Research Progress on the Mechanism of Ketamine in Neuropathic Pain Comorbid Depression

Abstract

This review systematically summarizes the research progress of ketamine and its interaction with specific brain regions in the context of neuropathic pain comorbid with depression. As a non-competitive inhibitor of N-methyl-D-aspartate (NMDA) receptors, Ketamine exerts complex mechanisms and controversial topic. The structure and function of NMDA receptors, as well as the binding sites of ketamine, are summarized, and the hypothesis of disinhibition and neuroplasticity of ketamine's antidepressant effect is elaborated. The mechanism of key brain regions, such as hippocampus and anterior cingulate cortex, is discussed in detail, and the antidepressant effect of ketamine is explored from the perspective of transcriptomics. Finally, this review integrates bioinformatics, molecular biology and other interdisciplinary approaches to elucidate the therapeutic effects and potential mechanisms of ketamine in treating neuropathic pain and depression comorbidity, providing a comprehensive theoretical basis, new directions for subsequent research and novel insights for the clinical application of ketamine.

Keywords: depression; ketamine; neuropathic pain; specific brain regions.

Figure 1

Converging synaptic signaling pathways underlying ketamine action. (A) The antidepressant mechanism of ketamine predominantly depends on its antagonistic action on NMDARs located in GABAergic interneurons, blocking the release of GABA. By inhibiting the release of GABA, the inhibition of pyramidal glutamatergic neurons is averted. As a result, glutamate is released, leading to the subsequent downstream consequences triggered by a sudden increase in glutamate levels. Glutamate then binds to postsynaptic AMPARs, enabling calcium to flow in, results in the release of BDNF from the postsynaptic membrane, triggering TrkB receptor signaling. The TrkB pathway and resulting rapid homeostatic synaptic plasticity are crucial for both ketamine’s rapid and sustained actions. Activation of downstream mTOR causes structural plasticity, generating fast and long - lasting antidepressant effects. BDNF autocrine signaling directs downstream pathways like MAPK, PLC - γ, and PI3K - Akt. MAPK and PLC - γ are linked to synaptic plasticity, and PI3K - Akt to anti - apoptotic signaling and cell survival. (B) Ketamine is proposed to selectively block extrasynaptic GluN2B-containing NMDARs, which are tonically activated by low levels of ambient glutamate regulated by glutamate transporter 1 located on astrocytes. (C) The transient decrease in the excitatory drive of inhibitory interneuron-resident NMDARs mediated by ketamine is thought to inhibit the tonic release of GABA and relieve the activity of target excitatory neurons. The resulting increase in glutamatergic activity activates the downstream mammalian target of rapamycin (mTOR) function, leading to structural plasticity and producing rapid and sustained antidepressant effects. (D) Ketamine blocks NMDAR-mediated spontaneous neurotransmission, which inhibits eukaryotic elongation factor 2 kinase (eEF2K) activity, thus stopping the phosphorylation of its eEF2 substrate. (E) (2R,6R)-HNK increases AMPAR-dependent synaptic transmission. (F) A special firing pattern in the lateral habenula - burst firing is a sufficient condition for the occurrence of depression, and the effect of ketamine is to effectively prevent burst firing in this brain region. (G) T - VSCCs can serve as a novel antidepressant molecular target. (H) Another rapid antidepressant molecular target was revealed - the potassium ion channel Kir4.1 present in glial cells, which is crucial for triggering the burst firing of neurons. (I) The rapid elevation of NE by ketamine and the activation of astrocyte α1 - AR play an antidepressant role in sustained resilience. (J) Tiam1 links NMDARs stimulated by chronic pain to the activation of Rac1 in the ACC.

Figure 2

The effects of ketamine on various brain regions of rats with comorbid chronic pain and depression. Adapted from Borsellino P, Krider RI, Chea D, et al. Ketamine and the Disinhibition Hypothesis: neurotrophic Factor-Mediated Treatment of Depression. J Pharmaceuticals. 2023;16(5):742. Under Creative Commons License https://creativecommons.org/licenses/by/4.0/.