[Clinical Skills] Elevated Body Temperature

April 3, 2016 Clinical Skills, Practice No comments , , , , , , , , ,

Regulation of Body Temperature

Internal body temperature is tightly regulated to maintain vital organ function, particularly the brain. Temperature deviation of more than 4 C above or below normal can produce life-threatening cellular dysfunction. Internal temperature is regulated be the hypothalamus, which maintains a temperature set point. The autonomic nervous system maintains body temperature by regulating blood flow, conducting heat from the internal organs to the skin, and innervating sweat glands. Increasing flow and dilating cutaneous capillaries radiate heat away by conductive loss whereas sweat increases evaporative heat loss. Behavioral adaptations are also important; in hot conditions, people become less active and seek shade or a cooler environment. Decreased body temperature is countered by shivering (increasing heat generation in muscles) and by behavioral adaptations such as putting on clothes and seeking warmer environs. Deviations of body temperature indicate changes in the set point, increased heat production, decreased heat dissipation, failure of regulatory system, or any combination of these.

  • Hypothalamus
  • ANS (blood flow [from internal to superficial; skin blood flow], sweat glands, and shivering)
  • Behavioral adaptations

Normal Body Temperature

Internal body temperature is maintained within a narrow range, +- 6 C, in each individual. However, the population range of this set point varies from 36.0 C to 37.5 C making it impossible to know an individual's normal temperature without an established baseline. Without a baseline it is reasonable to regard an oral temperature above 37.5 C and a rectal temperature over 38.0 C as fever. The minimum normal temperature is more difficult to define; the oral temperature often dips to 35.0 C during sleep.

Diurnal variation of body temperature. Daytime workers, who sleep at night, register their minimum temperature at 3 to 4 AM, whence it rises slowly to a maximum between 8 and 10 PM. This pattern is reversed in night-shift workers. The transition from one pattern to the other requires several days.

Simultaneous temperatures in various regions. Heat is produced by the chemical reactions of cellular metabolism, so a temperature gradient extends from a maximum in the liver to a minimum on the skin surface. Customarily, the body temperature is measured in the rectum, the mouth, the ear, the axilla, or the groin. Among these sites, the rectal temperature is approximately 0.3 C higher than that of the oral or groin reading; the axillary temperature is approximately 0.5 C less than the oral value.

Elevated Temperature

Increased body temperature results from excessive heat production or interference with heat dissipation. Each of these mechanisms may be physiologic (i.e., occurring as a normal response to a physiologic challenge) or pathologic (i.e., temperature elevation as a result of damage to the normal thermoregulatory pathways). Physiologic elevation of temperature results from an elevation of the hypothalamic physiologic point for body temperature, a feve. Pathologic elevations of body temperature, hyperthermia, result from unregulated heat generation and/or impairment of the normal mechanisms of heat exchange with the environment.

Physiologic Elevated Temperature – Fever

Release of endogenous pyrogens, particular interleukin (IL-1), triggered by tissue necrosis, infection, inflammation, and some tumors, elevates the hypothalamic set point leading to increased body temperature. Onset of fever may be marked by a chill with shivering and cutaneous vasoconstriction as the body begins generating increased heat and decreasing heat loss; particularly severe chills are called rigors. When the new set point is reached, the skin is usually warm, moist, and flushed; but absence of these signs does not exclude fever. Occasionally, the skin temperature may be subnormal or normal, while the core temperature is markedly elevated. Tachycardia usually accompanies fever, the increase in pulse rate being proportionate to the temperature elevation. During the fever, the patient usually feels more comfortable in a warm environment. The new set point and the pattern of the fever reflect the dynamics of particular pathophysiologic process. Return of the set point to normal, either temporarily or permanently, is marked by sweat and flushing as the body dissipates the accumulated heat. Night sweats occur in many chronic infections, inflammatory diseases, and some malignancies, particularly lymphomas. They represent an exaggeration of the normal diurnal variation in temperature, the sweat marking the decline of the temperature at night.

Fever Pattern

  • Continuous fever. The diurnal temperature fluctuation is 0.5 C to 1.0 C.
  • Remittent fever. The diurnal temperature fluctuation is more than 1.1 C without any normal readings.
  • Intermittent fever. Episodes of fever are separated by days of normal temperature.
  • Relapsing fever. Fevers occur every 5 to 7 days in borreliosis (Lyme disease) and Colorado tick fever.
  • Episodic fever. Fever lasts for days or longer following by remission of fever and clinical illness for at least 2 weeks.
  • Pel-Epstein fever. Several days of continuous or remittent fever are followed by afebrile remissions lasting an irregular number of days. This is characteristic of Hodgkin disease.

