A delta fiber
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| A delta fiber | |
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| A delta fiber not labeled, but fibers terminate at Rexed lamina I, labeled at upper left. | |
| Dorlands/Elsevier | f_05/12360464 |
A delta fibers, or Aδ fibers, are a type of sensory fiber. They are associated with cold and pressure, and as nociceptors they convey fast pain information.
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[edit] Comparison with C fibers
The sensation of pain is subserved by a complex network of peripheral and visceral nerves, the spinal cord, and the brain. Sensory neurons have either small, myelinated fibers (A delta fibers) that conduct impulses rapidly or small unmyelinated fibers (C fibers) that conduct impulses more slowly. The presence of these two types of fibers allow for the experience of “double pain”, which is characterized by an initial, sharp, and well-localized pain, which is mediated by the myelinated A delta fibers. This process is then followed by a poorly localized, aching pain mediated by the slower unmyelinated C fibers.1 8 Information about either noxious or painful stimuli is conveyed to higher centers of processing via specific receptors and pathways distinct from those used for position sense, touch, or pressure. The harmful stimuli activate several classes of nociceptor terminals, which are sensory receptors that send signals that cause the perception of pain in response to potentially damaging stimuli. These nociceptor terminals are peripheral endings of the primary sensory neurons whose cell bodies are located in the dorsal root ganglia and trigerminal ganglia. One class separation of nociceptors consists of dividing the nociceptors into thermal, mechanical, and polymodal. Thermal nociceptors are activated by extremes of temperature (either greater than 45°C or less than 5°C) and their activated signals are mediated and carried by A delta fibers. The thinly myelinated, small-diameter A delta fibers are extensions of pseudounipolar neurons and conduct the signals they receive at a conduction velocity of between 5 and 30 m/s. Mechanical nociceptors are activated by intensive pressure applied to the skin. Polymodal nociceptors are activated by high-intensity mechanical, chemical, or thermal stimuli. The polymodal nociceptors, in contrast, have small-diameter unmyelinated C fibers that conduct signals slowly, with velocities under 1.0 m/s. Polymodal nociceptors also show increased activity and a decreased firing threshold with repeated activation, which is unlike most sensory receptors, which fatigue with repeated firing. This process is responsible for the lasting, blunted pain that C fibers carry. The afferent axons that are directly involved in pain transmission fall into two classes: A delta axons that are 1 to 4 μm in diameter and are thinly myelinated, or unmyelinated C axons that are 0.1 to 1 μm in diameter, which conduct at a slower speed (0.5 to 2 m/s). Both classes respond to either painful or noxious stimuli in a similar manner, characterized by slow rate of adaptation and continuing discharge after removal of the stimulus. The two fiber types, however, mediate different pain sensations. A brief, intense stimulus delivered to a distal limb will give rise to a sharp and relatively brief pricking sensation, which is carried by A delta fibers. This pain is followed by a dull, prolonged burning sensation, mediated by C fibers.8 10 12 These three types of nociceptors are widely distributed in the skin and deep tissues, and they often work together. A delta fibers carry pain information from thermal and mechanical nociceptors, while C fibers carry the slow, dull pain as a result of polymodal nocicptor activation. Electrophysiological experiments of the double pain phenomenon have shown that the fast, sharp pain is transmitted by A delta fibers that carry information from thermal and mechanical nociceptors, while the second pain, characterized by feeling slow and dull, is transmitted by C fibers. Electrical recordings of A delta fibers and C fibers show a compound action potential representing the summed action potentials of all the component axons in the nerves. Even though the nerve contains mostly unmyelinated axons, the major voltage spikes (first pain) are due to the relatively small number of A delta fibers. Studies showed that when C fibers were selectively blocked, only an initial voltage spike that quickly dissipated was observed. However, if