Role of Nociceptors in Pain
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Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.
A nociceptor is a sensory receptor that sends signals that cause the perception of pain in response to potentially damaging stimulus. Nociceptors are the nerve endings responsible for nociception. They are silent receptors and do not sense normal stimuli. Only when activated by a threatening stimulus do they invoke a reflex.
Nociceptors were discovered by Charles Scott Sherrington in 1906. Sherrington used many different styles of experiments to discover that pain was a nociceptive reaction and was sensed through specific receptors called nociceptors.
In mammals, nociceptors are sensory neurons that are found in any area of the body that can sense pain either externally or internally. External examples are in tissues such as skin (cutaneous nociceptors), cornea and mucosa. Internal nociceptors are in a variety of organs, such as the muscle, joint, bladder, gut and continuing along the digestive tract. The cell bodies of these neurons are located in either the dorsal root ganglia or the trigeminal ganglia (Jessell et al 1991). The trigeminal ganglia are specialized nerves for the face, whereas the dorsal root ganglia associate with the rest of the body. The axons extend into the peripheral nervous system and terminate with the dendrites wherever a receptive field is found.
Nociceptors develop from neural crest stem cells. The neural crest is responsible for a large part of early development in vertebrates. More specifically it is responsible for neuronal development. The neural crest stem cells form the neural tube and nociceptors grow from the dorsal part of this tube.
The peripheral terminal of the mature nociceptor is where the noxious stimuli are detected and transduced into electrical energy. When the electrical energy reaches a threshold value, an action potential is induced and driven towards the CNS. This leads to the train of events that allows for the conscious awareness of pain. The sensory specificity of nociceptors is established by the high threshold only to particular features of stimuli. Only when the high threshold has been reached by either chemical, thermal, or mechanical environments, the nociceptors triggered. Majority of nociceptors are classified by which of the environmental modalities they respond to. Some nociceptors respond to more than one of these modalities and are consequently designated polymodal. Other nociceptors respond to none of these modalities (although they may respond to stimulation under conditions of inflammation) and have thereby earned the more poetic title of sleeping or silent nociceptors.
Nociceptors have two different types of axons. The first are the AÎ´ fiber axons. They are myelinated and can allow an action potential to travel at a rate of about 20 meters/second towards the CNS. The other type is the more slowly conducting C fiber axons. These only conduct at speeds of around 2 meters/second (Williams and Purves 2001). This is due to the light or non-myelination of the axon. As a result, pain comes in two phases. The first phase is mediated by the fast-conducting AÎ´ fibers and the second part due to (polymodal) C fibers. The pain associated with the AÎ´ fibers can be associated to an initial extremely sharp pain. The second phase is a more prolonged and slightly less intense feeling of pain as a result from the damage. If there is massive or prolonged input to a C fiber, there is progressive build up in the spinal cord dorsal horn. This phenomenon is similar to tetanus in muscles but is called wind-up. If wind up occurs there is a probability of increased sensitivity to pain (Howard et al 1998).
Nociceptor neuron sensitivity is modulated by a large variety of mediators in the extracellular space (Hucho and Levine 2007). Peripheral sensitization represents a form of functional plasticity of the nociceptor. The nociceptor can change from being simply a noxious stimulus detector to a detector of non-noxious stimuli. The result is that low intensity stimuli from regular activity, initiates a painful sensation. This is commonly known as hyperalgesia. Inflammation is one common cause that results in the sensitization of nociceptors. Normally hyperalgesia ceases when inflammation goes down, however, sometimes genetic defects and/or repeated injury can result in allodynia: a completely non-noxious stimulus like light touch causes extreme pain. Allodynia can also be caused when a nociceptor is damaged in the peripheral nerves. This can result in deaf erentation, which means the development of different central processes from the surviving afferent nerve. With this situation, surviving dorsal root axons of the nociceptors can make contact with the spinal cord, thus changing the normal input (Howard et al 1998).
Pain fibres can be broadly classified into low and high threshold primary afferents. Low threshold afferents are myelinated fibres with specialised nerve endings that convey innocuous sensations such as light touch, vibration, pressure (AÎ²) and proprioception (AÎ±). High threshold afferents are thinly myelinated (AÎ´) or unmyelinated (C) fibres located in the dermis and epidermis, which convey pain and temperature.
Comparative properties of primary afferent fibres
Pain and temperature afferents do not have any specialised receptors; they use "free nerve endings". They are polymodal, i.e. they respond to more than one kind of stimulus, e.g. chemical, thermal or mechanical stimuli.
