How the Brain Mediates and Controls the Sensation of Pain - Term Paper Example

Proposal: How the Brain Mediates and Controls the Sensation of Pain Introduction In the last twenty or so years, until the introduction of non-invasive brain imaging technologies, the understanding of brain functions in processing pain was very much limited. Most studies were also based on animal studies and human electromagnetic analysis. The more specific roles of the different parts of the brain, most specifically the cerebral cortex were unsettled. Practitioners were not sure about the participation of the cerebral cortex in pain perception and even doubted any participation of the cerebral cortex in pain perception. Now, with the advent of Magnetic Resonance Imaging, and other non-invasive assessment technologies, the less invasive, but more direct and accurate examination of the brain has been made possible. The areas of the brain which now respond and which manage pain perception and sensation can now be laid out and understood by practitioners. The more technical processes of pain sensation and mediation can now be assessed and evaluated. It is popular knowledge that the brain controls and manages all types of sensation and feelings in our body. Understanding the more specific patterns which explain these control functions in the brain are more complicated and need a more thorough analysis. This study shall now seek to discuss how the brain mediates and controls the sensation of pain. It shall first present an anatomical discussion of pain sensation, and then a deeper analysis of brain mediation and control of pain shall be carried out. An emphasis on the central mechanisms of pain and the biological and neurochemical processes underlying them shall be presented in this paper. This study is being undertaken with the purpose of establishing a clear and comprehensive understanding of the brain functions as it mediates and controls pain sensations. With this study an improved basis for managing pain can be established and implemented in the healthcare practice. Various processes in the peripheral and central nervous systems are accountable for the sensory symptoms, including the spontaneous and the evoked pain sensations in peripheral neuropathies. In effect, sensitized nociceptors can cause secondary shifts in the central activity processing which causes hyperactivity, making input from the Aβ fibers to be felt as pain (Baron, 2000). As a result, these patients spontaneously experience pain alongside sensitivity to heat. A similar analysis by Pawl (1999) discussed pain as assessed by the brain through function images. In his analysis, he was able to confirm that during the pain experience, increased activity in the sensory pathways from the thalamus to the sensorimotor cortex was apparent. Pawl (1999) also established that the contralateral hippocampus became active during experimental heat pain; during acute pain, activity in the amygdala was also increased. In studies covering chronic pain, the nociceptive disruptions often activated the same areas; but these same areas were manifestly less active in instances of pain which originated psychogenically (Pawl, 1999). This analysis implies the more apparent pathways for pain depending on the kind and the source of pain. Based on the analysis by Yaksh (1999), the regulation of afferent processing is at the level of the spine. Yaksh analysis is more detailed in terms of the involvement of the NMDA and the NKI receptors. Aside from systems which can reduce excitability, the post-tissue injury pain condition is marked by the upregulation of gain. As a result, continuous small afferent excitation triggers a cascade which is instigated by the release of amino acids and peptides. With the activation of the NMDA and NKI receptors, there is a rise in intracellular calcium and the stimulation of the kinases and the phospholipase A2 (Yaksh, 1999). The NMDA then acts as the phosphorylate membrane channels and receptors; while the NKI causes the formation of the arachidonic acid and the stimulation of the nitric oxide synthase (Yaksh, 1999). As the interneurons are stimulated, the higher order projection neurons via NMDA receptors are also stimulated. This causes an increase in the intracellular calcium, as well as the stimulation of the phospholipase A2 (Yaksh, 1999). Cyclooxygenase and prostaglandins are also formed. With the phosphorylation of intracellular proteins, there is an added sensitivity to the pain receptors thereby leading to the pain experience (Yaksh, 1999). In considering the manifestation of acute pain caused by tissue injury stimuli seen in postoperative pain, there are various elements involved. Pain receptors transduce energy into generator and action potentials (Sorkin and Wallace, 1999). Nociceptors are considered unencapsulated nerve endings