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 ] 13 spinothalamic tract and synapse onto t hird-order neurons in the thalamus. The axons of the third-order cells then project diffusely to cortical and subcortical regions. 15 Scratching might relieve itch by inhibitory neurons within the spinal cord o r by top-down modulation from the supraspinal level. 10 This physiologic pathway can explain how the act of scratching an itch might produce pain in addition to relieving the pruritic sensation, thus illustrating the importance of the neurosensory matrix when evaluating these complaints. In pathological conditions promoting CPr, sensitization of itch might modify the neural pathway involved, possibly initiating spontaneous itching or inducing hypersensitivity to itch. Sensitization of itch can occur in one or more of the following four ways. First, altered processing of itch by the nervous system can cause nociceptive stimuli that would normally evoke pain to instead evoke itch. Second, peripheral sensitization involves decreased threshold for activation, increased responsiveness, and the presence of ongoing activity of neural pathways. Third, central sensitization involves altered activity of CNS neurons such that stimuli that would normally be nonpruritic become coupled to pruritic sensations. 15 Central sensitization might be caused by altered expression of itch- sensing molecules in the CNS, though the mechanism by which this occurs remains under investigation. 16 Fourth, increased nerve fiber density can also potentially mediate chronic pruriceptive itch. 15,16 It has been postulated that neurotrophins, though not pruritogenic, might contribute to increased nerve fiber density and number. Neurotrophins are a class of growth factors that include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3) and neurotrophin 4/5 (NT-4/5). These molecules bind to three different subtypes of tropomysin-receptor-kinase (Trk) receptors thereby mediating an increase in sensory nerve growth and sprouting. 15 NAUSEA Chronic functional nausea and vomiting include both chronic idiopathic nausea (CIN) and functional vomiting, as defined by the Rome III criteria for functional gastrointestinal (GI) disorders. C IN refers to bothersome nausea occurring at least several times weekly, not necessarily associated with vomiting, with the absence of abnormalities at upper endoscopy or any metabolic d isease that explains the nausea. Functional vomiting, likewise, refers to an average of one or more episodes of vomiting weekly in the absence of any eating disorder, rumination, major psychiatric disease, self-induced vomiting, chronic cannabinoid use, CNS abnormalities, or metabolic disease that explains the vomiting. In each of these disorders, criteria need to be fulfilled for the previous three months, with symptom onset at least six months prior to diagnosis. 17 In order to understand the pathophysiology underlying nausea, it is important to introduce the concept of the dynamic threshold. It is proposed that each individual has a threshold for nausea that changes minute by minute. At any given moment, the threshold depends on the interaction of certain inherent factors of the individual with the more changeable psychological states of anxiety, anticipation, expectation, and adaptation. This dynamic interaction likely explains the inter- and intra-individual variability that is typically encountered in the face of a nauseogenic stimulus. 18 Briefly, stimuli giving rise to nausea and vomiting activate the chemoreceptor trigger zone (CTZ) in the area postrema and structures deeper in the medulla ("the vomiting center" [VC]) by emetic humoral agents and in the VC by neural input from factors such as vagal afferents and vestibular stimulation and from cerebral structures. 19 Despite the prevalence and importance of nausea, surprisingly little is known regarding the central mechanisms underlying this sensation. The neurocircuitry involved in emesis has been better characterized. Associated autonomic changes the occur during nausea and emesis (e.g., salivation, sweating) are coordinated at the level of the medulla oblongata. Chemosensitive receptors detect the presence of emetic agents in the blood, and this information is relayed via the area postrema to the nucleus tractus solitarius (NTS). Abdominal vagal afferents that detect g astric tone and contents also project to the NTS. Neurons from the NTS then project to a central-pattern generator, which coordinates the various actions involved in the act of emesis in addition t o directly projecting to neurons in the ventral medulla and hypothalamus, from which higher brain areas can be reached. 1 8 PATHOPHYSIOLOGY OF CHRONIC PAIN In the periphery, after an event that causes direct nerve damage, an inflammatory response ensues. Lysis of inflammatory cells results in the release of various chemical mediators, including serotonin, bradykinin, substance P, histamine, and products from the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism. These substances act to sensitize nociceptors in the periphery to subsequent input resulting in increased responsiveness to thermal and mechanical stimuli at the site of injury. This is mediated through thin, unmyelinated C-fiber primary afferent neurons and is referred to as hyperalgesia. Continuous discharge in C fibers might produce sensations of burning pain, whereas intermittent spontaneous discharges in A[δ] or A[b] fibers might produce lancinating dysesthesias or paresthesias. This leads to increased susceptibility to firing and increased firing frequency, possibly resulting in not only spontaneous pain, but also central sensitization. 20 Under these conditions, central neurons that normally receive high- threshold sensory input might begin to receive input from low-threshold mechanoreceptors, and this information might then be interpreted as nociceptive information ( i.e., allodynia). An alternative hypothesis is that allodynia is caused by a decrease in central inhibition of the mechanically induced nociceptive input. In addition, it is hypothesized that within the spinal cord, collateral sprouting of primary afferent neurons within the spinal cord might occur. According to this model, nerve fibers in deeper laminae that do not normally transmit pain sprout into

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