Nociception

Overview 

Nociception is a subclass of somatosensory. Nociception is the neural process that encodes and processes noxious stimuli. [1] Nociception is a signal that reaches the central nervous system due to stimulation of specialized sensory receptors in the peripheral nervous system called nociceptors. Nociceptors are activated by potentially noxious stimuli because nociception is a physiological process that protects body tissues from damage. Nociception is important for the body’s fight-or-flight response, protecting us from our surroundings environment.

Nociceptors can be activated by three types of stimuli within the target tissue – temperature (heat), mechanical (e.g. stretch/strain) and chemical (e.g. pH changes due to local inflammatory processes). Therefore, noxious stimuli can be classified into one of these three groups.

The terms nociception and pain should not be used synonymously, as both can occur on their own. [1]. Pain caused by activation of nociceptors is called nociceptive pain. Nociceptive pain can be classified according to the tissue in which nociceptor activation occurs: Superficial Somatic (e.g. skin) deep body (e.g. ligaments/tendons/bones/muscles) or viscera (internal organs).

Nociception pathway

Not every nociceptor responds to every noxious stimulus. Apparent lack of response to noxious stimuli may be due to different receptors on terminal membranes (free nerve endings) or insufficient stimulus intensity. [2] Usually stimulating The threshold of nociceptors is below the intensity of tissue damage. Nociceptors have the heterogeneous property of responding to multiple modes of stimulation (multimodal). However, application of noxious stimuli in one modality may alter the response properties of nociceptors to other modalities. return Application of specific stimuli for a given length of time may result in long-term changes in the response properties of nociceptors. [3] Injury and inflammation lower the threshold and increase the magnitude of the response to a given stimulus, a phenomenon known as peripheral Sensitized. Of particular interest are thermally responsive but mechanically insensitive unmyelinated afferents, which develop mechanosensitivity only in response to injury.

Nociceptors have the morphological appearance of free nerve endings. The term “free nerve endings” denote (red blood cell) receptive structures that cannot be identified under a light microscope. Currently, there are no apparent ultrastructural differences between non-nociceptive free nerves Terminals (such as sensitive mechanoreceptors and thermoreceptors) and nociceptors. functionally distinct free nerve endings

Schematic diagram of a nociceptor showing the four regions of the cell.

Supposed to have a distinct set of receptor molecules in their axonal membranes. A receptor molecule of particular importance to the function of muscle nociceptors is the acid-sensitive ion channel (ASIC), which opens P2X3 receptors at low tissue pH and is activated by binding adenosine triphosphate (ATP) and transient receptor potential receptor subtype 1 (TRPV1), which is sensitive to high-temperature capsaicin chemicals and low pH. The neuropeptide substance P has been reported to be predominantly present in nociceptive afferent fibers. Although there are countless Neurotransmitters within the nervous system, the three most commonly involved in nociceptive transmission are peptide purines and excitatory amino acids (EAAs). EAA, especially glutamate, produces an initial excitatory response to postsynaptic secondary neurons, followed by the release of Peptides including substance P lead to longer depolarization and sustained nociceptive transmission

Nociceptors are present in many body tissues but have not been found in articular cartilage, visceral pleura, lung parenchyma, pericardium, brain and spinal cord tissues.

Types 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 various chemical mediators. Nociceptors, although multimodal, can be further divided into two broad categories Mechanical stimulation results in a distinction between mechanosensitive afferents (MSA) and mechanoinsensitive afferents (MIA), defined as afferents with a very high mechanical threshold or unresponsive to mechanical stimulation.

Nociceptors can be classified according to their axonal conduction velocity [3] or fiber diameter [4], which are groups III and IV, Aδ and C, respectively.

Aδ-type medium-diameter myelinated afferents mediate acute, well-localized, sharp, prickly pain known as group III afferents. Aδ afferent fibers have an average fiber diameter of 2-5 mm and a conduction velocity of 5-30 m/s. Aδ nociceptors can be further divided into two classes (it Each type seems to be present about 50%)

• Type I Aδ are mechanosensitive afferents (MSAs) that have slow adaptive firing responses to intense punctate pressure. They also respond to thermal and chemical stimuli and have a relatively high thermal threshold (>50C).
• Type II Aδ nociceptors have a lower thermal threshold than type I units, but have a very high mechanical threshold (termed mechano-insensitive afferents – MIA). The activity of such afferents almost certainly mediates the “first” acute pain response to noxious heat. they have Reported in the knee joint [5] viscera [6] and cornea [7]

Type C unmyelinated afferent fibers deliver a locally poorer, dull, burning pain, the so-called “second” pain or slow pain, referred to as Group IV. The average fiber diameter is less than 2mm, and the conduction velocity is less than or equal to 2m/s. Unmyelinated C fibers are also heterogeneous. C fiber afferents can be Divided into two categories based on the response to mechanical stimuli. Like myelinated Aδ afferent fibers, most C fibers are multimodal, i.e. they include populations that are mechanically and thermally sensitive (CMH). CMHs responses are also strongly influenced by stimuli history. Fatigue and sensitization were observed. [8] Attenuated responses to heat were also observed after mechanical stimulation of the receptive field or electrical stimulation of the nerve trunk. [9] This suggests that fatigue responses to a given stimulus modality can be Induced by heterologous stimuli, i.e. evoked by different forms of stimuli. These are the major C-fiber nociceptor types in mammalian skin. Mechanically insensitive C fibers (C-MIA) are either unresponsive to mechanical stimuli or have very high mechanical strength critical point. These afferents respond to heat and various noxious chemical stimuli (such as capsaicin histamine) and are often considered chemoreceptors.