which are triggered by stimuli which cause tissue damage. Some of these receptors respond to chemical or noxious heat and others respond to noxious stimuli (Sorkin and Wallace, 1999). Pain is based on stimulating fibers which are specific in triggering real tissue damage. Activation of the Aδ nociceptors causes a brief prickling sensation and the activation of the C nociceptors cause poorly localized burning sensation (Sorkin and Wallace, 1999). The authors considered their discussion on noxious stimuli which is more involved in actual tissue damage. This is another aspect of the pain experience which is essential in the analysis of pain and the brain processing. Tissue injuries cause sensory shifts which can sometimes be measured in the clinical setting. The response to stimuli inflicted near the injury site is often enhanced; these involve the peripheral and central mechanisms (Price, 2000). The increase of sensitivity which covers ininjured areas after surgical incision largely depends on the excitability of the central neurons (Urban and Gebhart, 1999). These shifts are seen first on the spinal level, but supraspinal areas also impact on the maintenance of secondary hyperalgesia. As perceived by the spinal cord, peripheral tissue injury is seen as increased afferent input from the active nociceptors and the inactive nociceptors (Urban and Gebhart, 1999). Apfel (2000) discusses that neurotrophic factors have significant roles in the transmission of pain. Nerve growth factors seem to be particularly important as it is crucial in the development of sympathetic and sensory neurons which are acting as nociceptors. It triggers the expression of neuropeptides seen in pain transmission and coordinates with cellular mediators of inflammation (Apfel, 2000). Using nerve growth factor antiserum manifests the role of the nerve growth factor in reducing pain and inflammation (Apfel, 2000). In a paper by Brooks and Tracy, (2007) the authors set out to review the literature involving imaging of the spinal and the supraspinal pathways from nociception to pain perception. In the process, they were able to establish through the current technologies in the medical practice, non-invasive examinations on the pain processing network. The PET scans and fMRI studies have made possible the resolution of the main elements of the pain network (Brooks and Tracy, 2007). Pain was discussed in their study as an “unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (International Association for the Study of Pain, as cited by Brooks and Tracy, 2007, p. 20). In effect, although pain is triggered by stimuli, it may also be experienced even without such stimuli. The cortex of the brain is highly involved in pain sensitization and management. The main structures involved are the primary sensory cortex (SI), secondary sensory cortex (SII), the anterior part of the insula and the cingulate gyrus. According to Bushnell, et.al., (1999), the SI cortex has a significant role in pain processing, particularly in the discriminative areas of somatic sensation; it also plays a role in pain localization; and it is involved in both the perception and modulation of the painful and non-painful somatosensory sensations. A study by Maihofner, et.al., (2006) considered the complicated cortical network which is said to encode the human pain experience. Their study subjected about 14 subjects to painful mechanical and heat stimulations. The subjects were assessed for their sensory-discriminative and affective-motivational pain aspects. Based on imaging studies, there was an increased activation of the bilateral secondary somatosensory (SII) during mechanical impact pain; in effect, activations of the SII were very much related with scores for sensory-discriminative aspect of mechanical impact pain. Their study further linked SII with the sensory-discriminatory pain experience. Other studies also considered the areas discussed above and their contribution to pain processing. In a study by Jackson, et.al., (2005), the authors discussed that pain is a psychological condition with a significant evolutionary importance; it can be experienced by oneself and it may also be perceived in others. People’s reaction to a person’s physiological pain can be reflex and may be blended in with avoidance motor reactions. But, in order to truly appreciate how a person is suffering from the pain, a person is more likely to introspectively recall how it felt or to consider the perspective of the other (Jackson, et.al., 2005). Although the experience of pain is a complicated and mostly subjective process, the processing of pain comes from a combination of perceptual sensory and emotional elements (Ploghaus, et.al., 2003). Various brain regions have been constantly associated with pain processing, mostly in the anterior cingulated cortex, the insula, and