CUTANEOUS, DEEP, & VISCERAL SENSATION INTRODUCTION The sense organs primary afferent neurons have their cell

l bodies in the dorsal root ganglia or equivalent ganglia in cranial nerves. They enter the spinal cord or brain stem and make polysynaptic reflex connections to motor neurons at many levels as well as connections that relay impulses to the cerebral cortex. The particular form of energy to which a receptor is most sensitive is called its adequate stimulus. Sensory cortex-The primary sensory cortex consists of regions that receive projections from thalamic relay nuclei. (Note that olfactory stimuli have no thalamic relay stations.) PATHWAYS Introduction The dorsal horns are divided on the basis of histological characteristics into LAMINAS I-VI, with I being the most superficial and VI the deepest. Lamina II and part of lamina III make up the substantia gelatinosa, a lightly stained area near the top of each dorsal horn. There are three types of primary afferent fibers that mediate cutaneous sensation: 1) Large myelinated A fibers that transmit impulses generated by mechanical stimuli; {I,II,III & IV} 2) Small myelinated Afibers, some of which transmit impulses from cold receptors and nociceptors that mediate fast pain and some of which transmit impulses from mechanoreceptors; {III & IV} 3) Small unmyelinated C fibers that are concerned primarily with pain and temperature. {I & II} Fibers mediating fine touch and proprioception ascend in the dorsal columns to the medulla, where they synapse in the gracile and cuneate nuclei. The second-order neurons from the gracile and cuneate nuclei cross the midline and ascend in the medial lemniscus to end in the ventral posterior nucleus and related specific sensory relay nuclei of the thalamus. This ascending system is frequently called the dorsal column or lemniscal system. Other touch fibers, along with those mediating temperature and pain, synapse on neurons in the dorsal horn. The axons from these neurons cross the midline and ascend in the anterolateral quadrant of the spinal cord, where they form the anterolateral system of ascending fibers. In general, touch is associated with the ventral spinothalamic tract whereas pain and temperature are associated with the lateral spinothalamic tract, but there is no rigid localization of function.

Collaterals from the fibers that enter the dorsal columns pass to the dorsal horn. These collaterals may modify the input into other cutaneous sensory systems, including the pain system. The dorsal horn represents a "gate" in which impulses in the sensory nerve fibers are translated into impulses in ascending tracts Pain and temperature impulses are relayed via the spinal nucleus of the trigeminal nerve, and touch and proprioception mostly via the main sensory and mesencephalic nuclei of this nerve. The posterior column pathway carries sensations of highly localized ("fine") touch, pressure, vibration, and proprioception (position sense). The spinal tracts involved are the left and right fasciculus gracilis (gracilis, delicate) and the left and right fasciculus cuneatus (cuneus, wedgeshaped). On each side of the posterior median sulcus, the fasciculus gracilis is medial to the fasciculus cuneatus.

CORTICAL REPRESENTATION 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: I. Somatic sensory area I (SI) in the postcentral gyrus and II. 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. 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 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 validity of the doctrine of specific nerve energies 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. Cortical Plasticity It is now clear that the extensive neuronal connections described in the previous paragraph are not innate and immutable but, at least in sensory areas,

can be changed relatively rapidly by experience to reflect the use of the represented area. The explanation of these shifts appears to be that cortical connections of sensory units to the cortex have extensive convergence and divergence, with connections that can become weak with disuse and strong with use. 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. 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. Principles of Sensory Physiology o Each sense organ is specialized to convert one particular form of energy into action potentials in the sensory nerves. o Each modality has a discrete pathway to the brain, and the sensation perceived as well as the part of the body to which it is localized is determined by the particular part of the brain activated. o Differences in intensity of a given sensation are signaled in two ways: a. By changes in the frequency of action potentials in the sensory nerves, and b. By changes in the number of receptors activated. o Another principle that applies to cutaneous sensation is that of punctate representation. If the skin is carefully mapped, millimeter by millimeter, with a fine hair, a sensation of touch is evoked from spots overlying touch receptors. None is evoked from the intervening areas. o Similarly, pain and temperature sensations are produced by stimulation of the skin only over the spots where the sense organs for these modalities are located. TOUCH Touch is present in areas that have no specialized receptors. However, in areas where they exist, Meissner corpuscles and pacinian corpuscles are rapidly adapting touch receptors, and Merkel disks and Ruffini endings are slowly adapting touch receptors. 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. The A 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. PROPRIOCEPTION Proprioceptive 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. 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. TEMPERATURE There are discrete cold-sensitive and warmth-sensitive spots in the skin. There are four to ten times as many cold spots as warm. The temperature sense organs are naked nerve endings that respond to absolute temperature, not the temperature gradient across the skin.