Clinical Occurrence

  • Congenital: familial Mediterranean fever, other familial periodic fevers, porphyrias
  • Endocrine: hyperthyroidism, pheochromocytoma
  • Infection: bacterial, viral, rickettsial, fungal, and parasitic infections either localized, or systemic
  • Inflammatory/Immune: systemic lupus erythematosus (SLE), acute rheumatic fever, Still disease, vasculitis, serum sickness, any severe local or systemic inflammatory process
  • Mechanical/Traumatic: tissue necrosis, exercise
  • Metabolic/Toxic: drug reactions, gout
  • Neoplastic: leukemia, lymphomas, and solid tumors
  • Neurologic: seizures
  • Psychosocial: factitious
  • Vascular: thrombophlebitis, tissue ischemia, and infarction, vasculitis, subarachnoid hemmorrhage

Fever of Unknown Origin/FUO

Fever of Unknown Origin. Three conditions define a fever of unknown origin (FUO): 1.the illness has lasted >3 weeks; 2.the temperature is repeatedly >38.3 C; and 3. >= three outpatient visits or >=3 days in the hospital have not yielded a diagnosis.

Clinical Occurrence

  • Nonifectious inflammatory diseases: still disease, SLE, sarcoidosis, Crohn disease, polymyalgia rheumatica, vasculitis (giant cell arteritis, Wegener disease, polyarteritis nodosa)
  • Infections: Endocarditis, tuberculosis, urinary tract infection, cytomegalovirus, Epstein-Barr virus, HIV, subphrenic abcess, cholangitis and cholecystitis
  • Neoplasms: Non-Hodgkin lymphoma, Hodgkin disease, leukemia, adenocarcinoma
  • Miscellaneous: habitual hyperthermia, subacute thyroiditis, Addison disease, drug fever

Pathologic Overproduction and Impaired Dissipation of Heat

  • Hyperthermia. Unregulated heat production or damage to the heat dissipation systems leads to rapid and severe uncompensated temperature elevations.

    • Impaired heat loss: high environmental temperature and humidity, moderately hot weather for a person with congenital absence of sweat glands, congestive heart failure, heat stroke, a ticholinergic drugs and toxins; poverty, homelessness, and psychosis all of which inhibit the ability to adapt to environmental challenges
    • Increased heat generation: malignant hyperthermia, neuroleptic malignant syndrome, heavy exertion in hot and humid environment.

Lowered Body Temperature


Decreased hypothalamic set point, insufficient heat generation, and excessive heat loss due to behaviors and environmental conditions all lead to a sustained decline in core temperature. Low body temperature impairs cellular metabolism and brain function, particularly judgement, and the combination prevents protection from continued exposure leading to fatal hypothermia. Hypothermia also protects the tissue from ischemic injury, so complete recovery is possible from rapid and sustained cooling even when the patient appears clinically dead. Relative or absolute hypothermia in situations where fever would be expected is a poor prognostic sign.

Clinical Occurrence

Endocrine: Hypothyroidism

Idiopathic: Advanced age

Infectious: Sepsis

Mechanical/Traumatic: Exposure and immersion, hypothalamic injury from trauma or hemorrhage, burns

Metabolic/Toxic: Antipyretics, hypoglycemia, drug overdoses

Neoplastic: Brain tumors

Neurologic: Stroke

Psychosocial: Poverty, homelessness, and psychosis

Vascular: Stroke

Gastric Secretion and Its Regulation

April 2, 2016 Gastroenterology, Physiology and Pathophysiology No comments , , , , , , , , , ,

Regulation Mechanism of Gastrirc Secretion

Short and Long Reflexes

Neural input provides an important mechanism for regulation of gastric secretion. Reflexes contribute to both the stimulation and inhibition (e.g., CGRP) of secretion. For example, distension of the stomach wall, sensed by stretch receptors, activates reflexes that stimulate acid secretion at the level of the parietal cell. These reflexes may be so-called short reflexes, which involve neural transmission contained entirely within the enteric nervous system. In addition, long reflexes also contribute to the control of secretion. These involve the activation of primary afferents that travel through the vagus nerve, which in turn are interpreted in the dorsal vagal complex and trigger vagal outflow via efferent nerves that travel back to the stomach and activate parietal cells or other components of the secretory machinery. These long reflexes are aslo called vagovagal reflexes. The relative contribution of short and long reflexes to the control of secretion is unknown. However, it is clear that selective gastric vagotomy eliminates some, although not all, of the gastric secretory response to distension as well as a portion of related gastric motor responses.