Pain fibres terminate mainly in the superficial dorsal horn (laminae I- II). AÎ´ fibres enter lamina I (and V) and synapse on a second set of neurons. These neurons will carry the signal to the thalamus and are part of the spinothalamic tract (STT). The C fibres enter the spinal cord and synapse on lamina I cells and lamina II interneurons - neurons that make synaptic connections with other cells within the local environment. The interneurons convey the signal to the STT cells that reside mainly in laminae I, IV and V. The axons of the STT cells project across the spinal cord to the STT, which is located in the ventrolateral quadrant of the contralateral spinal cord white matter.
The STT transmits information about temperature and pain, as well as "simple" touch (i.e. related to localisation of stimulus) and visceral sensations. It mediates the discriminative and arousal-emotional components of these sensations by separating out the "fast" (discriminative aspect) and "slow" (affective aspect) components of pain into different regions of the tract that are transmitted in parallel to the thalamus. Discriminative pain reaches the thalamus directly without making connections elsewhere in the nervous system, whereas arousal-emotional pain reaches the thalamus indirectly via connections with brainstem regions. Slow pain is also transmitted by other pathways such as the spinoreticular tract.
The STT may be divided into the lateral STT and the anterior STT. Pain and temperature is transmitted mainly in the lateral STT. The lateral-STT transmits the sensations of both fast and slow pain. The anterior STT conveys sensations of simple touch (stimulus localisation). The STT ascends the entire length of the cord and the brainstem, staying in about the same location all the way up. It is here in the brainstem that the different modalities separate out to terminate in different thalamic and brainstem nuclei. The fast pain STT axons terminate in the ventroposterior nucleus, which comprises the ventral posterolateral (VPL) and ventral posteromedial (VPM) and the posterior (PO) nuclei. These axons seem to mediate mainly the sense of "simple touch" and pain. These sensations are separated within the thalamus: neurons in the VPL and VPM do not respond specifically to noxious stimulation, whereas cells in the PO receive inputs from both low- and high-threshold afferents. These cells are associated with the conscious perception of pain.
The slow pain-STT axons innervate the non-specific intralaminar nuclei of the thalamus, and the reticular formation in the brainstem. These axons form at least part of the forebrain pain pathway associated with the affective quality (unpleasantness and fear of further injury) of pain and can be dissociated from the discriminative quality (the type and nature of the injury itself). The projections to the reticular formation may underlie the arousal effects of painful stimuli. The arousal itself may activate noradrenergic neurons in the locus coeruleus, and thus decrease the upward pain transmission. This may be an example of a negative feedback loop in the nervous system.
It has long been known that the STT is an important pain pathway because when it is damaged, pain and temperature sense is abolished on the contralateral side of the body below the lesion.
Comparison of central pathways for pain transmission
Spinoreticular tract (SRT)
Lamina I &IV, V
Lamina I, IV,V, (and VII, VIII)
Synapse in reticular formation
Ventral posterolateral (VPL)
Other midline nuclei
Parietal lobe (SI cortex)
Discriminative pain (quality intensity, location)
Affective-arousal components of pain
There are a few important receptors involved in the transduction of a pain signal. They are the ion channels transient receptor potential family and tetrodotoxin-resistant sodium channel. They are both found on C fibers which are important in the sensitisation process. Many chemicals cause peripheral sensitisation via these receptors. Bradykinin is a 9-amino acid peptide chain formed by proteolytic cleavage of its kininogen precursor, high-molecular-weight kininogen. Levels are increased with noxious stimulation. It activates G protein coupled receptors (BK2) which then activates protein kinase C. This increases activity at the ion channel in a G-protein coupled manner. Bradykinin also sensitises receptors through a protein kinase C independent manner. Bradykinin also contributes to vasodilation and increased vascular permeability of the injury site.
Prostaglandins are autocrine and paracrine lipid mediators that act upon neurons to sensitise them. They are formed by the action of cyclooxygenase on arachidonic acid. Prostaglandins, especially PGE2 and PGI are thought to activate protein kinases C and A. Hence nociception transmission is enhanced. Interestingly PGE2 may also be involved in the enhancement of activity at the central terminals of primary afferents at the spinal cord.
Substance P is an important neuropeptide in primary afferents, especially in a subset of C fibers. It is released by sensory nerve endings locally by noxious stimuli and also via the axon reflex. It activates the neurokinin-1 receptor. It causes increased vascular permeability, vasodilation and increased synthesis of prostaglandins.
