potential is a self-regenerating Wave of Electrochemical activity that allows Nerve cells to carry a signal [2]

In experiments where nerve injury is caused but nearby C fibers remain intact, increased spontaneous activity in the C fibers is observed. [2] This phenomenon supports the theory that damaged nerve fibers may release factors that alter the function of neighboring undamaged fibers. [2] Study of Remak bundles has important implications in nerve regeneration after sustaining injury. [2] Currently, recovery of distal C fiber function takes months and may still only regain incomplete function. [2] This may result in abnormal sensory function or neuropathic pain. Neuropathy is a medical term usually short for Peripheral neuropathy. [2] Remak bundles are thought to release certain trophic factors that promote the regeneration of the damaged axons. [2]

Pathway

C fibers synapse to second-order projection neurons in the spinal cord at the upper laminae of the dorsal horn in the substantia gelatinosa. The posterior horn ( posterior cornu, dorsal horn, spinal dorsal horn) of the Spinal cord is the dorsal (more towards the back grey matter of The apex of the Posterior horn of the gray matter of the Spinal cord is capped by a V-shaped or crescentic mass of translucent gelatinous neuroglia termed the substantia [4] The second-order projection neurons are of the wide dynamic range (WDR) type, which receive input from both nociceptive terminals as well as myelinated A-type fibers. [4] There are three types of second order projection neurons in the spinothalamic tract: wide dynamic range (WDR), high threshold (HT), and low threshold (LT). The spinothalamic tract is a sensory pathway originating in the spinal cord [5] These classifications are based on their responses to mechanical stimuli. [5] The second-order neurons ascend to the brain stem and thalamus in the ventrolateral, or anterolateral, quadrant of the contralateral half of the spinal cord, forming the spinothalamic tract. The brain stem (or brainstem) is the lower part of the Brain, adjoining and structurally continuous with the Spinal cord. The thalamus (from Greek θάλαμος = room chamber, IPA= /ˈθæləməs/ is a pair and symmetric part of the brain In fields of Anatomy, anatomical terms of location are descriptive terms to help identify relative positions or directions within a species In fields of Anatomy, anatomical terms of location are descriptive terms to help identify relative positions or directions within a species In fields of Anatomy, anatomical terms of location are descriptive terms to help identify relative positions or directions within a species The spinal cord is a long thin tubular bundle of Nerves that is an extension of the Central nervous system from the brain and is enclosed in and protected [1] The spinothalamic tract is the main pathway associated with pain and temperature perception, which immediately crosses the spinal cord laterally. [1] This crossover feature is clinically important because it allows for identification of the location of injury.

Function

Because of their higher conduction velocity, Aδ fibers are responsible for the sensation of a sharp first pain. Pain, in the sense of physical pain, is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm [1] They respond to a weaker intensity of stimulus. [1] C fibers, however, respond to a stronger intensity of stimulus and are responsible for the slow, dull, longer-lasting, second pain. [1]

C fibers are considered polymodal because they can respond to thermal, mechanical, and chemical stimuli. [1] C fibers respond to all kinds of physiological changes in the body. [6] For example, they can respond to hypoxia, hypoglycemia, hypo-osmolarity, the presence of muscle metabolic products, and even light or sensitive touch. Chronic Hypoxia is a pathological condition in which the body as a whole ( generalized hypoxia) or region of the body ( tissue hypoxia) is deprived of adequate Hypoglycemia or hypoglycaemia is the medical term for a pathologic state produced by a lower than normal level of Glucose ( sugar) in the blood [6] C fiber receptors include:

This variation of input signals calls for a variety of cells of the cortex in lamina 1 to have different modality-selectiveness and morphologies. The cerebral cortex is a structure within the Brain that plays a key role in Memory, Attention, perceptual Awareness, Thought, [6] These varying neurons are responsible for the different feelings we perceive in our body and can be classified by their responses to ranges of stimuli. [6] The brain uses the integration of these signals to maintain homeostasis in the body whether it is temperature related or pain related. Homeostasis (from Greek: ὅμος hómos, "equal" and ιστημι istēmi, "to stand" lit [6]

