Sunday, April 19, 2009
Receptors & Stimuli
An important recent event was the isolation of vanilloid receptor-1 (VR1). Vanillins are a group of compounds, including capsaicin, that cause pain. This necessitated revision of the concept that a single pathway carries pain and only pain to the cerebral cortex. The VR1 receptors respond not only to the pain-causing agents such as capsaicin but also to protons and to potentially harmful temperatures above 43 °C. Another receptor, VRL-1, which responds to temperatures above 50 °C but not to capsaicin, has been isolated from C fibers. There may be many types of receptors on single peripheral C fiber endings, so single fibers can respond to many different noxious stimuli. However, the different properties of the VR1 and the VRL-1 receptors make it likely that there are many different nociceptor C fibers systems as well.
Receptors & Pathways
The sense organs for pain are the naked nerve endings found in almost every tissue of the body. Pain impulses are transmitted to the CNS by two fiber systems. One nociceptor system is made up of small myelinated Aδ fibers 2-5 um in diameter, which conduct at rates of 12-30 m/s. The other consists of unmyelinated C fibers 0.4-1.2 um in diameter. These latter fibers are found in the lateral division of the dorsal roots and are often called dorsal root C fibers. They conduct at the low rate of 0.5-2 m/s. Both fiber groups end in the dorsal horn; Aδ fibers terminate primarily on neurons in laminas I and V, whereas the dorsal root C fibers terminate on neurons in laminas I and II. The synaptic transmitter secreted by primary afferent fibers subserving fast mild pain (see below) is glutamate, and the transmitter subserving slow severe pain is substance P.
The synaptic junctions between the peripheral nociceptor fibers and the dorsal horn cells in the spinal cord are the sites of considerable plasticity. For this reason, the dorsal horn has been called a gate, where pain impulses can be "gated," ie, modified.
Some of the axons of the dorsal horn neurons end in the spinal cord and brain stem. Others enter the anterolateral system, including the lateral spinothalamic tract. A few ascend in the posterolateral portion of the cord. Some of the ascending fibers project to the ventral posterior nuclei, which are the specific sensory relay nuclei of the thalamus, and from there to the cerebral cortex. PET and fMRI studies in normal humans indicate that pain activates cortical areas SI, SII, and the cingulate gyrus on the side opposite the stimulus. In addition, the mediofrontal cortex, the insular cortex, and the cerebellum are activated.
Pain was called by Sherrington "the physical adjunct of an imperative protective reflex." Painful stimuli generally initiate potent withdrawal and avoidance responses. Furthermore, pain is unique among the sensations in that it has a "built-in" unpleasant affect.
The synaptic junctions between the peripheral nociceptor fibers and the dorsal horn cells in the spinal cord are the sites of considerable plasticity. For this reason, the dorsal horn has been called a gate, where pain impulses can be "gated," ie, modified.
Some of the axons of the dorsal horn neurons end in the spinal cord and brain stem. Others enter the anterolateral system, including the lateral spinothalamic tract. A few ascend in the posterolateral portion of the cord. Some of the ascending fibers project to the ventral posterior nuclei, which are the specific sensory relay nuclei of the thalamus, and from there to the cerebral cortex. PET and fMRI studies in normal humans indicate that pain activates cortical areas SI, SII, and the cingulate gyrus on the side opposite the stimulus. In addition, the mediofrontal cortex, the insular cortex, and the cerebellum are activated.
Pain was called by Sherrington "the physical adjunct of an imperative protective reflex." Painful stimuli generally initiate potent withdrawal and avoidance responses. Furthermore, pain is unique among the sensations in that it has a "built-in" unpleasant affect.
TEMPERATURE
Mapping experiments show that there are discrete cold-sensitive and heat-sensitive spots in the skin. There are four to ten times as many cold-sensitive as heat-sensitive spots. Cold receptors respond from 10 °C to 38 °C and heat receptors from 30 °C to over 45 °C. The afferents for cold are Aδ and C fibers, whereas the afferents for heat are C fibers. Temperature has generally been regarded as closely related to touch, but new evidence indicates that in addition to ending in the postcentral gyrus, thermal fibers from the thalamus end in the ipsilateral insular cortex. It has even been suggested that this is the true primary thermal receiving area.