Acetylcholine is an important mediator of both short and long reflexes in the stomach. It participates in the stimulation of parietal, cheif, and ECL cells; the supression of D cells; and the synapses between nerves within the enteric nervous system. In addition, a second imporant gastric neurotransmitter is gastrin releasing peptide, or GRP. This neuropeptide is the mammalian homologue of one known as bombesin originally isolated from frog skin. GRP is released by enteric nerves in the vicinity of gastrin-containing G cells in the gastric antrum.

  • Short reflexes, ENS (ACh)
  • Long reflexes/vagovagal reflexes, ANS (ACh)
  • GRP
  • CGRP

Humoral Control

The gastric secretory response is also regulated by soluble factors that originate from endocrine and other regulatory cell types, such as ECL cells. The primary endocrine regulator of gastric secretion is gastrin, which actually consists of a family of peptides. Gastrin travels through the bloodstream from its site of release in the antral mucosa to stimulate parietal and ECL cells via their CCK2 receptors.

PS: CCK2 receptors are expressed on the parietal and ECL cells.

Gastric secretion is also modified by paracrine mediators. Histamine is released from ECL cells under the combined influence of gastrin and ACh, and diffuses to neighboring parietal cells to activate acid secretion via histamine H2 receptors. At one time histamine was thought to be the final common mediator of acid secretion, based in part on the clinical observation that histamine H2 receptor antagonists can profoundly inhibit acid secretion. However, it is now known that parietal cells express receptors for not only histamine, but also ACh (muscarinic m3) and gastrin (CCK2). Because histamine H2 receptors are linked predominantly to signaling pathways that involve cAMP, while ACh and gastrin signal through calcium, when the parietal cell is acted upon simultaneously by all three stimuli, a potentiated, or greater than additive, effect on acid secretion results. The physiological implication of this potentiation, or synergism, is that a greater level of acid secretion can be produced with relatively small increases in each of the three stimuli. The pharmacological significance is that simply interfering with the action of any one of them can significantly inhibit acid secretion.

Acid secretion is also subject to negative regulation by specific mediators. Specifically, somatostatin is released from D cells in response to an axon reflex that release CGRP (calcitonin gene-related peptide) in the antral mucosa when luminal pH falls below 3, and inhibits the release of gastrin from G cells. Elsewhere in the stomach, somatostatin can also exert inhibitory influences on ECL, parietal, and chief cells. The SSTR2 somatostatin receptor is responsible for the inhibitory effects of the peptide in the stomach. In fact, there is data to support the idea that gastirc secretion under resting conditions is tonically suppressed by somatostatin. When stimulated responses occur, they are due not only to the active stimulatory mechanisms disscussed above, but also specific suppression of the inhibitory effects of somatostatin, involving the actions of both ACh (via m2 and m4 receptors) and histamine (via H3 receptors) on D cells.

  • Gastrin
  • Histamine
  • Somatostatin (negative regulation)

Luminal Regulators

Specific luminal constituents also modulate gastric secretion indirectly. The example of pH is described earlier, but acid output, at least, is also increased by components of the meal. Short peptides and amino acids, derived from dietary protein secondary to the action of pepsin released from chief cells, are capable of activating gastrin release from G cells. Aromatic amino acids are the most potent, and "receptors" for these are assumed to reside on the apical membrane of the open G-type endocrine cells, although their structure remains to be defined.

Gastric acid secretion is also activated by alcoholic beverages, coffee, and dietary calcium. The effects of alcoholic beverages may not be due to ethanol itself, but rather the amino acids present in the veverage, particularly in beer and wine. Likewise, the effect of coffee does not appear to be attributable to caffeine, since decaffeinated coffee also increases secretion.