Vanilloid Receptor

The vanilloid receptor (VR-1) is a receptor that is found on the free nerve endings of both C and Aδ fibers that responds to elevated levels of heat (>43°C) and the chemical capsaicin. In a Sensory system, a sensory receptor is a structure that recognizes a stimulus in the internal or external environment of an Organism. Capsaicin /ˌkæpˈseˌɪsɪn/ (8- Methyl - N - Vanillyl -6-nonen Amide) is the active component of Chili peppers [1] Capsaicin activates C fibers by opening a ligand-gated ion channel and causing an action potential to occur. In Chemistry, a ligand is either an Atom, Ion, or Molecule (see also Functional group) that bonds to a central metal generally Ion channels are pore-forming Proteins that help establish and control the small Voltage Gradient across the Plasma membrane of all living [1] Because this receptor responds to both capsaicin and heat, chili peppers are sensed as hot. [1] VR-1 is also able to respond to extracellular acidification and can integrate simultaneous exposure to all three sensory stimuli. In Cell biology, Molecular biology and related fields the word extracellular (or sometimes extracellular space) means "outside the cell [7] VR1 is essential for the inflammatory sensitization to noxious thermal stimuli. [7] A second type of receptor, a vanilloid-like receptor (TRPV1), has a higher threshold of activation regarding heat of about 52°C and also does not respond to capsaicin. The Transient receptor potential vanilloid 1 or TRPV1 can refer to the TRP cation channel receptor or the gene which encodes it in Homo sapiens. [1] Both types of receptors are transmembrane receptors that are closed during resting conditions. Transmembrane receptors are Integral membrane proteins which reside and operate typically within a cell's Plasma membrane, but also in the membranes of [1] When open, these receptors allow for an influx of sodium and calcium which initiates an action potential across the fibers. Sodium (ˈsoʊdiəm is an element which has the symbol Na( Latin natrium, from Arabic natrun) atomic number 11 atomic mass 22 Calcium (ˈkælsiəm is the Chemical element with the symbol Ca and Atomic number 20 [1] Both receptors are part of a larger family of receptors called transient receptor potential (TRP) receptors. Transient receptor potential or TRP channels are a family of loosely related Ion channels that are non-selectively permeable to Cations including Calcium [1] If damage to these heat transducer receptors occurs, the result can be chronic neuropathic pain caused by lowering the heat pain threshold for their phosphorylation. Phosphorylation is the addition of a Phosphate (PO4 group to a Protein molecule or a small molecule [8]

Role in Neuropathic Pain

Activation of nociceptors is not necessary to cause the sensation of pain. [8] Damage or injury to nerve fibers that normally respond to innocuous stimuli like light touch may lower their activation threshold needed to respond; this change causes the organism to feel intense pain from the lightest of touch. [8] Neuropthaic pain syndromes are caused by lesions or diseases of the parts of the nervous system that normally signal pain. [9] There are four main classes:

After a nerve lesion of either C fibers or Aδ fibers, they become abnormally sensitive and cause pathological spontaneous activity. In Medicine, ischemia ( Greek ισχαιμία, isch- is restriction hema or haema is Blood) is a restriction Polyneuropathy is a Neurological disorder that occurs when many Peripheral nerves throughout the body malfunction simultaneously Metabolism is the set of Chemical reactions that occur in living Organisms in order to maintain Life. In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. A stroke is the rapidly developing loss of brain functions due to a disturbance in the blood vessels supplying blood to the brain Multiple sclerosis (abbreviated MS also known as disseminated sclerosis or encephalomyelitis disseminata) is an autoimmune condition in which the Complex Regional Pain Syndrome (CRPS is a chronic progressive disease characterized by severe pain swelling and changes in the skin Pathology (from Greek grc πάθος pathos, "fate harm" and grc -λογία -logia) is the study and [4] This alteration of normal activity is explained by molecular and cellular changes of the primary afferent nociceptors in response to the nerve damage. Afferent is an Anatomical term with the following meanings Conveying towards a center for example the Afferent arterioles conveying blood [4] The abnormal activity of the damaged nerves is associated with the increased presence of mRNA for voltage-gated sodium channels. Messenger ribonucleic acid ( mRNA) is a molecule of RNA encoding a chemical "blueprint" for a Protein product Sodium channels are Integral membrane proteins that form Ion channels, conducting sodium ions ( Na+) through a cell's Plasma membrane [10] Irregular grouping of these channels in sites of the abnormal activity may be responsible for lowering the activation threshold, thus leading to hyperactivity. Hyperactivity can be described as a physical state in which a person is abnormally and easily excitable or exuberant [10]

