Nociception

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Tips for writing this page:

• Define and describe the physiological process and purpose of nociception
• Describe different nocipetors and explain the need for adequate stimuli to activate nociceptors in different tissue types (i.e. skin, muscle, joint, viscera)
  

Original Editor - Przemyslaw Jaczun

Top Contributors - Przemyslaw Jaczun, Uchechukwu Chukwuemeka, Jo Etherton, Amanda Ager, Michelle Lee, 127.0.0.1, Mathius Kassagga, WikiSysop and Chrysolite Jyothi Kommu  

Nociception

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Definition/Descrition

Nociception is the neural processes of encoding and processing noxious stimuli. In another ways, it refers to signal arriving in the central nervous system resulting from activation of specialized sensor receptors celled nociceptors (peripheral nerves endings) by adequate noxious stimuli. Nociception is physiological process that protects tissue against damage. This process is also known as nocioception or nociperception, but is not synonym of pain sense. Term ‘‘nociception” and ‘‘pain” should not be confused, because each can occur without the other. Pain arising from activation of nociceptors by actual or potentially harmful stimuli is called nociceptive pain. It is important to note that excitation of nociceptors does not always evoke pain.

Nociceptive pain can be classified by tissue origin:

• Superficial somatic (e.g. skin)
• Deep somatic (e.g. ligaments, tendons, bones and muscles)
• Visceral (e.g. internal organs)
  

Noxious stimuli is divided by type:

• Thermal
• Mechanical
• Chemical
  

Nociceptors

Nociceptors (noci- is derived from the Latin for “hurt”) are sensory receptors capable of transducing and encoding noxious stimuli. The initial reception of noxious input occurs in functionally specialized free nerve endings of the skin, muscles, joints, viscera, dura, blood vessels and in fascia. The cell bodies of nociceptors are located in the dorsal root ganglia (DRG) for the periphery and the trigeminal ganglion for the face. However, not every nociceptor responds to each type of the noxious stimuli. The apparent lack of a response to a noxious stimulus may result because of different receptors located on membrane of end terminal (free nerve ending) or the stimulus intensity is insufficient. Usually, the stimulation threshold of a nociceptor is below tissue-damaging intensity. Nociceptors have heterogeneous properties, responding to multiple stimulus modalities (polymodal). However, application of noxious stimulus of one modality may alter the response properties of the nociceptor to other modalities. Also application of particular stimulus for given length of time may induce long-term changes in the response properties of the nociceptor. Injury and inflammation decrease the threshold and increase the magnitude of the response for a given stimulus, a phenomenon known as peripheral sensitization. Of particular interest are the heat responsive, but mechanically insensitive unmyelinated afferents that develop mechanical sensitivity only in the setting of injury.

Nociceptors have the morphological appearance of free nerve endings. The term “free nerve ending” indicates that in the light microscope no (corpuscular) receptive structure can be recognized. At present, there are no clear ultrastructural differences between non-nociceptive free nerve endings (e.g., sensitive mechanoreceptors and thermoreceptors) and nociceptive ones. Functionally, different free nerve endings are assumed to possess different sets of receptor molecules in their axonal membrane. Receptor molecules that are particularly important for the function of muscle nociceptors are acid-sensing ion channels (ASICs) that open at a low tissue pH, P2X3 receptors that are activated by binding adenosine triphosphate (ATP), and the transient receptor potential receptor subtype 1 (TRPV1) that is sensitive to high temperatures, capsaicin chemical and low pH. The neuropeptide substance P has been reported to be present predominantly in nociceptive afferent fibres. While there are numerous neurotransmitters within nervous system, the three most common participating in nociceptive transmission are peptides, purines, and excitatory amino acids (EAA). The EAA, particularly glutamate, produce the initial excitatory response on the postsynaptic, second-order, neuron, followed by the release of peptides, including substance P, causing a more prolonged depolarization and sustained nociceptive transmission

Nociceptors are present in many body tissue but has not been found in articular cartridge, synovial membranes, visceral pleura, lung parenhyma, pericardium, brain and spinal cord tissue.

Clasification of nociceptors.

Several classes of nociceptors have been described. Some nociceptors respond to noxious cold, noxious heat and high threshold mechanical stimuli as well as a variety of chemical mediators. Nociceptors, although polymodal, can be further divided into two main classes on the basis of response to mechanical stimuli, leading to distinction between mechanically sensitive afferents (MSA) and mechanically insensitive afferents (MIA) defined as afferents that have very high mechanical thresholds or are unresponsive to mechanical stimuli.

Nociceptors can by classified by the conduction velocity of their axons or fibres diameter, this is group III or IV and Aδ or C respectively.

Type Aδ medium diameter myelinated afferents that mediate acute, well-localized, sharp pricking type pain, known as group III afferent. Aδ aferent fibres have average fibre diameter 2-5mm and conductive velocity 5-30 m/s. Aδ nociceptors can be further divided into two types (it appears to exist proximately 50% of each type)

• Type I Aδ are mechanically sensitive afferents (MSA) that respond with a slowly adapting discharge to strong punctuate pressure. Their also respond to heat and chemical stimuli, and have relatively high heat thresholds (>50C).
• Type II Aδ nociceptors have lower heat threshold than Type I units, but have very high mechanical thresholds (called mechanically insensitive afferents - MIAs). Activity of this afferent almost certainly mediates the “first” acute pain response to noxious heat. They have been reported in the knee joint, viscera and cornea.