in some instances the thalamus and the primary somatosensory cortex (Bushnell, et.al., 1999). Different brain imaging tests give support to the dissimilarity sometimes drawn from the pain literature between the sensory-discriminative elements of the pain processing, and the emotional one. For example, the primary SI and secondary SII sensory cortices are mostly concerned with the sensory and discriminative elements of pain (Bushnell, et.al., 1999); the anterior cingulated and the insula cortices describe mostly the affective-motivational component (Rainville, et.al., 1997). As assessed by Bushnell, (1999), it is complicated to disconnect the sensory and affective elements within the traditional pain process because they are very much related with each other. Even as the neural processing of individual pain perception has already been significantly assessed, not much is known about the perception of pain in others; and yet this element of pain perception has significant psychological implications (Jackson, et.al., 2005). A single-cell recording study in pre-cingulotomy patients has indicated that neurons in the anterior cingulated cortex involved in pain perception can release during the actual sensation and during the observation of the similar stimuli applied on another person; this suggests that this region has a role in the pain perception in others (Hutchinson, et.al., 1999). A study by Singer, et.al., (2004) expressed that feeling a pain and seeing pain about to be inflicted on a partner can cause changes in the hemodynamic processes of the anterior insula, the ACC, the brainstem, and the cerebellum. In effect, this study established that the feeling of a momentary pinprick and seeing another person go through the similar stimulation manifested activities in the right dorsal ACC (Singer, et.al., 2004). Dostrovsky (2000) sought to discuss the role of the thalamus in the manifestation of pain. He (2000, p. 245) discusses that the thalamus “receives and processes all nociceptive information that is destines to reach the cortex”. It is therefore a major element of the pain system. Even as perceiving pain is considered to manifest at the level of the cortex, the thalamus cannot be ruled out in some elements of pain perception. Due to the reciprocal relations of the thalamus and the cortex, there are expected crucial relations between the two structures, however, the role of the corticothalamic projections need to be made clear (Dostrovsky, 2000). The thalamus may indeed have a crucial role in the pathophysiology of the central pain; and they may also have a function in other areas of chronic pain (Dostrovsky, 2000). The function of the thalamus in pain mediation is not clearly understood, mostly because of the fact that the ascending nociceptive pathways end in several areas, and because some of these pathways are not particularly specified in the anatomical sense. Moreover, neurons which respond to nociceptive stimuli have been noted in widespread areas of the medial thalamus and in other regions of the lateral and posterior thalamus; however, it is still unsure whether these areas have anything to do with pain mediation. The authors Brooks and Tracy (2007) discussed the physiological elements of pain perception and also the psychological components in relation to imaging studies. They also discussed the modulation of pain by the brain. The link between pain intensity and peripheral stimulus which causes it is based on different factors including anxiety, depression, and expectation or anticipation. These psychological factors are currently being evaluated physiologically and pharmacologically through fMRI (Brooks and Tracy, 2007). These factors are also managed by overt and covert data including general cues which indicate the significance of the stimulus and the corresponding response to it. The primary impact of distracting the patients during moments of pain is mostly seen with the increased activity in the medial pain system; moreover, decrease in the activation of the lateral pain system also manifests with the application of distraction techniques (Petrovic, et.al., 2000). The latest studies on functional and connectivity assessment indicate that higher activities in the prefrontal and cingulated cortices during moments of distraction reduces pain perception through the descending pain modulation system, mostly through the antinociceptive pathways (Valet, et.al., 2004). Ploghaus and colleagues (2001) have also considered the impact on anticipation of a pain stimulus on regional brain activity. The authors carried out their study by using novel conditioning protocol on healthy volunteers undergoing fMRI while being shown two intensities of thermal stimulation. Colored lights were used in order to provide early signals on the two stimuli – one indicating pain and the other