Three receptors involved in temperature perception have been cloned. The receptor for moderate cold is the cold- and menthol-sensitive receptor 1 (CMR 1). Two receptors respond to high, potentially noxious heat: VR1, which also responds to the pain-producing chemical capsaicin and is clearly a nociceptor; and VRL-1, a closely related receptor that does not respond to capsaicin but is probably a nociceptor as well. All three are members of the TRP family of cation channels . The receptor that responds to moderate heat (warmth receptor) could be the ATP P2X receptor because injection of ATP causes a feeling of warmth, and mice in which the P2X receptor gene has been knocked out do not show the activity in the spinal cord normally produced by mild skin warming.
Because the sense organs are located subepithelially, it is the temperature of the subcutaneous tissues that determines the responses. Cool metal objects feel colder than wooden objects of the same temperature because the metal conducts heat away from the skin more rapidly, cooling the subcutaneous tissues to a greater degree.
Three receptors involved in temperature perception have been cloned. The receptor for moderate cold is the cold- and menthol-sensitive receptor 1 (CMR 1). Two receptors respond to high, potentially noxious heat: VR1, which also responds to the pain-producing chemical capsaicin and is clearly a nociceptor; and VRL-1, a closely related receptor that does not respond to capsaicin but is probably a nociceptor as well. All three are members of the TRP family of cation channels . The receptor that responds to moderate heat (warmth receptor) could be the ATP P2X receptor because injection of ATP causes a feeling of warmth, and mice in which the P2X receptor gene has been knocked out do not show the activity in the spinal cord normally produced by mild skin warming.
Because the sense organs are located subepithelially, it is the temperature of the subcutaneous tissues that determines the responses. Cool metal objects feel colder than wooden objects of the same temperature because the metal conducts heat away from the skin more rapidly, cooling the subcutaneous tissues to a greater degree.
PROPRIOCEPTION
roprioceptive information is transmitted up the spinal cord in the dorsal columns. A good deal of the proprioceptive input goes to the cerebellum, but some passes via the medial lemnisci and thalamic radiations to the cortex. Diseases of the dorsal columns produce ataxia because of the interruption of proprioceptive input to the cerebellum.
There is some evidence that proprioceptive information passes to consciousness in the anterolateral columns of the spinal cord. Conscious awareness of the positions of the various parts of the body in space depends in part upon impulses from sense organs in and around the joints. The organs involved are slowly adapting "spray" endings, structures that resemble Golgi tendon organs, and probably pacinian corpuscles in the synovia and ligaments. Impulses from these organs, touch receptors in the skin and other tissues, and muscle spindles are synthesized in the cortex into a conscious picture of the position of the body in space. Microelectrode studies indicate that many of the neurons in the sensory cortex respond to particular movements, not just to touch or static position. In this regard, the sensory cortex is organized like the visual cortex .
There is some evidence that proprioceptive information passes to consciousness in the anterolateral columns of the spinal cord. Conscious awareness of the positions of the various parts of the body in space depends in part upon impulses from sense organs in and around the joints. The organs involved are slowly adapting "spray" endings, structures that resemble Golgi tendon organs, and probably pacinian corpuscles in the synovia and ligaments. Impulses from these organs, touch receptors in the skin and other tissues, and muscle spindles are synthesized in the cortex into a conscious picture of the position of the body in space. Microelectrode studies indicate that many of the neurons in the sensory cortex respond to particular movements, not just to touch or static position. In this regard, the sensory cortex is organized like the visual cortex .
touch
As noted in , pressure is maintained touch. Touch is present in areas that have no visible specialized receptors. However, pacinian corpuscles and possibly other putative receptors may subsume special functions related to touch. Touch receptors are most numerous in the skin of the fingers and lips and relatively scarce in the skin of the trunk. There are many receptors around hair follicles in addition to those in the subcutaneous tissues of hairless areas. When a hair is moved, it acts as a lever with its fulcrum at the edge of the follicle, so that slight movements of the hairs are magnified into relatively potent stimuli to the nerve endings around the follicles. The stiff vibrissae on the snouts of some animals are highly developed examples of hairs that act as levers to magnify tactile stimuli.
