Central sensitization

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Fig. 4.1 Hypothetical model of pathogenesis of pain in DSP. (1) Injury of peripheral nerve fibers due to multifocal inflammation and secreted macrophage activation products results in abnormal spontaneous activity of neighboring uninjured nociceptive fibers ( peripheral sensitization ). (2) Furthermore, the aberrant inflammatory response in DRG leads to alterations in neuronal sodium and calcium channel expression and ectopic impulse generation. (3) This results in central remodeling within the dorsal horn due to A-fiber sprouting and synaptic formation with pain fibers in lamina 11, and maintenance of neuropathic pain ( central sensitization ). Reproduced with permission from (Keswani et al. 2002)...

Two current foci in pain management are to identify the mechanisms that are responsible for pain hypersensitivity and to prevent this initial hypersensitivity. Therefore, the goal of pain therapy is to reduce peripheral sensitization and subsequent central stimulation and amplification associated with wind-up, spread, and central sensitization.17... 

Central sensitization results in hyper-responsive dorsal horn neurons 933... 

Inflammatory pain results from changes both in primary sensory and dorsal horn neurons. The alterations in primary sensory neurons fall into two broad categories (a) a reduction in threshold and an increase in the response of the peripheral terminals of nociceptors (peripheral sensitization), and (b) an alteration in transmitter content modifying synaptic input to the spinal cord. In the dorsal horn, peripheral inflammation results in an increase in membrane excitability and synaptic efficacy, which is the phenomenon of central sensitization [12]. 

Features of central sensitization are pain in response to normally innocuous tactile stimuli, and the spread of pain sensitivity beyond the site of tissue injury. Central sensitization plays a major role in acute post-traumatic pain, and also in migraine, neuropathic pain (see below) and some diffuse chronic pain syndromes, such as fibromyalgia and irritable bowel syndrome. In these conditions, which have no detectable peripheral trigger, an autonomous central sensitization may be the pathology, increasing the gain in neuronal activity in the CNS and thereby producing abnormal responses to normal inputs. 

The activity-dependent changes in dorsal horn that constitute acute or immediate central sensitization are... 

Ectopic activity in C fibers elicits central sensitization in the dorsal horn, contributing to the generation of tactile allodynia, a prominent feature of neuropathic pain. 

FIGURE 57-6 Central sensitization of dorsal horn neurons and a loss of inhibition after nerve injury result in altered processing of sensory input. ATP activates microglia through the P2X4 receptor. The resulting release of cytokines contributes to the development of pain through a mechanism of action that is, as yet, unknown. 

PGI2, and PGF2e, contribute to so-called central sensitization, an increase in excitability of spinal dorsal horn neurons, that augments pain intensity, widens the area of pain perception, and results in pain from innocuous stimuli. 

Coderre, T. J. Contribution of protein kinase C to central sensitization and persistant pain following tissue injury, Neurosci. Letters 1992, 140, 181-184. 

Coderre, T.J. and Melzack, R. The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin-induced tissue injury, J. Neurosci. 1992, 12, 3665-3670. 

Nitric oxide inhibition has an analgesic effect in patients with chronic tension-type headache, probably due to a reduction in central sensitization at the level of the spinal dorsal horn, trigeminal nucleus or both (Ashina, 2002). 

The hyperexcitable sensory neuron bombards the spinal cord, leading to increased excitability and synaptic alterations in the dorsal horn (central sensitization). Such changes appear to be important in chronic inflammatory and neuropathic pain states (Basbaum, 1999 Woolf, 2000). 

It is well known that signal transduction of pain initiates in primary afferent neurons and transmits to the dorsal horn of the spinal cord (Scholz and Woolf, 2002). Signal transduction in the spinal cord is important for nociception, but dynamic change (i.e., central sensitization) and neuronal plasticity associated with glial activation also have important roles in neuropathic pain (Inoue et al., 2007 Tsuda et al., 2005). Central sensitization was demonstrated in neuropathic pain... 

Ji, R. R., Kohno, T., Moore, K. A., and Woolf, C. J. (2003). Central sensitization and longterm potentiation—Do pain and memory share similar mechanism Trends Neurosci. 26, 696-705. 

Kawasaki, Y., Kohno, T., Zhuang, Z. Y., Brenner, G. J., Wang, H., Van Der Meer, C., Befort, K., Woolf, C. J., and Ji, R. R. (2004). Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. J. Neurosci. 24, 8310-8321. 

Wu, J., Lin, Q, McAdoo, D. J., and Willis, W. D. (1998). Nitric oxide contributes to central sensitization following intradermal injection of capsaicin. NeuroReport 9, 589—592. 

Ziegler, E. A., Magerl, W., Meyer, R. A., and Treede, R. D. (1999). Secondary hyperalgesia to punctate mechanical stimuli. Central sensitization to A-fibre nociceptor input. Brain 122(Pt 12), 2245-2257. 

Fig. 2 Afferent pathways and central control of the cough reflex with peripheral and central sensitization of the reflex by a variety of mechanisms. CGRP calcitonin gene-related peptide, tiTS nucleus of the solitary tract, LTD4 leukotriene D4, NK neurokinin, PGE2 prostaglandin E2, RAR rapidly adapting receptors, SAR slowly adapting receptors, TRPV-1 transient receptor potential vanUloid-l...

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