Most of the sensory and somatosensory modalities are primarily informative, whereas pain is a protective modality. Pain differs from the classical senses (hearing, smell, taste, touch, and vision) because it is both a discriminative sensation and a graded emotional experience associated with actual or potential tissue damage. Pain is a submodality of somatic sensation. The word "pain" is used to describe a wide range of unpleasant sensory and emotional experiences associated with actual or potential tissue damage. Nature has made sure that pain is a signal we cannot ignore. Pain information is transmitted to the CNS via three major pathways (Figure 6.1). Most ailments of the body cause pain. The ability to diagnose different diseases depends to a great extent on the knowledge of the different qualities and causes of pain. Sensitivity and reactivity to noxious stimuli are essential to the well-being and survival of an organism. Pain travels through redundant pathways, ensuring to inform the subject: “Get out of this situation immediately.” Without these attributes, the organism has no means to prevent or minimize tissue injury. Individuals congenitally insensitive to pain are easily injured and most of them die at an early age. For thousands of years, physicians have tried to treat pain without knowing the details of the ways in which pain is signaled from the injured part of the body to the brain, or the ways in which any of their remedies worked. Recent discoveries about how the body detects, transmits and reacts to painful stimuli, have allowed physicians to relieve both acute and chronic pain. 6.1 Pain Receptors Pain is termed nociceptive (nocer – to injure or to hurt in Latin), and nociceptive means sensitive to noxious stimuli. Noxious stimuli are stimuli that elicit tissue damage and activate nociceptors. Nociceptors
are sensory receptors that detect signals from damaged tissue or the threat of damage and indirectly also respond to chemicals released from the damaged tissue. Nociceptors are free (bare) nerve endings found in the skin (Figure 6.2), muscle, joints, bone and viscera. Recently, it was found that nerve endings contain transient receptor potential (TRP) channels that sense and detect damage. The TRP channels are similar to voltage-gated potassium channels or nucleotide-gated channels, having 6
transmembrane domains with a pore between domains 5 and 6. They transduce a variety of noxious stimuli into receptor potentials, which in turn initiate action potential in the pain nerve fibers. This action potential is transmitted to the spinal cord and makes a synaptic connection in lamina I and/or II. The cell bodies of nociceptors are mainly in the dorsal root and trigeminal ganglia. No nociceptors are found inside the CNS.
Nociceptors are not uniformly sensitive. They fall into several categories, depending on their responses to mechanical, thermal, and/or chemical stimulation liberated by the damage, tumor, and/or inflammation. Skin Nociceptors. Skin nociceptors may be divided into four categories based on function. The first type is termed high threshold mechanonociceptors or specific nociceptors. These nociceptors respond only to intense mechanical stimulation such as pinching, cutting or stretching. The second type is the thermal nociceptors, which respond to the above stimuli as well as to thermal stimuli. The third type is chemical nociceptors, which respond only to chemical substances (Figure 6.2). A fourth type is known as polymodal nociceptors, which respond to high intensity stimuli such as mechanical, thermal and to chemical substances like the previous three types. A characteristic feature of nociceptors is their tendency to be sensitized by prolonged stimulation, making them respond to other sensations as well. Joint Nociceptors. The joint capsules and ligaments contain high-threshold mechanoreceptors, polymodal nociceptors, and "silent" nociceptors. Many of the fibers innervating these endings in the joint capsule contain neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP). Liberation of such peptides is believed to play a role in the development of inflammatory arthritis. Visceral Nociceptors. Visceral organs contain mechanical pressure, temperature, chemical and silent nociceptors. The visceral nociceptors are scattered, with several millimeters between them, and in some organs, there are several centimeters between each nociceptor (Figure 6.3). Many of the visceral nociceptors are silent. The noxious information from visceral organs and skin are carried to the CNS in different pathways (Figures 6.3 and 6.4).
Silent Nociceptors. In the skin and deep tissues there are additional nociceptors called "silent" or "sleep" nociceptors. These receptors are normally unresponsive to noxious mechanical stimulation, but become “awakened” (responsive) to mechanical stimulation during inflammation and after tissue injury. One possible explanation of the "awakening" phenomenon is that continuous stimulation from the damaged tissue reduces the threshold of these nociceptors and causes them to begin to respond. This activation of silent nociceptors may contribute to the induction of hyperalgesia, central sensitization, and allodynia (see below). Many visceral nociceptors are silent nociceptors. Activation of the nociceptor initiates the process by which pain is experienced, (e.g., we touch a hot stove or sustain a cut). These receptors relay information to the CNS about the intensity and location of the painful stimulus. 6.2 Factors that Activate Nociceptors Nociceptors respond when a stimulus causes tissue damage, such as that resulting from cut strong mechanical pressure, extreme heat, etc. The damage of tissue results in a release of a variety of substances from lysed cells as well as from new substances synthesized at the site of the injury (Figure 6.5). Some of these substances activate the TRP channels which in turn initiate action potentials. These substances include:
The release of these substances sensitizes the nociceptors (C fibers) and reduces their threshold. This effect is referred to as peripheral sensitization (in contrast to central sensitization that occurs in the dorsal horn).