  • Food (bufferring/increasing pH)
  • Food (short peptides and amino acids, alcoholic beverages, coffee, dietary calcium)

Summar of Regulators of Gastric Secretion

Product Source Function
Histamine ECL cells amplify acid secretion
    suppress somatostatin secretion
Gastrin G cells amplify acid secretion
    amplify histamine secretion
GRP Nerves stimuate the secretion of gastrin
CGRP Nerves stimulate the secreton of somatostatin
Ach Nerves amplify acid secretion
    amplify pepsinogen secretion
    amplify histamine secretion
    suppress somatostatin secretion
Somatostatin D cells suppress gastrin secretion
    suppress histamine secretion
    suppress acid secretion
    suppress pepsinogen secretion

Regulation of Gastric Secretion

Regulation of Scretion in the Interdigestive Phase

Between meals, the stomach secretes acid and other secretory products at a low level, perhaps to aid in maintaining the sterility of the stomach. However, because no food is present, and thus no buffering capacity of the gastric content, the low volume of secretions produced nevertheless have a low pH – usually around 3.0. Basal acid output in the healthy human is in the range of 0-11 mEq/h, which can be contrasted with the maximal rates that can be produced by ingestion of a meal, or intravenous administration of gastrin, of 10-63 mEq/h. The basal secretion rate is believed to reflect the combined influences of histamine and ACh, released from ECL cells and nerve endings, respectively, tempered by the influence of somatostatin from fundic D cells. Gastrin secretion during the interdigestive period, on the other hand, is minimal. This is because gastrin release is suppressed by a luminal pH of 3 or below, via the release of somatostatin from antral D cells.

Regulation of Postprandial Secretion

In conjunction with a meal, gastric acid secretion can be considered to occur in three phases – cephalic, gastric, and intestinal. The major portion of secretion occurs during the gastric phase, when the meal is actually present in the stomach. Secretion of other gastric products usually parallels that of the acid.

Cephalic Phase

Even before the meal is ingested, the stomach is readied to receive it by the so-called cephalic phase of secretion. In fact, during the cephalic phase, the functions of several gastrointestinal systems in addition to the stomach begin to be regulated, including the pancreas and gallbladder. Higher brain centers respond to the sight, smell, taste and even thought of food, and relay information to the dorsal vagal complex. In turn, vagal outflow initiates both secretory and motor behavior in the stomach and more distal segments. Gastric secretion occuring during the cephalic phase readies the stomach to receive the meal. Vagal outflow activates enteric nerves that in turn release GRP and ACh. Release of GRP in the vicinity of antral G cells releases gastrin that travels through the bloodstream to activate parietal and chief cells in the endocrine fashion. ACh also suppresss ongoing somatostatin release.

Gastric Phase

The gastric phase of secretion is quantitatively the most important. In addition to vagal influences continuing from the cephalic phase, secretion is now amplified further by mechanical and chemical stimuli that arise from the presence of the meal in the lumen. These include the luminal signals discussed earlier, and signals arising from stretch receptors embedded in the wall of the stomach. Thus, as the stomach distends to accommodate the volume of the meal, these receptors initiate both short and long reflexes to further enhance secretory responses either directly, via the release of ACh in the vicinity of parietal cells, or indirectly, via the release of ACh that activate ECL cells, or GRP that activates G cells to release gastrin. These vago-vagal reflexes also transmit information downstream to ready more distal segments of the intestine to receive the meal. The gastric phase of secretion is also accompanied by a marked increase in gastric blood flow, which supplies the metabolic requirements of the actively secreting cell types.

Due to the combined influence of neurocrine and endocrine signals, further amplified by histamine release from ECL cells, secretory cells of the stomach are highly active during the gastric phase. Moreover, pepsinogen released by chief cells is rapidly cleaved to pepsin in an autocatalytic reaction that occurs optimally at pH 2, and this pepsin then acts on ingested protein to release short peptides and amino acids that further enhance gastrin release. Moreover, many dietary substances, including proteins, are highly effective buffers. Thus, while acid secretory rates remain high, the effective pH in the bulk of the lumen may rise to pH 5. This ensures that the rate of acid secretion during the gastric phase is not attenuated by an inhibition of gastrin release that would otherwise be mediated by somatostatin (when pH <=3).

Intestinal Phase

As the meal moves out of the stomach into the duodenum, the buffering capacity of the lumen is reduced and the pH begins to fall. At a threshold of around pH 3, CGRP triggers somatostatin release from D cells in the gastric antrum, which acts on G cells to suppress gastrin release. Somatostatin released from D cells in the oxyntic mucosa, or from nerve endings, likely also acts directly to inhibit secretory function. This acid-sensing response is a neural pathway that involves the activation of chemoreceptors sensitive to pH, which in turn leads to the release of CGRP via an axon reflex. Other signals also limit the extent of gastric secretion when the meal has moved into the small intestine. For example, the presence of fat in the small intestine is associated with a reduction in gastric secretion. This feedback response is believed to involve several endocrine and paracrine factors, including GIP and CCK, the latter of which binds to CCK1 receptors on D cells.