A delta fibers were blocked, there was no initial voltage spike, and rather a longer bell curve shaped propagation. This experiment gave way to the idea that A fibers, specifically A delta fibers, are responsible for the first, sharp pain (sharpness due to high voltage peak) and C fibers are responsible for the longer lasting, dull pain (dull due to shorter voltage peak).9 4 Unlike the specialized somatosensory receptors for touch and pressure, most nociceptors are free nerve endings. The mechanism by which noxious stimuli depolarize free sensory endings and generate action potentials is not known. It is thought that the membrane of the nociceptor contain proteins that convert the thermal, mechanical, or noxious stimuli into a depolarizing electric potential. One potential protein may be the capsaicin receptor, which is the active ingredient in hot peppers. This receptor is also known as the vanilloid receptor, and it is exclusively found in the primary afferent nociceptors. It is known to mediate the pain-producing actions of capsaicin. This receptor also responds to heat stimuli, suggesting that it may be a transducer of painful heat stimuli and therefore implicated in the use of A delta fibers. The vanilloid receptor, especially vanilloid receptor 1 (VR1) has been known as a molecular integrator for pain, and nociceptive neurons such as A delta and C fibers, express this receptor and mediate conditions that include hyperalgesia, neurogenic inflammation, and neuropathic pain.11 Other factors besides the level of activity of the A delta fiber determine location, intensity, and quality of the pain. Electrical stimulation of touch-pressure receptors that activate the same nociceptor, can lead to different reported sensations. This is illustrated when one puts blood pressure cuffs around the arm and inflates it above systolic pressure for about 30 minutes. This causes temporary anoxia and blocks conduction in large diameter A alpha and A beta fibers, while C fibers are still able to conduct action potentials and respond to noxious stimuli. This blockage occurs in the large diameter fibers because they have a higher metabolic demand than C fibers and as a result large motor axons are unable to conduct impulses. In the absence of this conduction, pain is not felt normally. A pin prick, ice, or a pinch cannot be distinguished from each other and all produce the dull burning pain associated with C fibers. Thus, this simple experiment shows that the C and A fibers work in tandem, producing variable types of pain, and the blockage of one type of fiber leads to skewed pain perception.8 9 Nociceptive afferent fibers tend to terminate mostly in the dorsal horn of the spinal cord. The dorsal horn is subdivided into six layers (laminae). Nociceptive neurons are located in the superficial dorsal horn, the marginal layer (lamina I), and the substantia gelatinosa (lamina II). The majority of these neurons receive synaptic input from the A delta and C fibers. Projection neurons in lamina I receive direct input from myelinated A delta fibers and indirect input from unmyelinated C fibers by way of stalk cell interneurons in lamina II. Lamina V neurons are predominately wide dynamic-range type. They receive low-threshold input from the large diameter myelinated A beta fibers of mechanoreceptors. Lamina V also receives indirect input from nociceptive afferent fibers (A delta and C fibers).8 Nociceptive terminals appear as free nerve endings in both the skin and viscera. They respond only to strong stimuli, including pricking, excessive stretching, temperature extremes, and extremes of various chemicals such as histamine and bradykinin. By contrast, C fibers can respond to a broad range of painful stimuli, including mechanical, thermal, or metabolic factors. The neurotransmitter that the C fibers release is glutamate as well, along with certain peptides such as substance P. The receptors for the C fiber produced glutamate are not only for AMPA, but also for NMDA. NMDA receptors only open following prolonged depolarization, so continual stimulation of C fibers eventually causes greater excitation in the postsynaptic neurons in the dorsal horn as the NMDA receptors are added to the response. Thus, while C fibers are activated by a wide variety of noxious stimuli as evidenced by their polymodal activation, A delta fibers are primarily associated with mediating thermal responses. Synaptic transmission between nociceptors and dorsal horn neurons is mediated by neurotransmitters released from central sensory nerve endings. A delta fibers are known to release a major excitatory neurotransmitter, which is the amino acid glutamate. Glutamate’s release from sensory terminals induces fast synaptic potentials in dorsal horn neurons chiefly by activating the AMPA-type glutamate receptors.9