Within 15-30 seconds after injury, an area of several cm around the injured site shows reddening (caused by vasodilation) called a flare. This response (inflammation) becomes maximal after 5-10 minutes (Figure 6.6), and this region shows a lowered pain threshold (i.e., hyperalgesia). Hyperalgesia. Hyperalgesia is an increased painful sensation in response to additional noxious stimuli. One explanation for hyperalgesia is that the threshold for pain in the area surrounding an inflamed or injured site is lowered. An additional explanation is that the inflammation activates silent nociceptors and/or the damage elicits ongoing nerve signals (prolong stimulation), which led to long-term changes and sensitized nociceptors. These changes contribute to an amplification of pain or hyperalgesia, as well as an increased persistence of the pain. If one pricks normal skin with a sharp probe, it will elicit sharp pain followed by reddened skin. The reddened skin is an area of hyperalgesia. Allodynia. Allodynia is pain resulting from a stimulus that does not normally produce pain. For example, light touch to sunburned skin produces pain because nociceptors in the skin have been sensitized as a result of reducing the threshold of the silent nociceptors. Another explanation of allodynia is that when peripheral neurons are damaged, structural changes occur and the damaged neurons reroute and make connection also to sensory receptors (i.e., touch-sensitive fibers reroute and make synaptic connection into areas of the spinal cord that receive input from nociceptors). In conclusion, the several kinds of endogenous chemicals are produced with tissue damage and inflammation. These products have excitatory effects on nociceptors. However, it is not known whether nociceptors respond directly to the noxious stimulus or indirectly by means of one or more chemical intermediaries released from the traumatized tissue. 6.3 Pain Thresholds and Just Noticeable Differences Exposing the skin to controlled heat (produced by heating element or laser) makes it possible to measure the threshold for pain. When the temperature of the skin reaches 45 ± 1°C, subjects report pain. Non-noxious thermal (< 45°C) receptors are innervated by different types of nerve fibers than those responding to the pain. A temperature of approximately 45ºC denatures tissue protein and elicits damage in all subjects (Figure 6.7). That is, the pain threshold in all subjects is about the same. However, the response to pain is different among people.
Pain is measured by the degree of pain intensity. Different degrees of pain intensity are defined as Just Noticeable Differences (JND). There are 22 JND for pain elicited by heat to the skin (Figure 6.8A). This discrimination is possible because the discharge frequency of the nociceptors increases with increasing skin temperature (Figure 6.8B). Thus, nociceptors also supply information on the stimulus intensity (intensity coding) in addition to the injury location.
6.4 Pain Fibers The cell bodies of the primary afferent pain neurons from the body, face, and head are located in the dorsal root ganglia (DRG) and in the trigeminal ganglia respectively. Some of these cell bodies give rise to myelinated axons (A delta fibers), and others give rise to unmyelinated axons (C fibers). The free nerve endings arise from both A delta fibers and the unmyelinated C fibers, which are scattered together (Figure 6.9).
A delta fibers (group III fibers) are 2-5 mm in diameter, myelinated, have a fast conduction velocity (5-40 meters/sec), and carry information mainly from the nociceptive-mechanical or mechanothermal-specific nociceptors. Their receptive fields are small. Therefore, they provide precise localization of pain. 6.5 Double Pain Sensations Two sequential pain sensations in short time intervals is the result of sudden painful stimulation. The first one is immediately after the damage. It is followed several seconds later with additional pain sensation. These two separate sensations are several seconds apart because a fast transmitting information sensation is carried via A delta fibers and is followed several seconds later with slow transmitting pain information carried via C fibers. This phenomenon is known as “double pain sensation” (Figure 6.9). Two experimental procedures were used to verify which information is carried by which fibers.