(The End)

The Pain – The Basic Concepts

November 8, 2014 Critical Care, Physiology and Pathophysiology No comments , , , , ,

Pain is an unpleasant sensation localized to a part of the body. It is often described in terms of a penetrating or tissue-destructive process (e.g., stabbing, burning, twisting, tearing, squeezing) and/or of a bodily or emotional reaction (e.g., terrifying, nauseating, sickening). Furthermore, any pain of moderate or higher intensity is accompanied by anxiety and the urge to escape or terminate the feeling. These properties illustrate the duality of pain: it is both sensation and emotion. When it is acute, pain is characteristically associated with behavioral arousal and a stress response consisting of increased blood pressure, heart rate, pupil diameter, and plasma cortisol levels. In addition, local muscle contraction if often present.

The Pain Sensory System – The Anatomy

The nervous system has two anatomical divisions: the central nervous system (CNS) and the peripheral nervous system (PNS). CNS consists of the brain and the spinal cord, whereas PNS includes spinal nerves, their roots, and branches; cranial nerves and their branches; and components of the autonomic nervous system (ANS).

Collections of nerve cell bodies in the CNS form nuclei, meanwhile those in PNS form ganglia. Ganglia and nuclei contain either motor or sensory neurons.

Spinal Nerves

Spinal nerves are attached to the spinal cord. They transmit both motor and sensory impulses and are, thus, considered mixed nerves. Most cranial nerves are attached to the brain, of which some are either motor or sensory only, while others are mixed.

The spinal cord is composed of segments, as indicated by the 31 pairs of spinal nerves. Each segment has numerous dorsal and ventral rootlets that arise from the respective surfaces of the spinal cord and these respective rootlets unite to form dorsal and ventral roots. Dorsal rootlets contain neuronal processes that conduct afferent impulses to the spinal cord, whereas the ventral rootlets conduct efferent impulses from the spinal cord.

The dorsal root contains the central processes of sensory neuronal cell bodies that are located in the dorsal root ganglion (DRG). The peripheral processes of these sensory neuronal cell bodies are located in the spinal nerve, its rami, and their branches. These processes end at or form receptors. The ventral root contains motor fibers. Their neuronal cell bodies are found in the gray matter of the spinal cord: ventral horn if the axons innervate skeletal muscle; lateral horn if the axons supply smooth muscle, cardiac muscle, or glands.

Screen Shot 2014-11-03 at 5.08.36 PM

After that, the dorsal and ventral roots join to form a short, mixed spinal nerve. Almost immediately after its formation, the spinal nerve divides into mixed dorsal and ventral rami. Among them, the dorsal rami supply intrinsic (deep) muscles of the back and neck, joints of the vertebral column, and skin on the dorsal surface of the trunk, neck, and head. Ventral rami innervate all other muscles of the neck and trunk (including the diaphragm), skin of the anterior and lateral body walls, and all muscles, and skin of the limbs. Therefore in general, ventral rami are larger than dorsal rami.


All spinal nerves, with the exception of C1, transmit sensory information from the skin. Most of the skin of the face and scalp is supplied by the trigeminal nerve (one of  12 pairs of cranial nerves).

Cranial Nerves

There are 12 pairs of cranial nerves. The spinal part of CN XI takes origin from upper cervical spinal cord, enters the cranial cavity through foramen magnum and, in the jugular foramen, joins a cranial root from the brain stem. CN II-XII are attached to the brain stem. Cranial nevers are sensory, motor, or mixed.

Autonomic Nervous System

Autonomic Nervous System (ANS) is functional divided rather than anatomic divided. Autonomic nervous system and somatic motor system consist make up the motor (efferent) portion of the PNS.

The ANS has sympathetic, parasympathetic, and enteric (ENS/Enteric Nervous System) divisions. The ENS is a network of neurons located within the wall of the gastrointestinal tract. This part of the ANS can function autonomously, although it interacts with the sympathetic and parasympathetic divisions. Somatic efferent impulses utilize a single neuron to transmit information from the CNS to skeletal muscle. In contrast, sympathetic and parasympathetic efferent information is transmitted through two neurons.

