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Different stimuli applied to the skin can cause tissue damage, and information about this damage is conveyed to the brain via specific pathways. The resulting pain can be either acute or chronic. Describe briefly, the difference between acute and chronic pain (10%). Describe the primary afferent and central pathways that convey information about acute (transient) tissue damaging stimuli; how is information about fast and slow pain differentiated (60%). What are the spinal and central consequences of nociceptor stimulation that subserve the protective functions of acute pain? (30%).
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Pain is defined as ‘the unpleasant sensory and emotional experience associated with real or potential tissue damage, or described in terms of tissue damage by the International Association for the Study of Pain’ (Carpenter and Reddi, 2012). Pain can be categorised as acute or chronic, depending on the length of time the pain is felt. The general pathway to the detection of acute pain involves nociceptors (detectors of noxious stimuli), their nerve fibres and then anterolateral tracts in the spinal cord to different areas in the brain and brainstem. As a part of nociception, there are fast and slow transmissions of information about the noxious stimuli. The information provided by this process can then be used to form appropriate responses to prevent further damage to the body.
Acute pain is triggered by an injury or disease and warns the body of potential damage, so that it can form responses that reduce harm to the body, through actions such as avoidance or rest. The pain then ceases when the injury heals. Chronic pain is defined as lasting for over 6 months, persisting even when the trauma has healed and so unlike acute pain, chronic pain does not provide a useful biological function (Grichnik and Ferrante, 1991). Cancer or the treatment of it can be a cause of chronic pain because as tumours invade tissues, they may injure nerves, causing peripheral neuropathy. As a result, after the cancer has been treated, pain can still be felt (Mantyh et al., 2002).
Nociceptors and their nerve fibres makeup the primary afferent pathway to the spinal cord in the first step toward the perception of acute pain. The two main types of nociceptive nerve fibres are C fibres (the most common) and Aδ fibres, however there are a few Aβ fibres involved in high threshold mechanoreception. Aδ fibres are thinly myelinated and have a larger diameter than C fibres, that are unmyelinated, allowing Aδ fibres to transfer action potentials more quickly at 5-30 m/s compared to 1.0 m/s in C fibres (Kandel, Schwartz and Jessell, 2000). As a result, the sharp, first pain is carried mainly by Aδ and so provides information about mechanical stimuli rapidly. It gives good special discrimination due to their small receptive fields, so that the person can determine what has happened to their body and where. The second pain comes later as a more agonising pain with less information about the location of the noxious stimuli but more information about the pain intensity. It is this second pain relayed by C fibres that aims to cause the person to change their behaviour (Squire, 2013).
The nociceptors are free nerve endings that terminate in the skin, joints, muscles, bones and viscera, which display either slow or no adaptation and there are a wide variety of types that detect different noxious stimuli. The combination of protein channels in their membranes gives them this specificity and examples of this are provided in figure 1. High threshold mechanoreceptors, stimulated by powerful pressure, have mainly C fibres, but also some Aδ and Aβ fibres. Thermal nociceptors respond to extreme temperatures of over 40 ºC and under 5 ºC, with different channel receptors responding to specific temperatures and substances. For example, capsaicin found in hot peppers activates the TRPV1 receptor that also responds to temperatures of over 42 ºC (Squire 2013). These nociceptors have both C and Aδ fibres. Polymodal nociceptors can be activated by two or more noxious stimuli types and the signals are carried by the majority of C fibres. Silent nociceptors do not normally fire in respond to noxious stimuli, however they become activated after tissue damage or inflammation. These signals are also carried by C fibres (Kandel, Schwartz and Jessell, 2000).(Basbaum et al., 2009)
Figure 1: Examples of the protein channels found in thermal, peptidergic and nonpeptidergic polymodal nociceptors. Heat sensitive TRPV1 channels are present in both thermal and polymodal nociceptors. Other channels include TRPA1, a chemoreceptor, and mechano-transduction channels (Basbaum et al., 2009).
In the primary afferent pathway, nociceptive fibres enter the dorsal horn of the spinal cord and branch up and down to different spinal segments through the Lissauer tract before terminating (Bear, Connors and Paradiso, 2007). Noxious Aδ fibres synapse at laminae I and lamina V. C enters at the substantia gelatinosa (lamina II) but also contacts neurons in lamina V directly by its dendrites, or indirectly using excitatory interneurons. Glutamate is the major excitatory neurotransmitter used in these dorsal horn synapses and this stimulates AMPA-type glutamate receptors. C fibres also release neuropeptides such as substance P that evoke slow excitatory postsynaptic potentials that heighten and extend the actions of glutamate. Conversely, inhibitory neurons release GABA and (Kandel, Schwartz and Jessell, 2000). There are then multiple ascending nociceptive pathways, with the major three being the spinothalamic, spinoreticular and spinomesencephalic pathways that are illustrated in figure 2.