indicating warmth. Through the high temporal coverage of the fMRI, the brain regions related to pain experience were identified. The test also identified that anticipation of pain activated the rostral anterior insula and medial prefrontal cortices; during the pain experience itself however, the insula activity was caudal and within the anterior cingulated cortex (Ploghaus, et.al., 2001). In effect, anticipation of pain potentially exacerbated the actual pain experience in the same way as anxiety. In a study by May (2007) the author sought to analyze neuroimaging of the brain in pain. In her study, it was established that through PET scans patients with migraine without aura manifested with higher rCBF values during their acute attack. Similar to the Ploghaus study with actual pain experience, activation was also seen in the inferior anterocaudal cingulated cortex. In May’s study however, the visual and auditory association cortices were also activated. Her study also indicated that brainstem activation is specific for migraine; however, it was considered to be ipsilateral to the pain and in a different location. The same area was also activated for chronic pain sufferers. Zhuo (2007) carried out his study in order to establish the neuronal mechanism in neuropathic pain. The author discussed about the anterior cingulated cortex (ACC) as the major area of the brain related to pain perception. This was already seen in the two previous studies. The ACC has various layers of pyramidal cells, as well as local interneurons. Layers II and III have pyramidal cells and the neurons in layer II and III are recipients of inputs from the medial thalamus. The medial thalamus is the main relay station for somatosensory data, pain included (Zhuo, 2007). The neurons in layer V are bigger than those in layers II-III, and IV; they also receive sensory data, this includes noxious data. The ACC neurons connect with other ACC neurons in the other hemisphere via the callosal fibers; they also connect with the cortical areas on the same, as well as the opposite sides of the brain. The ACC neurons react to the noxious and nonnoxious stimuli. The non-pyramidal cells are considered inhibitory neurons which have GABA, as well as neuropeptides. These cells manifest decreased spike responses to the peripheral noxious stimuli, whereas the pyramidal cells manifest excitatory and higher spike reactions (Zhuo, 2007). Even as the soma of the pyramidal cells are only found in layer V, its peripheral branches cover the other layers of the ACC, which in some cases may include layer I. Therefore, the manifested responses seen in the layer V cells may include synaptic reactions seen at different layers of the ACC. In the local circuitry, the inhibitory neurons sometimes gain innervations from the pyramidal cells, and then “release GABA onto the perisomatic region of the pyramidal cells” (Zhuo, 2007, p. 2). According to differences in the pattern of spike activities, the pyramidal and the inhibitory neurons can be seen during MRI scans and in ECG tests. Deleo (2006) sought to discuss the basic science involved in pain. The author discussed that in the peripheral nerves, the myelinated A delta and the beta fibers and the unmyelinated C fibers are the two afferent axons which transmit impulses based on pain and inflammation. The first group transmits cold and well-localized pain sensations and the second group transmits pain which is mostly localized or which is due to heat or mechanical triggers. With tissue damage, these nociceptors are then sensitized and the release of the prostaglandins, potassium, histamine, leukotrienes, brandykins, and substance P (all analgesic mediators) are triggered (Deleo, 2006). This is the reason why the systemic and nonsteroidal anti-inflammatory drugs and aspirin are used because they reduce the production of the prostaglandins among patients experiencing acute pain. The fibers actually synapse in the dorsal horn of the spinal cord and in this area, modulation happens. When the gate control theory by Melzack and Wall is considered, “the neural signs in the dorsal horn from the peripheral input will increase or decrease the flow of impulses to higher processing centers in the central nervous system” (Deleo, 2006, p. 59). The ascending pathways carry messages higher and the descending pathways prevent the release of substance P in the substantia gelatinosa in the dorsal horn. The interneurons may directly transmit it or it may be indirectly released by the opiods. The transmission of data in the synapses between the nociceptors and dorsalhorn neurons is often mediated by the chemical neurotransmitters in the central nerve ends. With some of these nerves, constant stimulation may lead to continuous and chronic pain experiences. Anand, et.al., (2007) considered psychological factors and their