 Cold receptors respond from 10 to 38 C and warm receptors from 30 to 45 C. The afferents for cold are A and C fibers, whereas the afferents for warmth are C fibers. These afferents relay information to the postcentral gyrus via the lateral spinothalamic tract and the thalamic radiation. Because the sense organs are located subepithelially, it is the temperature of the subcutaneous tissues that determines the responses. Below a skin temperature of 20 C and above 40 C, there is no adaptation, but between 20 and 40 C there is adaptation, so that the sensation produced by a temperature change gradually fades to one of thermal neutrality. Above 45 C, tissue damage begins to occur, and the sensation becomes one of pain. Capsaicin receptors may mediate warmth responses in the 43-50 C range. PAIN 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. a) One nociceptor system is made up of small myelinated A fibers 25 um in diameter, which conduct at rates of 12-30 m/s. b) 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; A fibers terminate primarily on neurons in laminas I and V, whereas the dorsal root C fibers terminate on neurons in laminas I and II. There is evidence that the synaptic transmitter secreted by primary afferent fibers subserving fast mild pain is glutamate and that 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. The dorsal horn has been called a gate, where pain impulses can be "gated," i.e., modified. For example, stimulation of large-diameter afferent fibers from an area from which pain is being initiated reduces the pain. 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. Fast & Slow Pain

 A painful stimulus causes a "bright," sharp, localized sensation followed by a dull, intense, diffuse, and unpleasant feeling. These two sensations are variously called fast and slow pain or first and second pain. The farther from the brain the stimulus is applied, the greater the temporal separation of the two components. This and other evidence make it clear that fast pain is due to activity in the A pain fibers whereas slow pain is due to activity in the C pain fibers. Adequate Stimulus Pain receptors respond to warmth, electrical, mechanical, and, especially, chemical energy. It has been suggested that pain is chemically mediated and that stimuli which provoke it have in common the ability to liberate a chemical agent that stimulates the nerve endings. The chemical agent might be ATP. ATP opens ligand-gated channels on sensory neurons via P2X receptors A capsaicin receptor that is a nonselective ion channel permits flow of Na and Ca into nociceptive neurons when activated, producing depolarization. This receptor, which is also called a vanilloid receptor because of the structural similarity of capsaicin and vanilla, is also activated by warmth and may be the warmth receptor. In addition, it is activated by protons.

Subcortical Perception & Affect There is considerable evidence that sensory stimuli are perceived in the absence of the cerebral cortex, and this is especially true of pain. The cortical receiving areas are apparently concerned with the discriminative, exact, and meaningful interpretation of pain and some of its emotional components, but perception alone does not require the cortex. Postinjury & Neuropathic Pain Characteristically, stimuli in the injured area that would normally cause only minor pain produce an exaggerated response (hyperalgesia), and normally innocuous stimuli such as touch cause pain (allodynia). If the nerves to the area are damaged, the pain may persist and become excruciating even after the injury heals (neuropathic pain). In postinjury and neuropathic pain, there is increased sensitivity of peripheral pain receptors as a consequence of local release of sensitizing substances. There is also increased transmission at the synaptic junctions between the first and second order neurons in the dorsal horn. A variety of different mechanisms may play a role in this increase. One is increased activity of presynaptic NMDA {N-methyl d-aspartate} receptors on primary afferent endings, with increased release of substance P.

