Peripheral input and its importance for central sensitization

Abstract

Many pain states begin with damage to tissue and/or nerves in the periphery, leading to enhanced transmitter release within the spinal cord and central sensitization. Manifestations of this central sensitization are windup and long-term potentiation. Hyperexcitable spinal neurons show reduced thresholds, greater evoked responses, increased receptive field sizes, and ongoing stimulus-independent activity; these changes probably underlie the allodynia, hyperalgesia, and spontaneous pain seen in patients. Central sensitization is maintained by continuing input from the periphery, but also modulated by descending controls, both inhibitory and facilitatory, from the midbrain and brainstem. The projections of sensitized spinal neurons to the brain, in turn, alter the processing of painful messages by higher centers. Several mechanisms contribute to central sensitization. Repetitive activation of primary afferent C fibers leads to a synaptic strengthening of nociceptive transmission. It may also induce facilitation of non-nociceptive Aβ fibers and nociceptive Aδ fibers, giving rise to dynamic mechanical allodynia and mechanical hyperalgesia. In postherpetic neuralgia and complex regional pain syndrome, for example, these symptoms are maintained and modulated by peripheral nociceptive input. Diagnosing central sensitization can be particularly difficult. In addition to the medical history, quantitative sensory testing and functional magnetic resonance imaging may be useful, but diagnostic criteria that include both subjective and objective measures of central augmentation are needed. Mounting evidence indicates that treatment strategies that desensitize the peripheral and central nervous systems are required. These should generally involve a multimodal approach, so that therapies may target the peripheral drivers of central sensitization and/or the central consequences.

Defensive reflexes in people with pain – a biomarker of the need to protect? A meta-analytical systematic review

“…The process by which sensitisation occurs relates to a form of neuroplasticity whereby alterations in stimulusresponse patterns occur over time by virtue of repeated exposure to a particular stimulus, in this case, to excitatory neurotransmitters at the spinal terminals (Woolf and Salter, 2000). The most obvious source of these neurotransmitters is the proximal terminals of primary nociceptors, but descending facilitatory neurones may also be involved (Roberts et al, 2009;Baron et al, 2013).…”

Topical Phenytoin in Neuralgic Pain, Peripheral Modulation of Central Sensitization: Two Case Reports

“…Phenytoin (IC50=40 μm) has 6 times stronger sodium channel binding activity compared to lidocaine (IC50=240 μm) [26]. This is especially relevant in the context of the Baron and Dickenson hypothesis of 2013, were lidocaine was documented to be able to downregulate central sensitization read-outs after topical application [2]. Data on specific effects of phenytoin, as compared to other anticonvulsants, related to the various sodium channels in various tissues are sparse or even absent [27].…”

“…Furthermore, there are clear differences documented between anesthetics and anticonvulsants related to biological read-outs [1]. In 2013 Baron and Dickenson published a seminal paper on the importance of peripheral modulation in chronic pain states characterized by central sensitization [2] They pointed out that both in the pathogenesis of chronic and neuropathic pain, as well as in the treatment, peripheral input is a neglected factor and presented neurophysiological evidence to illustrate that central sensitization read-outs are reduced after topical treatment with lidocaine. It is clear that this hypothesis opens a whole new chapter of the treatment of neuropathic pain.…”

New Developments in the Pathophysiology of Genital Pain: Role of Central Sensitization

“…Various mechanisms proposed to underlie synaptic plasticity pertinent to the development and persistence of chronic pain include: peripheral sensitization [13,14]; central sensitization, which involves alterations in glutamatergic excitatory neurotransmission [12] and changes in GABAergic inhibitory transmission [15]; and neuronal-glia interactions, particularly products released from activated astrocytes and microglia [16][17][18]. Central sensitization is defined as a state of facilitation, potentiation, augmentation, or amplification of response in secondorder or higher-order neurons and circuits within the nociceptive transmission pathway.…”