The Na+ channel BNC1 is closely associated with touch receptors. This channel is one of the degenerins, so called because when they are hyperexpressed they cause the neurons they are in to degenerate. However, it is not known if BNC1 is part of the receptor complex or the neural fiber at the point of initiation of the spike potential. The receptor may be opened mechanically by pressure on the skin.
The Aβ sensory fibers that transmit impulses from touch receptors to the central nervous system are 5-12 um in diameter and have conduction velocities of 30-70 m/s. Some touch impulses are also conducted via C fibers.
Touch information is transmitted in both the lemniscal and anterolateral pathways, so that only very extensive lesions completely interrupt touch sensation. However, there are differences in the type of touch information transmitted in the two systems. When the dorsal columns are destroyed, vibratory sensation and proprioception are reduced, the touch threshold is elevated, and the number of touch-sensitive areas in the skin is decreased. In addition, localization of touch sensation is impaired. An increase in touch threshold and a decrease in the number of touch spots in the skin are also observed after interrupting the spinothalamic tracts, but the touch deficit is slight and touch localization remains normal. The information carried in the lemniscal system is concerned with the detailed localization, spatial form, and temporal pattern of tactile stimuli. The information carried in the spinothalamic tracts, on the other hand, is concerned with poorly localized, gross tactile sensations.
The Na+ channel BNC1 is closely associated with touch receptors. This channel is one of the degenerins, so called because when they are hyperexpressed they cause the neurons they are in to degenerate. However, it is not known if BNC1 is part of the receptor complex or the neural fiber at the point of initiation of the spike potential. The receptor may be opened mechanically by pressure on the skin.
The Aβ sensory fibers that transmit impulses from touch receptors to the central nervous system are 5-12 um in diameter and have conduction velocities of 30-70 m/s. Some touch impulses are also conducted via C fibers.
Touch information is transmitted in both the lemniscal and anterolateral pathways, so that only very extensive lesions completely interrupt touch sensation. However, there are differences in the type of touch information transmitted in the two systems. When the dorsal columns are destroyed, vibratory sensation and proprioception are reduced, the touch threshold is elevated, and the number of touch-sensitive areas in the skin is decreased. In addition, localization of touch sensation is impaired. An increase in touch threshold and a decrease in the number of touch spots in the skin are also observed after interrupting the spinothalamic tracts, but the touch deficit is slight and touch localization remains normal. The information carried in the lemniscal system is concerned with the detailed localization, spatial form, and temporal pattern of tactile stimuli. The information carried in the spinothalamic tracts, on the other hand, is concerned with poorly localized, gross tactile sensations.
Effects of Cortical Lesions
Ablation of SI in animals causes deficits in position sense and in the ability to discriminate size and shape. Ablation of SII causes deficits in learning based on tactile discrimination. Ablation of SI causes deficits in sensory processing in SII, whereas ablation of SII has no gross effect on processing in SI. Thus, it seems clear that SI and SII process sensory information in series rather than in parallel and that SII is concerned with further elaboration of sensory data. SI also projects to the posterior parietal cortex , and lesions of this association area produce complex abnormalities of spatial orientation on the contralateral side of the body .
It is worth emphasizing that in experimental animals and humans, cortical lesions do not abolish somatic sensation. Proprioception and fine touch are most affected by cortical lesions. Temperature sensibility is less affected, and pain sensibility is only slightly affected. Thus, perception is possible in the absence of the cortex.
It is worth emphasizing that in experimental animals and humans, cortical lesions do not abolish somatic sensation. Proprioception and fine touch are most affected by cortical lesions. Temperature sensibility is less affected, and pain sensibility is only slightly affected. Thus, perception is possible in the absence of the cortex.
Cortical Representation
Mapping of cortical areas involved in sensation has been carried out in experimental animals and during neurosurgical procedures in humans, but it has also been carried out more recently in intact humans by techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). These techniques, which are described in and referenced in the , have led to major advances not only in sensory physiology but also in all aspects of cortical function in normal humans.