 Another is a gene switch in which a subpopulation of A fibers from mechanoreceptors start to produce substance P Deep Pain The main difference between superficial and deep sensibility is the different nature of the pain evoked by noxious stimuli. Unlike superficial pain, deep pain is poorly localized, nauseating, and frequently associated with sweating and changes in blood pressure. Pain can be elicited experimentally from the periosteum and ligaments by injecting hypertonic saline into them. The pain produced in this fashion initiates reflex contraction of nearby skeletal muscles. This reflex contraction is similar to the muscle spasm associated with injuries to bones, tendons, and joints. The steadily contracting muscles become ischemic, and ischemia stimulates the pain receptors in the muscles. The pain in turn initiates more spasm, setting up a vicious circle. Muscle Pain If a muscle contracts rhythmically in the presence of an adequate blood supply, pain does not usually result. However, if the blood supply to a muscle is occluded, contraction soon causes pain. The pain persists after the contraction until blood flow is reestablished. These observations are difficult to interpret except in terms of the release during contraction of a chemical agent (Lewis's "P factor") that causes pain when its local concentration is high enough. When the blood supply is restored, the material is washed out or metabolized. The identity of the P factor is not settled, but it could be K+ Visceral Pain Pain from visceral structures is poorly localized, unpleasant, and associated with nausea and autonomic symptoms. It often radiates or is referred to other areas. There are no proprioceptors in the viscera, and few temperature and touch sense organs. Pain receptors are present, although they are more sparsely distributed than in somatic structures. Afferent fibers from visceral structures reach the CNS via sympathetic and parasympathetic pathways. Their cell bodies are located in the dorsal roots and the homologous cranial nerve ganglia. Specifically, there are visceral afferents in the facial, glossopharyngeal, and vagus nerves; in the thoracic and upper lumbar dorsal roots; and in the sacral roots; there may also be visceral afferent fibers from the eye in the trigeminal nerve.

 In the CNS, visceral sensation travels along the same pathways as somatic sensation in the spinothalamic tracts and thalamic radiations, and the cortical receiving areas for visceral sensation are intermixed with the somatic receiving areas. Stimulation of Pain Fibers Because there are relatively few pain receptors in the viscera, visceral pain is poorly localized. The receptors in the walls of the hollow viscera are especially sensitive to distention of these organs. Visceral pain is particularly unpleasant not only because of the affective component it has in common with all pain but also because so many visceral afferents excited by the same process that causes the pain have reflex connections that initiate nausea, vomiting, and other autonomic effects. Muscle Spasm & Rigidity Visceral pain, like deep somatic pain, initiates reflex contraction of nearby skeletal muscle. This reflex spasm is usually in the abdominal wall and makes the abdominal wall rigid. The spasm protects the underlying inflamed structures from inadvertent trauma. Indeed, this reflex spasm is sometimes called "guarding." The classic signs of inflammation in an abdominal viscus are pain, tenderness, autonomic changes such as hypotension and sweating, and spasm of the abdominal wall. The tenderness is due to the heightened sensitivity of the pain receptors in the viscus, the autonomic changes due to activation of visceral reflexes, and the spasm due to reflex contraction of skeletal muscle in the abdominal wall. Referred Pain Irritation of a viscus frequently produces pain which is felt not in the viscus but in some somatic structure that may be a considerable distance away. Deep somatic pain may also be referred, but superficial pain is not. When visceral pain is both local and referred, it sometimes seems to spread (radiate) from the local to the distant site. Dermatomal Rule When pain is referred, it is usually to a structure that developed from the same embryonic segment or dermatome as the structure in which the pain originates. This principle is called the dermatomal rule. Role of Experience

Experience also plays an important role in referred pain. Although pain originating in an inflamed abdominal viscus is usually referred to the midline, in patients who have had previous abdominal surgery the pain of abdominal disease is frequently referred to their surgical scars. Pain originating in the maxillary sinus is usually referred to nearby teeth, but in patients with a history of traumatic dental work such pain is regularly referred to the previously traumatized teeth. This is true even when the teeth are a considerable distance away from the sinus.

Role of Convergence There is presumably a considerable degree of convergence of peripheral sensory fibers on the spinothalamic neurons. One theory of the mechanism underlying referred pain is based on this premise. It holds that somatic and visceral afferents converge on the same spinothalamic neurons. Since somatic pain is much more common than visceral pain, the brain has "learned" that activity arriving in a given pathway is caused by a pain stimulus in a particular somatic area. When the same pathway is stimulated by activity in visceral afferents, the signal reaching the brain is no different and the pain is projected to the somatic area. Facilitation Effects Facilitation could also play a role in the origin of referred pain. Collateral connections from visceral afferents to dorsal horn neurons receiving pain impulses from somatic structures could provide a pathway by which increased activity in the visceral afferents could produce EPSPs and thus increase the excitability of the neurons from somatic structures. Minor activity in somatic afferents could then cause continuous pain. Both convergence and facilitation play a role in the pathogenesis of referred pain. Central Inhibition & Counterirritants It is well known that soldiers wounded in the heat of battle may feel no pain until the battle is over (stress analgesia). Many people have learned from practical experience that touching or shaking an injured area decreases the pain of the injury. Stimulation with an electric vibrator at the site of pain also gives some relief. These and other observations make it clear that pain transmission and perception are subject to inhibition as well as facilitation in the CNS.