impact on pain. Their study discussed that hypervigilance is a normal response to a perceived threat; this can be further associated with the experience of visceral sensations (palpitations, butterflies in the stomach, urgency during fearful experiences). Based on imaging studies, some patients with FGIDs are continually hypervigilant to physiological stimuli. Those with IBS often manifest in times of stress; based on animal studies, pain is associated with stress (Anand, et.al., 2007). The Corticotropin-releasing factor (CRF) is seen in pain caused by stress; the hormone is released by the hypothalamus during intense limbic activity. The causes of hypervigilance and hyperresponsiveness to stress with others not feeling such is unclear; however based on animal studies, previous childhood adversities may be considered a factor; a life stressor may also be another cause (Deleo, 2007). The authors cite studies which indicated a link between gastric hypersenstitivity, epigastric pain and burning and neuroticism, somatization, history of psychological abuse. In effect, these elements mediate in the processing of pain by the brain and impact on the efficient control and management of the pain experience. A discussion by Boyce-Rustay and Jarvis (2009) emphasized that specific sensory mechanisms impact on physiological pain, on pain caused by tissue damage, and on pain caused by injuries to the nervous system. However, as nociceptive pain can come and go, neuropathic pain can persist even after the injury-causing event has passed and tissue damage has healed. Abnormal processing of sensory data by the nervous system can arise. Nerve pain can either be peripheral or central. Peripheral is painful peripheral mononeuropathy and polyneuropathy and central can be caused by stroke or spinal cord damage (Boyce-Rustay and Jarvis, 2009). Neuropathic pain can be caused by different conditions or situations including trauma to the nerves, toxins, neurological illnesses. After nerve injury occurs, changes in the nervous system can be seen for indefinite periods. It may then occur even without stimuli or can manifest pain disproportionate to the intensity of the stimulus. Neuropathic pain can also manifest as something constant or intermittent, as well as with other sensations like tingling, prickling, shooting, and spasms (Boyce-Rustay and Jarvis, 2009). It can cause the release of pronociceptive mediators which trigger sensitization in the peripheral nerve terminals then cause phenotypic changes in the neurons and higher excitability in the spinal cord dorsal horn neurons. The descending supraspinal systems act to modify the nociceptive responses. With this, various receptors, transmitters, second transmitter systems are involved in the pain pathways (Boyce-Rustay and Jarvis, 2009). Peripheral sensitization can be seen with the sensitization of nociceptors from inflammatory mediators, neurotrophic factors during tissue damage, and by pro-inflammatory cytokines. There may also be peripheral sensitization caused by intense or prolonged action in sensory afferents mediated by activity of voltage-gated sodium and calcium channels (Boyce-Rustay and Jarvis, 2009). Through peripheral sensitization, central sensitization can be developed and maintained. In central sensitization in the brain, there is persistent spontaneous dorsal horn neuron activity, with responses mostly seen in low intensity stimuli. With central sensitization, pain is spread to undamaged tissue. It causes different changes in the spinal cord which may impact on dorsal horn neuron excitability. Central sensitization impacts more on neuropathic pain whereas both central and peripheral sensitization impacts on nociceptive and chronic pain (Boyce-Rustay and Jarvis, 2009). For which reason, established pain is often more difficult to manage than acute pain mainly due to the maladaptive changes which can manifest in the CNS. The neurons, as well as the glial cells and infiltrating mast cells impact in the generation and maintenance of central sensitization. With the activation of the pro-nociceptive inflammatory and neurotrophic messengers, the CNS responding to chronic pain would involve changes or activation of the neurotransmitter systems. In effect, there is an increase in the glutamergic activity and an increase in the GABA-ergic inhibitory neuromodulation at the dorsal spinal horn. Changes in the balance of inhibitory systems can include the activation of intracellular signaling cascades as well as inclusion of the neurotrophic neuropeptides. All in all, chronic pain is linked with skewed patterns of neurotransmission at different levels of neuro-axis with significant pathway redundancy. As a result, even without ongoing injury, chronic pain, by itself can be considered a disease (Boyce-Rustay and Davis, 2009). Vranken (2009) took the time