6.6 Nociceptive Neurons in the Spinal Cord (Nocineurons) The synaptic terminals of the axons of the dorsal root ganglion, which carry noxious information arriving to Rexed layers I and II (Figure 6.10), release neurochemical agents such as substance P (SP), glutamate, aspartate, vasoactive intestinal peptide (VIP), cholecystokinin (CCK), somatostatin, calcitonin gene-related peptide (CGRP), galanin, and other agents. These agents activate the nocineurons. It was shown that when SP and CGRP are applied locally within the spinal cord dorsal horn, glutamate is released. The release of glutamate excites the nocineurons. Furthermore, SP receptors (neurokinin receptors) and NMDA receptors (glutamate) interact which result that the NMDA receptors will become more sensitive to glutamate, which results in central sensitization. The functions of these peptides are largely unknown but they presumably mediate slow, modulatory synaptic actions in the dorsal horn neurons. The neuropeptides are always co-localized with other "classical" neurotransmitters. There are four general types of nocineurons in the spinal cord (Figure 6.10):
Rexed lamina I contains a higher proportion of nociceptive specific neurons, whereas Rexed lamina II contains predominantly multi-receptive wide dynamic range neurons. The nociceptive-specific neurons alert the subject when a stimulus is noxious, and the multi-receptive neurons provide the subject with information about the parameters of the noxious stimulus. In general, C fibers release neuropeptides such as substance P whereas the A delta fibers release glutamate. 6.7 Classification of Pain Pain has been classified into three major types:
Test Your Knowledge
All of the following are released in response to noxious stimulation at the damaged site(s) EXCEPT:
All of the following are released in response to noxious stimulation at the damaged site(s) EXCEPT:
All of the following are released in response to noxious stimulation at the damaged site(s) EXCEPT:
All of the following are released in response to noxious stimulation at the damaged site(s) EXCEPT:
All of the following are released in response to noxious stimulation at the damaged site(s) EXCEPT:
All of the following are released in response to noxious stimulation at the damaged site(s) EXCEPT:
C fibers transmit which type of pain?
C fibers transmit which type of pain?
C fibers transmit which type of pain?
C fibers transmit which type of pain?
C fibers transmit which type of pain?
C fibers transmit which type of pain?
C fibers are
C fibers are
C fibers are
C fibers are
C fibers are
C fibers are
Aspirin acts to block the formation of
Aspirin acts to block the formation of
Aspirin acts to block the formation of
Aspirin acts to block the formation of
Aspirin acts to block the formation of
Aspirin acts to block the formation of
A delta fibers transmit primarily
A delta fibers transmit primarily
A delta fibers transmit primarily
A delta fibers transmit primarily
A delta fibers transmit primarily
A delta fibers transmit primarily
Pain receptors/nociceptors are
Pain receptors/nociceptors are
Pain receptors/nociceptors are
Pain receptors/nociceptors are
Pain receptors/nociceptors are
Pain receptors/nociceptors are
Double pain sensation results from
Double pain sensation results from
Double pain sensation results from
Double pain sensation results from
Double pain sensation results from
Double pain sensation results from
A delta fibers transmit which type of pain to VPL?
A delta fibers transmit which type of pain to VPL?
A delta fibers transmit which type of pain to VPL?
A delta fibers transmit which type of pain to VPL?
A delta fibers transmit which type of pain to VPL?
A delta fibers transmit which type of pain to VPL?
Sharp pain, induced by a skin cut for example, is classified by
Sharp pain, induced by a skin cut for example, is classified by
Sharp pain, induced by a skin cut for example, is classified by
Sharp pain, induced by a skin cut for example, is classified by
Sharp pain, induced by a skin cut for example, is classified by
Sharp pain, induced by a skin cut for example, is classified by
What receptors are always active?Type I receptors are typically located in the superficial layers of the joint capsule. Physiologically, type I receptors are low-threshold, slowly adapting mechanoreceptors. A portion of the type I receptors is always active in every joint position (Wyke, 1972).
What receptors respond to stimuli in body?Interoceptors or visceroceptors respond to stimuli arising within the body such as chemical stimuli, deep pressure, and many others. Proprioceptors respond to muscle or tendon stretch and help the body monitor body position (body sense).
Which type of sensory receptor detects pressure changes in an organ quizlet?When blood pressure increases, what type of sensory receptor detects this? *Interoceptors receive stimuli from inside the body. Baroreceptors respond to changes in pressure.
What type of receptor cell is involved in the sensation of sound and balance?Pressure, vibration, muscle stretch, and the movement of hair by an external stimulus, are all sensed by mechanoreceptors. Hearing and balance are also sensed by mechanoreceptors.
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