Taken together, direct well-localized tingling sensations are mediated by small-diameter myelinated nerve fibers of the Aδ type. C-fiber mediated poorly localized anatomical type of pain It is characterized by pain and burning, later than the initial first sensation, it is It is difficult to estimate its strength.

TRP Channels

Nociceptors respond to specific temperature ranges and mechanical stimuli.

The peripheral ends of axons contain encapsulated proteins called transducin proteins (TRPs), which are activated by specific stimuli. The transient receptor potential (TRP) multigene superfamily encodes integral membrane proteins that function as ion channels. TRP channel series are It was of interest because several members are involved in nociceptor signaling. Aδ and C fiber nociceptors detect noxious cold stimuli and noxious hot stimuli. The TRP channel family provides a group of molecules capable of detecting thermal changes. full temperature range The transition from noxious cold to noxious heat appears to be transduced by activity in these ion channels. TRPM8 and TRPV3/4 encode cold and warm, respectively, TRPA1 transduces noxious cold, and TRPV1/2 senses noxious heat. Some thermosensitive TRP channels respond to chemical and mechanical stimuli such as [10] For example, TRPV1 is critical for the transduction of nociception through the inflammatory and hypothermic effects of vanilloid compounds and contributes to acute thermal nociception and thermal hyperalgesia following tissue injury. TRPV1 currents are enhanced by bradykinin and nerve growth factor Through several possible mechanisms, it is also activated by protons and capsaicin, the “hot” compound in peppers. [11] In contrast to hyperalgesia following intense noxious stimuli, prolonged exposure to capsaicin leads to subsequent desensitization. Although The discovery of heat-sensitive TRP channels has greatly enhanced our understanding of the transduction mechanisms found by heat stimulation in animals with selective gene deletions, clearly showing that heat stimulation is involved in multiple but unknown transduction mechanisms.

Chemical mediators

Injury results in the local release of large quantities of chemicals from nonneuronal cells such as fibroblasts, mast cells, neutrophils, monocytes, and platelets, as well as from the sensory terminals of primary afferent fibers that mediate or promote inflammatory processes. Inflammatory mediators include Prostaglandins Leukotrienes Bradykinin Serotonin Histamine SP Thromboxane Platelet Activating Factor Purines such as adenosine and ATP Protons and free radicals. Cytokines such as interleukins and tumor necrosis factor as well as neurotrophic factors, especially NGF, are also produced during inflammation. this is It is worth noting that most of these chemicals (principally such as bradykinin and prostaglandin E2) are generally considered not to directly activate nociceptors, but rather to enhance response to natural stimuli and other endogenous chemicals by increasing pain frequency. physical pain Action potential triggering. [3]

Membrane chemoreceptors of nociceptive nerve endings.

Activation of nociceptors not only conveys afferent information to the dorsal horn of the spinal cord, but also initiates neurogenic inflammatory processes. Neurogenic inflammation results in the release of neurotransmitters, particularly substance P and calcitonin gene-related peptide (CGRP), leading to Severe vasodilation and plasma leakage of protein and fluid from postcapillary veins. [3]

Two chemicals are of particular interest:

• Adenosine triphosphate (ATP)

ATP is the energy-carrying molecule in all cells of the body. It is released from all tissues during trauma and other pathological changes associated with cell death. Therefore, ATP is considered to be a general signal substance of tissue trauma and pain. microneuron studied that injection of ATP activated 60% of mechanoresponsive and mechanoinsensitive C nociceptive fibers without sensitizing these fibers to mechanical or thermal stimuli. ATP activates purinergic P2X3 receptors in nociceptors, resulting in firing. ATP is especially important for muscle pain because It is present in muscle cells in high concentrations.

• Protons alteration in tissue pH

Acid-sensitive ion channels (ASICs) constitute a family of receptor molecules that are sensitive to a drop in pH and open at different pH levels. Channel proteins have responded to too small a pH change. This family of receptors, such as ASIC1 and ASIC3, is particularly important for muscle pain because A decrease in tissue pH is associated with almost all pathological changes in muscle, such as exhaustive exercise ischemia and inflammation.

Location of Nociceptors

The cell bodies of nociceptors are located in the dorsal root ganglion (DRG) peripherally and the trigeminal ganglion in the face. Their axons extend into the peripheral nervous system and terminate in branches that form receptive fields.

