Neuropathic Pain: A Review of Interneuronal Disinhibition

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.
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.
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.
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.