to evaluate the mechanisms and treatment of pain in his paper. He also discussed the peripheral and central processes in neuropathic pain. In his discussion of central processes, he set forth that pain stimulus normally leads to the release of excitatory amino acids (glutamate, aspartate), the neurotoxins (BDNF) and peptides from the central terminals of nociceptive A and C fibers of the dorsal horn. The BDNF is known to activate the tyrosine kinase receptors B; the substance P reacts with the neurokinin receptors and the neurokinin A interacts with the neurokinin 2 receptors and they also impact on the induction of dorsal horn sensitization (Vranken, 2009). The CGRP retards the metabolism of the SP and thereby increases the discharge of SP and EAA. Therefore, the CGRP works to improve sensitization. The EAAs react with receptor subtypes and with ionotropic receptors like AMPA, NMDA, and Kainate; they also react with metabotropic glutamate receptors. With noxious stimuli, glutamate release reacts with postsynaptic AMPA receptor causing an initial and excitatory postsynaptic potentials lingering for some milliseconds. Then, VDCC is triggered and is followed by depolarization. With intensive and persistent noxious stimulation by glutamate, a cumulative depolarization is seen and this leads to the elimination of the Mg2+ ion plug from the NMDA receptor (Vranken, 2009). Glutamate causes dual excitatory actions by binding the AMPA and NMDA receptors; this causes cell depolarization and Ca2+ influx. Higher levels of Ca2+ then trigger activation of the protein kinases causing phosphorylation of NMDA receptors and improved relief of the Mg2+ block (Vranken, 2009). Such changes can causes shifts in the signal transduction which then impacts on the increase of synaptic strength. Furthermore, the activation of the presynaptic NMDA receptors on central terminals of the PAF activates SP and EAA causing the excitability of the second-order neurons of the dorsal horn (Vranken, 2009). The metabotropic glutamate receptors have an important role in higher calcium release; and the stimulation of the NMDA receptor causes central sensitization. Consequently, the sub-threshold noxious input can trigger postsynaptic second-order neurons. The central sensitization is seen as an overstated or inflated response to harmful stimuli, an increase of pain sensitivity beyond the area of injury, and as a decreased threshold in eliciting pain (Vranken, 2009). The C-fiber output triggers the increase in excitability in the course of the stimulus (wind-up phenomenon). When this phenomenon is started, the obstruction of the peripheral nociceptive input may not necessarily stop the dorsal horn neurons from firing. Due to peripheral nerve injury the AB fibers branch into superficial layers of the dorsal horn in order to ensure corresponding interactions with the nociponsive neurons. This may cause innocuous stimulation to be wrongly seen as toxic. Low-threshold mechanical stimuli activating the AB fibers may cause the excitability of the neurons which then results to pain. After the peripheral nerve injury, the microglia, oligodendrocytes and the astrocytes in the dorsal horn are activated; they then release proinflammatory mediators which regulate pain processing by impacting on the presynaptic release of neurotransmitters and postsynaptic excitability (Vranken, 2009). The neurotrophins, such as the NGF and the BDNF are also released. They enhance pain. With microglial activation, the self-propagating mechanism of enhanced cytokine expression is triggered; this is responsible for the cascade of inflammatory responses in the CNS. The activated glia triggers the increased release of nociceptive neurotransmitters; it also increases activity of the nociceptive second-order neurons causing significant changes in the spinal cord. With higher emphasis on the roles of these cells, new therapeutic strategies may be created in the management of neuropathic pain (Vranken, 2009). Conclusion The brain mediates and controls pain via several pathways and processes. Mainly, the brain’s cortex plays a crucial role, as well as the thalamus. The roles of the brain in central processing and perception all impact on the actual sensation of pain. Brain imaging studies indicate cortical and sub-cortical substrate which is at the very core of pain perception. There is no one area of the brain which is involved in pain perception; instead, there is a network of somatosensory, limbic, and associative elements which receive similar inputs from these pathways. Pain triggers early activation of S2 and IC which plays a major role in sensory-discriminative roles of pain. The major affective and motivational quality of pain is manifested by the interplay of different regions of the cingulated gyrus. 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