Central Sensitization

After nerve damage, WDR neurons experience a general increase in excitability. Sensitization is an example of non-associative Learning in which the progressive amplification of a response follows repeated administrations of a stimulus (Bell [4] This hyper-excitability can be caused by an increased neuronal response to a noxious stimulus, a larger neuronal receptive field, or spread of the hyper-excitability to other segments. The receptive field of a sensory Neuron is a region of space in which the presence of a stimulus will alter the firing of that neuron [4] This condition is maintained by C fibers. [4] C fibers cause central sensitization of the dorsal horn in the spinal cord in response to their hyperactivity. [4] The mechanism underlying this phenomenon involves the release of glutamate by these pathologically sensitized C fibers. Glutamic acid (abbreviated as Glu or E) is one of the 20 Alpha Amino acids It is not among the human Essential amino acids Its [4] Presynaptic neuronal voltage-gated N-calcium channels contribute to central sensitization by the release of glutamate and the neuropeptide, substance P. Chemical synapses are specialized junctions through which Neurons signal to each other and to non-neuronal cells such as those in Muscles or Glands A neuropeptide is any of the variety of Peptides found in Neural tissue; e In Neuroscience, Substance P is a Neuropeptide: a short-chain Polypeptide that functions as a Neurotransmitter and as a Neuromodulator [4] After a nerve lesion, these presynaptic channels are over expressed. [4] The glutamate interacts with the postsynaptic NMDA receptors, which aids the sensitization of the dorsal horn. Chemical synapses are specialized junctions through which Neurons signal to each other and to non-neuronal cells such as those in Muscles or Glands The NMDA receptor ( NMDAR) is an Ionotropic receptor for Glutamate ( NMDA ( N -methyl D -aspartate is a name of its selective [4] Once this abnormal central sensitization is established, previously non-noxious stimuli evoke a pain response. [4]

Central sensitization of the dorsal horn neurons that is evoked from C fiber activity is responsible for temporal summation of “second pain” (TSSP). [11] This event is called ‘windup’ and relies on a frequency greater or equal to 0. Frequency is a measure of the number of occurrences of a repeating event per unit Time. 33Hz of the stimulus. The hertz (symbol Hz) is a measure of Frequency, informally defined as the number of events occurring per Second. [11] Windup is associated with chronic pain and central sensitization. Chronic pain is defined as Pain that persists longer than the temporal course of natural healing associated with a particular type of injury or disease process [11] This minimum frequency was determined experimentally by comparing healthy patient fMRI’s when subjected to varying frequencies of heat pulses. Functional MRI or functional Magnetic Resonance Imaging (fMRI is a type of specialized MRI scan [11] The fMRI maps show common areas activated by the TSSP responses which include contralateral thalamus (THAL), S1, bilateral S2, anterior and posterior insula (INS), mid-anterior cingulate cortex (ACC), and supplemental motor areas (SMA). The cingulate cortex is a part of the Brain situated in the medial aspect of the cortex. [11] TSSP events are also associated with other regions of the brain that process functions such as somatosensory processing, pain perception and modulation, cognition, pre-motor activity in the cortex. Cognition is a concept used in different ways by different disciplines but is generally accepted to mean the process of awareness or thought [11]

Treatment

Currently, the availability of drugs proven to treat neuropathic pain is limited and varies widely from patient to patient. [8] Many developed drugs have either been discovered by accident or by observation. [8] Some past treatments include opiates like poppy extract, non-steroidal anti-inflammatory drugs like salicylic acid, and cocaine. For other uses see Opiate (disambiguation, or for the class of drugs see Opioid. A poppy is any of a number of showy Flowers typically withone per stem, belonging to the poppy family. Salicylic acid (from the Latin word for the willow tree Salix, from whose bark it can be obtained is a Beta hydroxy acid (BHA with the formula Cocaine ( benzoylmethyl ecgonine) is a Crystalline Tropane Alkaloid that is obtained from the leaves of the Coca plant [8] Other recent treatments consist of antidepressants and anticonvulsants, although no substantial research on the actual mechanism of these treatments has been performed. An antidepressant is a Psychiatric medication used for alleviating major depression or Dysthymia ('milder' depression The anticonvulsants, also called antiepileptic drugs (abbreviated "AEDs" are a diverse group of pharmaceuticals used in the treatment of epileptic [8] However, patients respond differently to these treatments possibly because of gender differences or genetic backgrounds. Genetics (from Ancient Greek grc-Latn genetikos, “genitive” and that from grc-Latn genesis, “origin” a discipline of Biology, is [8] Therefore, researchers have come to realize that no one drug or one class of drugs will reduce all pain. [8] Research is now focusing on the underlying mechanisms involved in pain perception and how it can go wrong in order to develop an appropriate drug for patients afflicted with neuropathic pain. [8]

Microneurography

Microneurography is a technique using metal electrodes to observe neural traffic of both myelinated and unmyelinated axons in efferent and afferent neurons of the skin and muscle. Human Microneurography or simply microneurography involves the insertion of metal microelectrodes into nerve fascicles An electrode is an Electrical conductor used to make contact with a nonmetallic part of a circuit (e In the Nervous system, efferent nerves – otherwise known as motor or effector Neurons – carry nerve impulses away from the [12] This technique is particularly important in research involving C fibers. [12] Single action potentials from unmyelinated axons can be observed. [12] Recordings from efferent postganglionic sympathetic C fibers of the muscles and skin yield important insights into the neural control autonomic effector organs like blood vessels and sweat glands. In the Autonomic nervous system, fibers from the Ganglion to the effector organ are called postganglionic fibers. &trade The autonomic nervous system ( ANS) (or visceral nervous system) is the part of the Peripheral nervous system that acts as a Control The blood vessels are part of the Circulatory system and function to transport Blood throughout the body The skin contains two different groups of sweat glands: Apocrine sweat glands and Merocrine sweat glands. [12] Readings of afferent discharges from C nociceptors identified by marking method have also proved as important tools to revealing the mechanisms underlying sensations such as itch. Itch ( Latin: pruritus) is an unpleasant Sensation that evokes the desire or Reflex to scratch [12]