Visceral Afferent fiber conduct sensory information (pain or reflexive) from organs to the CNS. Their neuronal cell bodies are located either in dorsal root ganglia or a sensory ganglion associated with CN IX and X. They are considered part of the ANS, but not classified as sympathetic or parasympathetic.

Adrenal Medulla is unique in that it “acts” as the ganglion. The chromatin cells of the adrenal medulla are equivalent to postganglionic sympathetic neutrons. Upon stimulation by preganglionic sympathetic axons, they release neurotransmitters (epinephrine and norepinephrine) directly into the circulation.

How The Pain Generates?

The stimuli that activate pain receptors vary from one tissue to another. The adequate stimulus for skin is one that has the potential to injure tissue, i.e., pricking, cutting, crushing, burning, and freezing. These stimuli are ineffective when applied to the stomach and intestine, where pain is produced by an engorged of inflamed mucosa, distention or spasm of smooth muscle, and traction on the mesenteric attachment. In skeletal muscle, pain is caused by ischemia, necrosis, hemorrhage, and injection of irritating solutions as well as by injuries of connective tissue sheaths. Prolonged contraction of skeletal muscle evokes an aching type of pain. Ischemia is also the most important cause of pain i cardiac muscle. Joints are insensitive to pricking, cutting, and cautery, but pain can be produced in the synovial membrane by inflammation and by exposure to hypertonic saline. The stretching and tearing of ligaments around a joint can evoke severe pain. Injuries to the periosteum give rise to pain but probably not to other sensation. Blood vessels are a source of pain when pierced by a needle or involved in an inflammatory process. Distention of arteries or veins, as occurs with thrombotic or embolic occlusion, may be sources of pain; other mechanisms of headache relate to traction on arteries or inflammation to he meningeal structures by which they are supported. Pain from intraneural lesions probably arises from the sheaths of the nerves. Nerve root(s) and sensory ganglia, when compressed, give rise to pain.

Pain and The Sensitization

Heuristically, pain can be divided into several distinct sets of events, including acute nociception, tissue injury, nerve injury, and the affective dimensions. Primary afferents are classified by their diameter, degree of myelination, and conduction velocity. The largest-diameter afferent fibers, Aβ, respond maximally to light touch and/or moving stimuli. They are present primarily in nerves that innervate the skin. In normal individuals, the activity of these fibers dose not produce pain. There are two other classes of primary afferents: the small-diameter myelinated Aδ and the unmyelinated C fiber axons. These fibers are present in nerves to the skin and to deep somatic and visceral structures.

The acute activation of Aδ and C fibers generates transient input into the spinal cord, which in turn leads to activation of neurons that project contralaterally to the thalamus and thence to the somatosensory cortex. Besides, a parallel spinofugal projection is to the medial thalamus and from there to the anterior cingulate cortex, part of the limbic system.

PS: Ascending Pathway for Pain. A majority of spinal neurons contacted by primary afferent nociceptors send their axons to the contralateral thalamus. These axons form the contralateral spinothalamic tract, which lies in the contralateral anterolateral white matter of the spinal cord (where the change from one side to the other starts), the lateral edge of the medulla, and the lateral pons and midbrain.

When Aδ fibers are activated, glutamate is released as the neurotransmitter and pain is produced immediately. This type of pain is called first pain, or fast pain/epicritic pain, which is a rapid response and mediates the discriminative aspect of pain or the ability to localize the site and intensity of the noxious stimulus.

Activation of C fibers, which release a combination of glutamate and substance P, is responsible for the delayed second pain (also called slow pain or protopathic pain) which is the dull, intense, diffuse, and unpleasant feeling associated with a noxious stimulus. Itch and tickle are also related to pain sensation.

Molecular Mechanism of Pain

On the organizations and tissues on the endings of nociceptive sensory nerves that respond to noxious thermal, mechanical, or chemical stimuli, there are distribution of a variety of receptors. Many of these are part of a family of nonselective cation channels called transient receptor potential (TRP) channels. This includes TRPV1 receptors (the V refers to a group of chemicals called vanilloids) that are activated by intense heat, acid, and chemicals such as capsaicin. TRPV1 receptors can also be activated indirectly by initial activation of TRPV3 receptors in keratinocytes in the skin.

