Neuropathic Pain: A Review of Interneuronal Disinhibition

Abstract

Context: Dysfunction of pain circuitry may alter normal pain perception, leading to neuropathic pain. The underlying mechanisms are still unclear, although several animal models of partial nerve injury have been developed. Objectives: This review aimed to describe some essential elements for understanding neuropathic pain after peripheral nerve injury and to discuss its mechanisms with an emphasis on interneuronal disinhibition. Evidence Acquisition: A PubMed search was undertaken with no date restrictions, using a combination of the following keywords: "mechanisms", "allodynia", "peripheral nerve injury", "neuropathic pain", and "interneuronal disinhibition". Then, relevant papers on the underlying mechanisms of neuropathic pain after peripheral nerve injury were selected. Results: Several hypotheses have been proposed to explain neuropathic pain, which are not necessarily independent of each other. Interneuronal disinhibition is one of the most promising hypotheses, which includes several possible mechanisms, such as death of inhibitory interneurons (1), reduced afferent drive to inhibitory interneurons (2), depletion of gamma-aminobutyric acid (GABA) (3), GABA dysfunction (4), altered membrane properties of inhibitory interneurons (5), and specific glycine disruption (6). Currently, only some of these hypotheses are promising. Technical discrepancies among experimental studies are partially responsible for some of these controversial results. Conclusions: Formerly neglected circuitries including the glycinergic system, as well as other disturbances such as shift of GABA activity, currently constitute the most promising hypotheses on neuropathic pain. Additional studies on cell types involved in nociceptive transmission and dorsal horn connectivity of the spinal cord are still needed for a better understanding of pain circuitry and its disorders.

Electroacupuncture at Zusanli and at Neiguan characterized point specificity in the brain by metabolomic analysis

“…A reduction in the number of GABA-A receptors reduces synaptic inhibition, and an increase in the number of glutamatergic receptors causes an imbalance between excitation and inhibition, resulting in epileptic seizure 17 . GABA dysfunction and glycine disruption involve the mechanism of neuropathic pain 18 .…”

Spinal protein kinase A and phosphorylated extracellular signal-regulated kinase signaling are involved in the antinociceptive effect of phytohormone abscisic acid in rats

“…It is well known that the spinal cord has an important role in pain transmission, regulation and processing. Specially, dorsal horn parts and laminas, connectivity of the pain first order neurons at spinal cord segments levels with another modality, such as tactile, have crucial responsibilities in pain control and transmission 14 .…”

Envolvimento da substância cinzenta periaquedutal, medula espinal e células da glia na analgesia induzida por estimulação insular em ratos com neuropatia periférica experimental.

“…A sensibilização central envolve o aumento da função neuronal individual (celular) e dos circuitos nociceptivos (multicelulares, neuronais e gliais) causados por aumento da excitabilidade da membrana, eficácia sináptica e também pela diminuição da inibição do sistema nervoso somatossensorial e plasticidade em resposta a inflamação periférica, atividade anormal ou lesão nervosa que ocorrem após estímulo nociceptivo intenso ou repetitivo (Wall and Melzack's, 2013) alterando a percepção da dor, resultando em fenótipos complexos de neuropatia que irão se manifestar pela ocorrência de dor espontânea, alodínia e hiperalgesia (COSTIGAN ET Al., 2009;YAN et al, 2017;ALVES, LIN, 2018), característicos da dor neuropática.…”