[edit] Role in Neuropathic Pain
A delta fibers have a role in neuropathic pain as well. Neuropathic pain deals with deranged function and structure of the peripheral motor, sensory, and autonomic neurons that connect the spinal cord to muscles, skin, and internal organs. Direct injury to nerves in the peripheral or central nervous systems is also known to be associated with neuropathic pain. It is known to affect as much as 3% of the population. Neuropathic pain normally affects the hands and feet, causing weakness, numbness, tingling, and pain. Peripheral neuropathy’s course is variable; slowly progressing, coming and going, or becoming severe and debilitating. Causes are variable as well. Approximately 30% of neuropathies are idiopathic, or of an unknown cause. In another 30% of cases, diabetes is the cause. Other causes include autoimmune disorders, tumors, heredity, nutritional imbalances, infections, or toxins. If diagnosed early, the pain can usually be managed well.6 In an experimental study of diabetic patients, the role of A delta fibers was examined. It seems neuropathy is one of the most common long-term complications of diabetes, affecting up to 50% of patients. The neuropathy is characterized by a progressive loss of both somatic and autonomic nerve fibers. Most attention has been paid to large fiber damage in diabetes. Alterations in thermal and pain sensation have not been studied intensively. One study, however examined the role of A delta fibers. A delta fibers are about one quarter of the size of large A fibers with a much slower conduction velocity (3-15 m/s compared to 30-100 m/s in large A fibers). A delta fibers are known to carry cold perception and play a role in cutaneous nociception as well.10 In this study performed by Quattrini, Jeziorska, and Malik, they discussed the variable methods for assessing neuropathic pain along with both large fiber and small fibers’ role in neuropathy. They found that small nerve fiber damage (A delta fibers) with regeneration has been invoked to produce symptoms of painful diabetic neuropathy. Small fiber neuropathy contributes to sensory loss, which renders the patient susceptible to foot ulceration. Anhydrosis, which is a consequence of small fiber denervation of sweat glands, can facilitate the process of ulceration of the skin through the development of dry fissures.6 There are many techniques for assessing neuropathic pain. Quantitative sensory testing (QST) is one of the older methods, and it is defined as the analysis of perception in response to external stimuli of controlled intensity. Detection and pain thresholds are determined by applying stimuli to the skin in an ascending and descending order of magnitude.7 One of the newer and more common assessment techniques of neuropathic pain involves the selective activation of pain afferents. This method involves radiant-heat pulse stimuli delivered by laser stimulators, which selectively excite the free nerve endings of both A delta and C fibers in the superficial skin layers. Late laser-evoked potentials (LEPs) reflect activity of the A delta fibers, and ultralate LEPs indicate the activity of the unmyelinated C fibers. Late LEPs have been reliable in assessing damage to both the peripheral and central nociceptive system in peripheral neuropathies, neuralgia, and multiple sclerosis. In peripheral and central neuropathic pains, LEPs are more sensitive than any other neurophysiological tests and the finding of a LEP suppression helps to diagnose neuropathic pain. This technique has been preferentially used in the assessment of neuropathic pain in both diabetic patients and patients with Fabry’s disease.7
[edit] A delta Fibers' role in Fabry's Disease