Unfortunately, interpretation of the microneurographic readings can be difficult because axonal membrane potential can not be determined from this method. [13] A supplemental method used to better understand these readings involves examining recordings of post-spike excitability and shifts in latency; these features are associated with changes in membrane potential of unmyelinated axons like C fibers. In Neurophysiology, the action potential is a self-regenerating Wave of Electrochemical activity that allows Nerve cells to carry a signal [13] Moalem-Taylor et al. experimentally used chemical modulators with known effects on membrane potential to study the post-spike super-excitability of C fibers. [13] The researchers found three resulting events. [13] Chemical medulators can produce a combination of loss of super-excitability along with increased axonal excitability, indicating membrane depolarization. In biology depolarization is a decrease in the Absolute value of a cell's Membrane potential. [13] Secondly, membrane hyperpolarization can result from a blockade of axonal hyperpolarization-activated current. [13] Lastly, a non-specific increase in surface charge and a change in the voltage-dependent activation of sodium channels results from the application of calcium. [13]

References

  1. ^ a b c d e f g h i j k l m n o p q r s t Purves, Dale; et. al (2004). Neuroscience. Massachusetts: Sinauer Associates, Inc. . ISBN 0-87893-725-0.  
  2. ^ a b c d e f g h i j k l m Murinson, BB; JW Griffin (2004). "C-fiber structure varies with location in peripheral nerve". Journal of Neuropathology and Experimental Neurology 63: 246–254.  
  3. ^ a b c Fagan, Tom (2003). "Glial Cells Critical for Peripheral Nervous System Health". News from Harvard Medical, Dental and Public Health Schools.  
  4. ^ a b c d e f g h i j k l m n Baron, Ralph (2006). "Mechanisms of Disease: neuropathic pain—a clinical perspective". Nature Clinical Practice Neurology 2.  
  5. ^ a b Chung, J. M. ; et. al (1979). "Excitation of primate spinothalamic neurons by cutaneous C-fiber volleys". . ” Journal of Neurophysiology 42: 1354–1369.  
  6. ^ a b c d e f Craig, AD (2003). "Interoception: the sense of the physiological condition of the body". Current Opinion in Neurobiology 13: 500–505. doi:10.1016/S0959-4388(03)00090-4. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  7. ^ a b Davis, JB; et. al (2000). "Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia". Nature 405: 183–7. doi:10.1038/35012076. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  8. ^ a b c d e f g h i j Scholz, Joachim; Clifford Woolf (2002). "Can we conquer pain?". Nature Neuroscience 5: 1062–1067. doi:10.1038/nn942. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  9. ^ Baron, Ralph (2000). "Peripheral neuropathic pain: from mechanisms to symptoms". Clinical Journal of Pain 16: S12–20. doi:10.1097/00002508-200003000-00003. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  10. ^ a b Lai, J (2003). "The role of voltage-gated sodium channels in neuropathic pain". Current Opinion Neurobiology 13: 291–297. doi:10.1016/S0959-4388(03)00074-6. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  11. ^ a b c d e f Staud, Roland; et. al (2007). "Brain activity related to temporal summation of C-fiber evoked pain". Pain 129: 130–142. doi:10.1016/j.pain.2006.10.010. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  12. ^ a b c d e Mano, Tadaaki; et. al (2006). "Microneurography as a tool in clinical neurophysiology to investigate peripheral neural traffic in humans". Clinical Neurophysiology 117: 2357–2384. doi:10.1016/j.clinph.2006.06.002. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  13. ^ a b c d e f g Moalem-Taylor, Gila; et. al (2007). "Post-spike excitability indicates changes in membrane potential of isolated c-fibers". Muscle and Nerve 36: 172–182.  

See also

A free nerve ending ( FNE) is an unspecialized Afferent nerve ending meaning it brings information from the body's periphery to the brain A nociceptor is a Sensory receptor that sends signals that cause the perception of Pain in response to a potentially damaging stimulus Pain, in the sense of physical pain, is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm Sensory neurons are Neurons that are activated by sensory input (vision touch hearing etc A thermoreceptor is a Sensory receptor, or more accurately the receptive portion of a sensory neuron that codes absolute and relative changes in temperature primarily Group B fibers are nerve fibers which are moderately myelinated which means less myelinated than group A fibers and more myelinated than C fibers Their conduction
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