In the anterolateral system, the spinothalamic pathway consists of second order neurons that decussate and then project directly from the dorsal horn of the spinal cord to the VPL (ventral posterolateral) and VPI (ventral posterior inferior) nuclei of the thalamus. Third order neurons starting here then terminate in several cortex areas including the somatosensory cortex and cingulate gyrus and insula. (Squire, 2013). The somatosensory cortex indicates the location and intensity of the noxious stimuli, while as part of the limbic system, the cingulate gyrus contributes to the emotional component of pain and lastly the insular cortex that influences the overall pain response due to integration of sensory, affective and cognitive components. (Kandel, Schwartz and Jessell, 2000).
In the spinoreticular pathway, neurons project to the medullary-pontine formation, a part of the reticular formation, and synapse with neurons that ascend to the thalamic intralaminar nuclei as well as directly to the cerebral cortex to activate the forebrain and increases alertness (Kandel, Schwartz and Jessell, 2000). Neurons from the thalamic intralaminar nuclei project to various parts of the cerebral cortex where pain becomes conscious. Spinomesencephalic axons terminate in the mesencephalic reticular formation and the periaqueductal grey which descending pain modulation is primarily controlled (Squire, 2013).
There are several other collateral terminations of these three tracts. For example, the spinoparabrachial tract travels from the spinomesencephalic tract to the parabrachial nuclei. From here, neurons project to the amygdala, which is involved in emotion. Another key example is the terminations in the hypothalamus that lead to autonomic and endocrine effects such as vomiting and sweating (Kandel, Schwartz and Jessell, 2000). Together, these ascending pathways contribute to the perception of pain along with the primary pathways can contribute to the consequential protective responses of the body.
Figure 2: The three major ascending nociceptive pathways (Kandel, Schwartz and Jessell, 2000).
One initial response to a harmful, noxious stimulus is neurogenic inflammation, which is also known as the axon reflex. A branch of a C fibre will be stimulated by the noxious stimuli and will send action potentials to other peripheral branches of the C fibre as well as along the axon to the CNS. These peripheral branches release substance P and calcitonin gene-related peptide (CGRP) that act upon the smooth muscle of peripheral blood vessels and on mast cells. Vasodilation of the peripheral blood vessels increases blood flow to this area, to cause plasma extravasation, white blood cell and platelet adhesion. Mast cells are also stimulated to produce histamine that further contributes to the inflammatory response and activates other sensory nerve endings. The purpose of this is to provide the damaged tissue with the components it needs for protection from the external environment and reparation (Rosa and Fantozzi, 2013). Hyperalgesia is also an effect of this axon reflex. The oedema causes extracellular fluid pH to decrease from 7.4 to below 6 and this change in H+ ion concentration increases the sensitivity of the C fibre nociceptors. Some of the neighbouring nociceptors may be silent nociceptors that are activated by these changes and so become responsive to noxious stimuli that they will not have responded to under normal conditions (Squire, 2013).
Neurogenic inflammation causes peripheral sensitisation as there is an increase firing rate of Adelta and C fibres from peripheral nociceptors. Central sensitisation occurs in the dorsal horn of the spinal cord, where second order neurons in lamina I to V become more responsive as a result of repetitive C fibre firing. This ‘wind-up’ effect is due to the activation and opening of receptors and ion channels such as the N-methyl-D-aspartate (NMDA)-type receptors that responds to glutamate (Haines and Mihailoff, 2018). Activation of kinases in the dorsal horn neuron leads to the upregulation of the expression of receptors and protein channels. The process causes heightened sensitivity to both noxious and innocuous stimuli, causing allodynia and hyperalgesia (Kandel, Schwartz and Jessell, 2000). This increased sensitivity can cause further behavioural changes in the person, as they try to protect the injured area from innocuous stimuli such as gentle touch. This avoidance gives the injury more opportunity to heal.
Another response is due to fibre collaterals that terminate on interneurons in the spinal grey matter. These connections participate in the circuits that mediate spinal reflexes such as the flexor withdrawal reflex (Squire, 2013). The nociceptive input activates interneurons that excite motoneurones of all the flexor muscles in the affected limb, to withdraw it from the painful stimulus. Simultaneously, extensor motoneurons are inhibited to cause the relaxation of the antagonistic muscles and this process is known as reciprocal innervation. When a painful stimulus is applied to a foot, the crossed extensor reflex illustrated in figure 3, is used to provide postural support and balance. Branches of an excitatory interneuron stimulate the motoneuron of the ipsilateral leg flexor and the motoneuron of the contralateral leg extensor. Inhibitory interneurons then cause the relaxation of the antagonistic muscles through their relative motoneurons (Kandel, Schwartz and Jessell, 2000).
Figure 3: The crossed-extensor reflex. The excitatory interneurons are red, the inhibitory interneurons are blue, and the motoneurons and white and red (Kandel, Schwartz and Jessell, 2000).
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