A delta fibers have been known to play a large role in the neuropathic pain seen in Fabry’s disease as well. Fabry’s disease is an X-linked disorder that is caused by an alpha-galctosidase A deficiency with accumulation of ceramide trihexoside in various organs. Many patients with this disease suffer severe episodes of feeling stabbing pain and burning paraesthesias (tickling or itching feeling) in the extremities often triggered by changes in temperature. These findings show that A delta fibers may be involved as patients suffer from pain associated with changes in temperature, which is mediated by A delta fibers.5 Research that followed, showed that in studies of nerve biopsies, there is evidence of a decrease of thin, myelinated A delta fibers as well as unmyelinated C fibers in patients with Fabry’s Disease. In 2004, scientists Massimiliano Valeriani and Paolo Mariotti among others used the laser evoked potential method to assess the function of A delta fibers and C fibers in the neuropathic pain seen in Fabry’s Disease patients. Before the laser evoked potential method became the preferred technique for A delta and C fiber activity, scientists studying Fabry’s Disease used QST, which is considered a psychophysical method to determine functional assessment of nociceptive fibers. These tests showed large intersubject variability, so scientists turned to the CO2 laser evoked potentials for direct assessment of A delta and C fiber systems because they have been demonstrated to stimulate the nociceptive afferents selectively without activating the larger A beta fibers. Seven men with Fabry’s disease were studied, with their diagnosis confirmed by enzymatic analysis on white blood cells and their identified mutation. LEPs were then recorded after stimulation over the dorsum of the right and left hands and the perioral region of the face. The sensory threshold was established as the minimal stimulus energy required to elicit a direct sensation. What the scientists found after applying two different intensities (1.5 and 2.5 times sensory threshold, respectively) was that the Fabry’s Disease patients showed A delta fiber LEP amplitudes after both hand and face stimulation that were significantly lower than in healthy subjects. This reduction in amplitude suggests an A delta fiber impairment in Fabry’s Disesase.5 Although Fabry’s Disease patients showed a reduction in C fibers as well, at least in a late phase of the disease, it can be hypothesized that in Fabry’s Disease patients with severe pain, the loss of A delta fiber inputs exceeded the loss of C fiber inputs, leading to an imbalance between the A delta and C fiber systems. A continuous and exaggerated input on C fibers, which is no longer gated by A delta fibers, caused sensitization of dorsal horn neurons, which in turns increases their excitability to the point that they respond to normal inputs in an extended way. Thus, stimuli that would normally be innocuous, become painful. This study also made note of Garcia-Larrea and colleagues report that neuropathic pain due to lesions of the central nervous system is associated with an amplitude reduction of A delta fiber LEPs with only the occasional recording of C fiber LEPs after painful skin stimulation. These findings have been attributed to an imbalance between reduced A delta fiber inputs and C fiber afferents that remain constant and preserved. This disparity was also seen in the face, where most patients with Fabry’s Disease do not experience neuropathic pain. This result provided evidence of a reduction of A delta fiber inputs in spite of preserved C fiber inputs in a normally nonpainful area.5
[edit] References
"Structural and Functional Specialization of A delta and C Fiber Free Nerve Endings Innervating Rabbit Corneal Epithelium" . Journal of Neuroscience.
"Facilitation of A[delta]-fiber-mediated acute pain by repetitive transcranial magnetic stimulation." . Neurology.
"Free nerve ending terminal morphology is fiber type specific for A delta and C fibers innervating rabbit corneal epithelium" . Journal of Neuroscience.
"Differential presynaptic effects of opioid agonists on Adelta- and C-afferent glutamatergic transmission to the spinal dorsal horn" . Anesthesiology.
"Functional assessment of A and C fibers in patients with Fabry's disease" . Muscle & Nerve.
"Small Fiber Neuropathy in Diabetes: Clinical Consequence and Assessment" . Sage Journals Online.
"Assessment of Neuropathic Pain" . Neurological Sciences.
Kaudel, Schwartz, and Jessell. Principles of Neural Science Fourth Edition, 474.
Squire, Bloom, McConnell, Roberts, Spitzer, Zigmond. Fundamental Neuroscience Second Edition, 674-675.
Ochs. Elements of Neurophysiology, 31-32, 39-40, 43, 347.
"Expression of Vanilloid Receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structure" . Experimental Dermatiology.
Nicholls, Martin, Wallace. From Neuron to Brain Third Edition, 494-495.
[edit] See also
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