Type C unmyelinated afferent fibres that convey poorly localized dull, burning, so called “second” or slow pain are known as group IV. Avarege fibre dimeter is 3mm and conductive velocity is 3 m/s or less. The unmyelinated C fibres are also heterogeneous. C fiber afferents can be divided into two classes based on their response to mechanical stimuli. Like the myelinated Aδ afferent fibres, most C fibres are polymodal, that is, they include a population that is both mechanically and heat sensitive (CMHs). The response of CMHs is also strongly influenced by the stimulus history. Both fatigue and sensitization are observed. A decrease in the response to heat is also observed following mechanical stimuli applied to the receptive field or electrical stimuli applied to the nerve trunk. This suggests that fatigue in response to a given stimulus modality can be induced by heterologous stimulation, that is, by excitation with a stimulus of a different modality. These are the predominant type of C-fibre nociceptors in mammalian skin. Mechanically insensitive C-fibers (C-MIAs) are either unresponsive to mechanical stimuli or have a very high mechanical threshold. These afferents respond to heat and various noxious chemical stimuli (e.g., capsaicin, histamin) and are often considered to be chemoreceptors.

In summury to the above, immediate, well localised, stingy pain sensation is mediated by small diameter mylinated nerve fibres, type Aδ. C fibres madate poorly localized anatomically type of pain, it has an aching and burning character, comes later than the initial first sensation and it is difficult to estimate its strength.

TRP Chanels

The peripheral end of the axon contains encapsulated proteins called transduction proteins (TRP), which can be activated by a specific stimulus. The transient receptor potential (TRP) multigene superfamily encodes integral membrane proteins that function as ion channels. The TRP channel family is of interest because several members have been implicated in nociceptor signal transduction.
Noxious cold and noxious heat stimuli are detected by Aδ and C fiber nociceptors. The TRP channel family provides a group of molecules equipped to detect thermal changes. The full range of temperatures, from noxious cold to noxious heat, appears to be transduced by the activity in these ion channels. TRPM8 and TRPV3/4 encode cool and warm, respectively, TRPA1 transduces noxious cold and TRPV1/2 sense noxious heat. Some of the thermosensitive TRP channels respond to chemical and mechanical stimuli as well.
For example, TRPV1 is essential for transducing the nociceptive by inflammatory, and hypothermic effects of vanilloid compounds and contributes to acute thermal nociception and thermal hyperalgesia following tissue injury. TRPV1 current is potentiated by bradykinin and nerve growth factor via several possible mechanisms and is also activated by protons and capsaicin, the ‘‘hot’’ compound in chili peppers. In contrast to the hyperalgesia following intense noxious stimuli, prolonged exposure to capsaicin can result in a subsequent desensitization.
While the discovery of thermosensitive TRP channels has greatly enhanced our understanding of transduction mechanisms of thermal stimuli, findings in animals with selective gene deletions clearly indicate that multiple and yet unknown transduction mechanisms are engaged by thermal stimuli.

Chemical mediators

Injury results in the local release of numerous chemicals from non-neuronal cells (e.g., fibroblasts, mast cells, neutrophils, monocytes, and platelets), as well as from the sensory terminals of primary afferent fibers that mediate or facilitate the inflammatory process. Inflammatory mediators include prostaglandins, leukotrienes, bradykinin, serotonin, histamine, SP, thromboxanes, platelet-activating factor, purines such as adenosine and ATP, protons, and free radicals. Cytokines, such as interleukins and tumor necrosis factor, and neurotrophins, especially NGF, are also generated during inflammation. It is worth to note that most of those chemicals (mainly substances such as bradykinin and prostaglandin E2) are generally considered to not activate nociceptors directly but rather enhance the sensation of pain in response to natural stimuli and other endogenous chemicals by increasing the frequency of action potential firing.
Activation of nociceptors not only transmits afferent messages to the dorsal horn of the spinal cord but also initiates the process of neurogenic inflammation. Neurogenic inflammation causes release of neurotransmitters, notably substance P and calcitonin gene–related peptide (CGRP), which leads to severe vasodilation, as well as plasma leakage of proteins and fluid from post capillary venules.

Two chemicals are of particular interest:

• Adenosine triphosphate (ATP)

ATP is the energy-carrying molecule in all cells of the body; accordingly, it is present in every tissue cell. It is released from all tissues during trauma and other pathologic changes that are associated with cell death. For this reason, ATP has been considered a general signal substance for tissue trauma and pain. In human microneurographic studies, injection of ATP activated 60% of mechano-responsive and mechano-insensitive C-nociceptive fibers without sensitizing these fibers to mechanical or heat stimuli. ATP activates purinergic P2X3 receptors in nociceptors cousing discharge. ATP is particularly important for muscle pain, because it is present in muscle cells in high concentration.

• Protons lteration in tissue pH

Acid-sensing ion channels (ASICs) constitute a family of receptor molecules that are sensitive to a drop in pH and open at various pH values. The channel proteins react already to small pH changes. This receptor family (for instance ASIC1 and ASIC3) is particularly important for muscle pain, because almost all pathologic changes in muscle are accompanied by a drop in tissue pH, e.g., exhausting exercise, ischemia, and inflammation (Immke and McCleskey . In these conditions, the pH of the muscle tissue can drop to 5–6. ASICs signal moderate decreases in extracellular pH, in contrast to TRPV1, which is activated by severe acidosis. The proton-sensitive nociceptors may be of importance for the induction of chronic muscle pain.

References

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