Neurotrophic factors are produced in peripheral targets of nociceptors such as fibroblasts and mast cells and is over expressed in tissue injury. Although implicated more in chronic pain, inflammation and tissue damage increase their expression in the acute phase promoting thermal sensitivity. Nerve growth factor is such an example, which sensitise nociceptors to substance P and other noxious stimuli. They also exert long term gene expression changes in nerve cells.
As a response to inflammatory reaction of tissue damage, mast cells are attracted to the site. When activated they release histamines which, via H1 receptors, are important in smooth muscle contraction, vasodilation, pain and separation of endothelial cells. Mast cells also release prostaglandins. Increased blood flow caused by this and other agents encourages immune cells to reach the injury site.
Serotonin is another important mediator released from mast cells and platelets. Serotonin (5-HT), is known to be an algogen capable of directly (via ion channels) or indirectly (via protein phosphorylation) activating nociceptive afferent fibers.
Silent nociceptors, found in both visceral and peripheral targets of afferents neurons are activated by noxious stimuli such as tissue inflammation and are normally dormant and not reactive to innocuous stimuli. They can be recruited as part of tissue injury and contribute to hyperalgesia.
All the above are mediators which take variable time frames to occur. Hence, after an initial period post-injury, pain experience often becomes worse with further stimuli, even innocuous ones. This hyperalgesia and allodynia is commonly seen. The inflammatory 'soup' all conspire together, with one facilitating the other, to cause peripheral sensitisation.
The two main types of primary afferent neurons which respond to pain are the AÎ´ and C type fibres. These transmit thermal, mechanical and chemical induced pain. AÎ² fibres play a smaller part in mechanical and thermal type nociception.
In thermal pain (>45 and <5oC) thermal sensitive fibers alter firing thresholds and are interpreted as noxious. For mechanical nociception, the perception involves integrated activity of several afferents in the same region involving chemical mediators like 5-HT and ATP. In other chemical nociception, tissue damage or ischaemia release hydrogen ions, histamine and bradykinin which activate C-fibres mainly but also some AÎ´ fibers. Activation of primary afferents by these stimuli through receptors like TRPV1 and Nav1 initiate action potentials which then travel towards the central terminals.
The central terminations are on the dorsal horns neurons of the spinal cord. Dorsal horn neurons are organized into different laminae. Lamina I neurons receive inputs from AÎ´ and C fibres, and have little projections elsewhere, due to restricted dendritic trees. The neurons here have been characterized by their specific physiological responses. There are 'nociceptive' cells which correspond to the three main modalities of nociception. They have been identified to correspond to the first sharp pain and also the second burning indistinct phases of pain. Lamina II (substantia gelatinosa) also receives inputs from AÎ´ and C fibres. Neurotransmitters are released when the action potentials arrive at the laminae. Glutamate is the main excitatory neurotransmitter but Substance P and CGRP are also important. These dorsal horn neurons then send projections to the central nervous system for pain transmission, including the spinothalamic tract, spinomesenchephalic and spinoparabrachial tracts. The spinothalamic tract project to the thalamus which then sends projections to the somatosensory cortex for pain and temperature sensations.
Besides lamina I, lamina V in the dorsal horn is thought to be important for integration of pain information. They receive C fibres directly, interneurons from other laminae and larger myelinated fibres. The neurons here have been termed wide dynamic range neurons as they respond in a graded manner to innocuous and noxious pain. They are thought of as an integration centre for stimuli within the spinal cord and is dynamic in function.
Clinical pain, hence, depends partly on the interaction of these neurons. The landmark gate theory alludes to convergent mechanisms in this area. For example, larger fibers, when activated by touch or vibration can activate inhibitory interneurons resulting in decreased signal transmission to higher centres (TENS, rubbing). In addition to peripheral mechanisms, clinical or 'felt' pain phenomena of hyperalgesia and allodynia are also the result of central sensitization. Hyperexcitability of dorsal horn neurons can account for mechanical hyperalgesia. Sproutings of new terminals from AÎ² fibers to lamina II in the dorsal horn can also account for chronic allodynia. Other mechanisms accounting for central sensitisation include receptor changes centrally, neuronal cell death and second messenger signalling cascade changes.
Ascending tracts to the brain integrate sensory and affective-motivational meaning of noxious stimuli. From these centres, a descending modulation is initiated via centres like the periaqueductal and nucleus raphe magnus. These are known to be important in decreasing pain perception by sending projections to the dorsal horns. Via opioid, 5-HT, noradrenaline and GABA as mediators, primary afferent neuron signals can be attenuated via synapses within the dorsal horn. Mood, distraction and cognitions may thus augment pain perception via these descending pathways.
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