From the specific sensory nuclei of the thalamus, neurons carrying sensory information project in a highly specific way to the two somatic sensory areas of the cortex: somatic sensory area I (SI) in the postcentral gyrus and somatic sensory area II (SII) in the wall of the sylvian fissure. In addition, SI projects to SII. SI corresponds to Brodmann's areas 1, 2, and 3. Brodmann was a histologist who painstakingly divided the cerebral cortex into numbered areas based on their histologic characteristics.
The arrangement of the thalamic fibers in SI is such that the parts of the body are represented in order along the postcentral gyrus, with the legs on top and the head at the foot of the gyrus (. Not only is there detailed localization of the fibers from the various parts of the body in the postcentral gyrus, but also the size of the cortical receiving area for impulses from a particular part of the body is proportionate to the number of receptors in the part. The relative sizes of the cortical receiving areas are shown dramatically in , in which the proportions of the homunculus have been distorted to correspond to the size of the cortical receiving areas for each. Note that the cortical areas for sensation from the trunk and back are small, whereas very large areas are concerned with impulses from the hand and the parts of the mouth concerned with speech.
Studies of the sensory receiving area emphasize the very discrete nature of the point-for-point localization of peripheral areas in the cortex and provide further evidence for the general validity of the doctrine of specific nerve energies . Stimulation of the various parts of the postcentral gyrus gives rise to sensations projected to appropriate parts of the body. The sensations produced are usually numbness, tingling, or a sense of movement, but with fine enough electrodes it has been possible to produce relatively pure sensations of touch, warmth, and cold. The cells in the postcentral gyrus are organized in vertical columns, like cells in the visual cortex . The cells in a given column are all activated by afferents from a given part of the body, and all respond to the same sensory modality.
SII is located in the superior wall of the sylvian fissure, the fissure that separates the temporal from the frontal and parietal lobes. The head is represented at the inferior end of the postcentral gyrus, and the feet at the bottom of the sylvian fissure. The representation of the body parts is not as complete or detailed as it is in the postcentral gyrus.
From the specific sensory nuclei of the thalamus, neurons carrying sensory information project in a highly specific way to the two somatic sensory areas of the cortex: somatic sensory area I (SI) in the postcentral gyrus and somatic sensory area II (SII) in the wall of the sylvian fissure. In addition, SI projects to SII. SI corresponds to Brodmann's areas 1, 2, and 3. Brodmann was a histologist who painstakingly divided the cerebral cortex into numbered areas based on their histologic characteristics.
The arrangement of the thalamic fibers in SI is such that the parts of the body are represented in order along the postcentral gyrus, with the legs on top and the head at the foot of the gyrus (. Not only is there detailed localization of the fibers from the various parts of the body in the postcentral gyrus, but also the size of the cortical receiving area for impulses from a particular part of the body is proportionate to the number of receptors in the part. The relative sizes of the cortical receiving areas are shown dramatically in , in which the proportions of the homunculus have been distorted to correspond to the size of the cortical receiving areas for each. Note that the cortical areas for sensation from the trunk and back are small, whereas very large areas are concerned with impulses from the hand and the parts of the mouth concerned with speech.
Studies of the sensory receiving area emphasize the very discrete nature of the point-for-point localization of peripheral areas in the cortex and provide further evidence for the general validity of the doctrine of specific nerve energies . Stimulation of the various parts of the postcentral gyrus gives rise to sensations projected to appropriate parts of the body. The sensations produced are usually numbness, tingling, or a sense of movement, but with fine enough electrodes it has been possible to produce relatively pure sensations of touch, warmth, and cold. The cells in the postcentral gyrus are organized in vertical columns, like cells in the visual cortex . The cells in a given column are all activated by afferents from a given part of the body, and all respond to the same sensory modality.
SII is located in the superior wall of the sylvian fissure, the fissure that separates the temporal from the frontal and parietal lobes. The head is represented at the inferior end of the postcentral gyrus, and the feet at the bottom of the sylvian fissure. The representation of the body parts is not as complete or detailed as it is in the postcentral gyrus.
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