 Inhibition in central sensory pathways may explain the efficacy of counterirritants. Stimulation of the skin over an area of visceral inflammation produces some relief of the pain due to the visceral disease. Action of Morphine & Enkephalins Morphine relieves pain. It is particularly effective when given intrathecally. There are at least three nonmutually exclusive sites at which opioids could act to produce analgesia: i. Peripherally, at the site of an injury; ii. In the dorsal horn "gate," where nociceptive fibers synapse on dorsal root ganglion cells; iii. At more rostral sites in the brain stem. Opioid receptors are produced in dorsal root ganglion cells and migrate both peripherally and centrally along their nerve fibers. Injections of morphine into the periaqueductal gray of the midbrain relieve pain by activating descending pathways that produce inhibition of primary afferent transmission in the dorsal horn. Placebos appear to be capable of producing the release of endogenous opioids, and this helps to relieve pain. Their effects are inhibited in part by morphine antagonists such as naloxone. Acupuncture at a location distant from the site of a pain also acts by releasing endorphins. Acupuncture at the site of the pain appears to act primarily in the same way as touching or shaking Acetylcholine Epibatidine, a cholinergic agonist first isolated from the skin of a frog, is a potent nonopioid analgesic agent nicotinic cholinergic mechanism is involved in the regulation of pain

Cannabinoids The cannabinoids anandamide and PEA are produced endogenously and bind to CB1 and CB2 receptors, respectively. Anandamide has now been shown to have definite analgesic effects, and there are amandamide-containing neurons in the periaqueductal gray and other areas concerned with pain. When PEA is administered, it acts peripherally to augment the analgesic effects of anadamide. Nociceptin Upon intracerebral injection in experimental animals, it causes hyperalgesia rather than analgesia. The nociceptin precursor protein also contains nocistatin, a polypeptide that antagonizes the effects of nociceptin. It is unclear how the

polypeptides interact, but it seems likely that they play a role in pain transmission. OTHER SENSATIONS Itch & Tickle Relatively mild stimulation, especially if produced by something that moves across the skin, produces itch and tickle. They are in regions where there are many naked endings of unmyelinated fibers. Scratching relieves itching because it activates large, fast-conducting afferents that gate transmission in the dorsal horn in a manner analogous to the inhibition of pain by stimulation of similar afferents Itching occurs only in the skin, eyes, and certain mucous membranes and not in deep tissues or viscera. Furthermore, low-frequency stimulation of pain fibers produces pain, not itch, and high-frequency stimulation of itch spots on the skin may merely increase the intensity of the itching without producing pain. These observations indicate that the C fiber system responsible for itching is not the same as that responsible for pain. It is interesting that a tickling sensation is usually regarded as pleasurable, whereas itching is annoying and pain is unpleasant. There is some itching when plasma concentrations of bile salts are elevated. Histamine produces intense itching, and injuries cause its liberation in the skin. The kinins cause severe itching. "Synthetic Senses The cutaneous senses for which separate receptors exist are touch, warmth, cold, pain, and possibly itching. Combinations of these sensations, patterns of stimulation, and, in some cases, cortical components are synthesized into the sensations of vibratory sensation, two-point discrimination, and stereognosis. Vibratory Sensibility When a vibrating tuning fork is applied to the skin, a buzzing or thrill is felt. The receptors involved are the receptors for touch, especially pacinian corpuscles, but a time factor is also necessary. A pattern of rhythmic pressure stimuli is interpreted as vibration. The impulses responsible for the vibrating sensation are carried in the dorsal columns. Two-Point Discrimination The minimal distance by which two touch stimuli must be separated to be perceived as separate is called the two-point threshold. It depends upon touch plus the cortical component of identifying one or two stimuli. Its magnitude varies from place to place on the body and is smallest where the touch receptors are

most abundant. The magnitude of the two-point threshold is approximately the diameter of the area of skin supplied by a single sensory unit.

Stereognosis The ability to identify objects by handling them without looking at them is called stereognosis. This ability obviously depends upon relatively intact touch and pressure sensation and is compromised when the dorsal columns are damaged. It also has a large cortical component; impaired stereognosis is an early sign of damage to the cerebral cortex and sometimes occurs in the absence of any detectable defect in touch and pressure sensation when there is a lesion in the parietal lobe posterior to the postcentral gyrus.