• Skin

Free nerve endings terminating in the skin are the mechanism for signaling local mechanical thermal and chemical changes. [3] Most free nerve endings in the skin are called multimodal nociceptors because they contain multiple receptors and thus respond to various combinations of nociceptors the aforementioned stimuli. [3] Type I Aδ high-threshold mechanoreceptor units are densely distributed in hairy and glabrous skin.

• Muscles

Receptor molecules of particular importance to the function of muscle nociceptors are acid-sensitive ion channels (ASICs), which open P2X3 receptors at low tissue pH by binding adenosine triphosphate (ATP) and transient receptor potential receptor subtype 1 ( TRPV1) activation) that Sensitive to high temperature and low pH. In skeletal muscle, free nerve endings appear to be fairly evenly distributed. No differences were found between the proximal and distal portions of the rat gastrocnemius-soleus muscle. However, in the same study, nerve fiber density found that the peritendineum in the rat Achilles tendon was several times higher than that in the GS muscle. In contrast, the collagen fiber bundles of tendon tissue itself have few free nerve endings.

• Tendons

Innervation of the human Achilles tendon is provided by nerves from surrounding muscles and small bundles from cutaneous nerves, but this involves all nerve endings. [12] Free nerve endings are located inside the tendon, but primarily located in the peritendon tissue are nociceptors. quantity and The location of all nerve fibers and nerve endings varies according to the function of the tendon, being more pronounced in smaller tendons involved in fine motor movements.

• Joint

Nociceptors in joints are located in the capsular ligaments and proximal tendon-periosteal joint fat pads and blood vessels, but not in the articular cartilage. High-threshold nociceptive afferents terminate primarily in the synovium and periosteum, usually only to the Joint movement beyond working limits. Following joint injury, two factors conspire to alter the mechanosensitivity of joint nociceptors. The initial physical changes (joint effusion and tissue edema) alter the resting and motion-induced forces exerted on the joint tissue, and Secondary inflammatory mediators released in damaged tissue sensitize nociceptive afferent nerves in the joint by binding to receptors on nerve endings. Nociceptors in many joints respond to harmless movement but become increasingly activated when movement exceeds the physiological working range While other nociceptors are only active during noxious exercise. [5] A third group of so-called silent nociceptors are usually inactive and only respond in pathological situations such as inflammation. [5]

The lumbar facet capsule has been shown to be abundantly innervated by nociceptor and proprioceptor fibers. [13] Under normal conditions, nociceptors (such as those seen in the facet joint capsule) have high thresholds and are not expected to fire unless the load is supraphysiological. However, in the presence of pathological joint inflammation, synovitis chemical mediators may sensitize these nociceptors and supraphysiological levels of pressure may no longer be required to stimulate pain. This inflammatory mediator (substance P bradykinin phospholipase A2) has been facet joint capsule. [13]

Nociceptors in discs are usually restricted to the outer third of the annulus and may serve as the substrate for discogenic pain as they expand over the larger annulus and penetrate further along the vasculature and fissures into the degenerated disc. Those C- and A delta fibers May be responsible for transmitting pain responses. The posterior longitudinal ligament and the outer annulus fibrosus of the intervertebral disc contain a large number of pain-sensing fibers. Nerve fibers and nerve endings also arise in the subchondral bone of the facet joints. they happen in An eroded channel extending from the subchondral bone to the articular cartilage. A human study by (Kiter et al. 2010)[14] showed the presence of free and encapsulated nerve endings in the human iliolumbar ligament. (Hirsch et al. 1963)[15] showed the presence of thin nerve fibers and complexes Unencapsulated ends of the supraspinous and intraspinous ligaments.

• Viscera

Visceral nociceptors do not respond to cuts or burns like their counterparts in surrounding skin tissue. Instead, they are activated in response to pathological changes. Generating painful stimuli in the viscera, including traction on inflammation of the mesentery Strong contraction of muscular walled organs such as the gastrointestinal tract urinary tract gallbladder and the muscular layer surrounding such hollow organs chemical irritants or ischemia of organs such as the heart. The distribution of these fibers varies from organ to organ. High Threshold Receptor Proprietary Pain is the only organ innervated by conscious sensation (i.e., the ureters, kidneys, lungs, and heart), but relatively few in organs that provide both innocuous and noxious sensations (eg, the colon, stomach, and bladder) that are predominantly innervated by low-threshold receptors. organs such as liver, lung and kidney The pancreas has few receptors, but pain in these organs comes primarily from the activation of receptors in the sacs of these organs. Noxious stimulation of viscera causes diffuse pain that is difficult to localize. Discovery of afferent nociceptive fibers in viscera associated with Sympathetic and Parasympathetic. Most internal organs are innervated by the vagus nerve, but studies have not clearly shown whether this nerve is capable of carrying nociceptive afferent input. However, several studies clearly show that vagal afferent transmission is related to high Intensive mechanical stimulation of the central nervous system. Numerous studies involving humans or animals have shown that subjects with spinal cord injuries are able to report pain that may originate in areas of internal organs. [16]