Noxious mechanical, cold, and chemical stimuli may activate TRPA1 receptors (A, for ankyrin) on sensory nerve terminals. Acid sensing ion channel (ASIC) receptors are activated by pH changes within a physiological range and may be the dominant receptors mediating acid-induced pain.

Purinergic receptors (P2X, an ionotropic receptor, P2Y, an a G protein-coupled receptor) are activated by indirect stimuli. For example, some nociceptive stimuli release intermediate molecules like ATP, etc, and these intermediate molecules then activate purinergic receptors. Another example is the tyrosine receptor kinase A (TrkA), which is activated by nerve growth factor (NGF) that is released as a result of tissue damage.

Itch and tickle can be produced by repeated local mechanical stimulation of the skin, also, a variety of chemical agents including histamine and kinins such as bradykinin, which are released in the skin in response to tissue damage, can produce itch and tickle. Kinins exert their effects by activation of two types of G protein-coupled receptor, B1 and B2. At present we know that the activation of bradykinin B2 receptors is a downstream event in protease-activated receptor-2 (PAR-2) activation, which induce both a nociceptive and a pruritogenic response.

PS: pain-producing substances include histamine, prostaglandins, serotonin, kinins, potassium ions, hight H+, and others.

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Following tissue injury or local inflammation (e.g., local skin burn, toothache, rheumatoid joint, etc.), an ongoing pain state arises that is characterized by burning, throbbing, or aching and an abnormal pain response. This abnormal pain response is called hyperalgesia, or the sensitization, which can be divided into peripheral sensitization and central sensitization. Peripheral sensitization is the results of some active factors such as substance P, prostaglandins, bradykinin, cytokines, H+ ions, and so on. When these substances are released into the injury site, they have the ability to activate the terminal of small high-threshold afferents (Aδ and C fibers) and to reduce the stimulus intensity required to activate these sensory afferents. In addition, the ongoing afferent traffic initiated by the injury leads to the activation of spinal facilitatory cascades, enhancing the excitability of nerve cells in the dorsal horn of the spinal corda and yielding a greater output to the brain for any given input. This facilitation is thought to underlie the hyperalgesic states, which we called it the central sensitization. The pain caused by sensitization usually is called the “nociceptive” pain.

Injury to the peripheral nerve yields complex anatomical and biochemical changes in the nerve and spinal cord that induce spontaneous dysesthesia. This nerve injury pain state may not depend upon the activation of small afferents, but may be initiated by low-threshold sensory afferents like Aβ fibers. Such nerve injuries result in the development of ectopic activity arising from neuromas formed by nerve injury and the dorsal root ganglia of the injured axons as well as a dorsal horn reorganization, such that low-threshold afferent input carried by Aβ fibers evokes a pain state. This dorsal horn reorganization reflects changes in ongoing inhibition and in the excitability of dorsal horn projection neurons. Note that this kind of pain is typically considered to respond less well to opioid analgesics.

Emotional effect

Interestingly, painful stimuli have the certain ability to generate strong emotional components that reflect a distinction between pain as a specific sensation subserved by distinct neurophysiological structures, and pain such as suffering (the original sensation plus the reactions evoked by the sensation, the affective motivational dimension). When pain does not evoke its usual responses such as anxiety, fear, panic, and suffering, a patient’s ability to tolerate the pain may be markedly increased, even when the capacity to perceive the sensation is relatively unaltered.

Besides, a tickling sensation or itch usually is regarded as pleasurable. And the simple 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.

Referred Pain

The fundamentals of referred pain is that the axon of each primary afferent contacts many spinal neurons, and each spinal neuron receives convergent inputs from many primary afferents. The convergence of sensory inputs to a single spinal pain transmission neuron is of great importance because it underlies the phenomenon of referred pain. All spinal neurons that receive input from the viscera and deep musculoskeletal structures also receive input from the skin.

The convergence patterns are determined by the spinal segment of the dorsal root ganglion that supplies the afferent innervation of a structure. For example, the afferents that supply the central diaphragm are derived from the third and fourth cervical dorsal root ganglia. Primary afferents with cell bodies in these same ganglia supply the skin of the shoulder and lower neck. Thus, sensory inputs from both the shoulder skin and the central diaphragm converge on pain-transmission neurons in the third and fourth cervical spinal segments.

Because of this convergence and the fact that the spinal neurons are most often activated by inputs from the skin, activity evoked in spinal neurons by input from deep structures is mislocalized by the patient to a place that roughly corresponds with the region of skin innervated by the same spinal segment.