Innovations In Clinical Neuroscience

MAY-JUN 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 4 , N U M B E R 5 – 6 , M A Y – J U N E 2 0 1 7 ] 12 area, amygdala, striatum, thalamus, h ypothalamus, rostral ventromedial medulla, periaqueductal grey, pons (locus coeruleus), red nucleus, and medulla oblongata. 4 By conceptualizing this process of n eural transmissions of acute and chronic pain, pruritus, and nausea within the CNS and by better understanding CNS pathology and its potential effects on chronic sensory symptoms, clinicians might more accurately analyze and more effectively treat chronic sensory symptoms in their patients. PAIN Pain is a multimodal, complex experience that involves numerous neural sites, including peripheral nerves, the spinal cord, and higher brain centers. The specific receptive properties of thinly myelinated (A-δ fiber) and unmyelinated (C-fiber) nociceptors are determined by membrane-bound transducing ion channel receptors, which are sensitive to temperature, chemical stimuli, and mechanical forces. Upon activation, these ion channel receptors transduce an external stimulus into a change in membrane potential via the opening of a sodium/calcium channel or the closing of a potassium channel (nociceptive transduction or proportionate pain in response to identifiable noxious stimulus). 5 Nociceptive primary afferents release glutamate, activating postsynaptic glutamate receptors on spinal cord dorsal horn neurons. 6 The second-order neurons cross over at the spinal cord, then travel up the ascending tracts, mainly via the spinothalamic tract to the thalamus. The third-order neurons project to somatosensory cortex and then to prefrontal cortex and amygdala. 7 A confluence of processes, including structural reorganization and sensory gating changes within these circuits, decreases inhibition of these circuits and promotes chronic pain. 8 One mechanism used to describe the genesis of chronic pain is peripheral sensitization, which constitutes a decreased threshold and increased responsiveness of nociceptors because of post-translational changes in and altered trafficking of transducer receptors and ion channels. This is induced by local i nflammatory mediators, and results in pain hypersensitivity symptoms confined to the site of the inflamed tissue. This is referred to as the zone of primary hyperalgesia. 9 I n contrast, chronic neuropathic pain often extends spatially beyond the area of the initially involved root or nerve to create a zone of secondary hyperalgesia, which often becomes independent of the initial noxious event. These symptoms cannot be explained by changes in the peripheral nervous system, but rather reflect changes in spinal and supraspinal networks that culminate in a functional shift of the sensory system from physiological high-threshold nociception to pathological low-threshold pain hypersensitivity. 9 One major mechanism responsible for this shift of the sensory system is central sensitization, defined broadly as the "increased responsiveness of nociceptive neurons in the CNS to their normal or subthreshold afferent input." Activity- dependent mechanisms of central sensitization include homosynaptic long- term potentiation (i.e., exaggeration of nociceptor responsiveness) and heterosynaptic potentiation (i.e., recruiting low threshold Aβ fiber inputs into the pain pathway). These mechanisms might be driven and sustained by ectopic activity in the injured nerve. 9 In addition to the strengthening excitatory synapses in the spinal cord, loss of inhibition by decreasing gamma aminobutryic acid (GABA)-ergic and glycinergic tone also contributes to central hyperexcitability and can be produced by peripheral nerve lesions. Increasing spinal inhibition with intrathecal GABA or by activation of inhibitory interneurons results in an antinociceptive effect, while blocking inhibitory transmission (e.g., by selective ablation of glycinergic dorsal horn interneurons) leads to lowered pain thresholds and the development of hyperalgesia and tactile allodynia. 9 PRURITUS Chronic pruritus (CPr), or itch lasting six or more weeks, is a major symptom in numerous dermatological and systemic diseases. Similar to chronic pain, CPr ( colloquially known as "itchiness") can have a dramatic impact on the quality of life and can worsen the general condition of the patient considerably. 10 Itch is described as an unpleasant s ensation that evokes the desire to scratch. 11 It is a distinct sensory modality from pain, though both are initiated and mediated by primary sensory neurons with their cell bodies in the dorsal root ganglia (DRG) or trigeminal ganglia. These neurons vary in their somal sizes, expression of ion channels and receptors, regions that they innervate, and electrophysiological properties. Small- diameter DRG neurons with unmyelinated axons (C-fibers) are an important type of neuron for transmitting both pain and pruritus. Despite this similar pathway of neural transmission, pain and itch are perceived differently and cause distinctive behavioral responses. For example, pain stimulus might elicit retraction to avoid tissue injury, while an itch stimulus might instigate scratching to eliminate irritants. 11 The peripheral pathway of itch is initiated when pruritogens stimulate skin receptors that generate a signaling cascade and action potentials. 1 2 Two types of itch-sensitive pathways have been identified. 13 These include a histamine- stimulated pathway that uses mechanically insensitive C-fibers (CMi) and a cowhage-stimulated pathway mediated by protease-activated receptors (PAR2) that primarily uses polymodal C- fibers. 13 Just as various C-fibers play a role in pruritus, many different types of receptors can coexist on a single fiber thus enabling primary neurons to function in a polymodal manner. 9,12,14 Certain substances and physical factors, such as temperature, can activate C-fibers and trigger the release of neurotransmitters in the skin via an axon reflex. The itch signal proceeds along spinal nerves' peripheral processes, spinal ganglia, spinal nerves' central processes, and spinal cord's dorsal root and dorsal horn. 11 After this peripheral pathway, the central pathway of itch begins with a synapse of a primary to secondary afferent neuron in the dorsal horn. The axons of the secondary cells cross over and ascend in the contralateral

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