The therapeutic potential of GABA in neuron-glia interactions of cancer-induced bone pain

Abstract

The development of effective therapeutics for cancer-induced bone pain (CIBP) remains a tremendous challenge owing to its unclear mechanisms. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). Emerging studies have shown that disinhibition in the spinal cord dorsal horn may account for the development of chronic pain. However, the role of GABA in the development of CIBP remains elusive. In addition, accumulating evidence has shown that neuroglial cells in the peripheral nervous system, especially astrocytes and microglial cells, played an important role in the maintenance of CIBP. In this study, we investigated the expression of GABA and Gamma-aminobutyric acid transporter-1 (GAT-1), a transporter of GABA. Our results demonstrate that GABA was decreased in CIBP rats as expected. However, the expression of glutamic acid decarboxylase (GAD) 65 was up-regulated on day 21 after surgery, while the expression of GAD 67 remained unchanged after surgery. We also found that the expression of GAT-1 was up-regulated mainly in the astrocytes of the spinal cord. Moreover, we evaluated the analgesic effect of exogenous GABA and the GAT-1 inhibitor. Intrathecal administration of exogenous GABA and NO-711 (a GAT-1 selective inhibitor) significantly reversed CIBP-induced mechanical allodynia in a dose-dependent manner. These results firstly show that neuron-glia interactions, especially on the GABAergic pathway, contribute to the development of CIBP. In conclusion, exogenous GABA and GAT-1 inhibitor might be alternative therapeutic strategies for the treatment of CIBP.

Osteoporosis in Light of a New Mechanism Theory of Delayed Onset Muscle Soreness and Non-Contact Anterior Cruciate Ligament Injury

“…Central sensitisation mechanisms further involve the potentiation of NMDA receptor function, the activation of both microglia and astrocytes and the release of peptides, such as substance P [ 1 , 28 ]. Synaptic gamma-aminobutyric acid (GABA)-mediated inhibition (both at the pre- and post-synaptic level [ 36 ]) could also be impaired longitudinally by changes in GABA vesicular transport, GABA re-uptake, the alteration of intracellular chloride concentration and the modification of GABA receptor composition [ 37 , 38 , 39 ]. Indeed, aging women with osteoporotic fracture have significantly lower GABA levels [ 40 ].…”

Ligand-Gated Ion Channels as Targets for Treatment and Management of Cancers

“…Work in a rat model of CIBP found that GABA was downregulated in CIBP rats in combination with the upregulation of GABA transporter type-1 (GAT-1) in spinal cord astrocytes ( Ge et al, 2019 ). Interestingly, administration of exogenous GAD and NO-711 (a GAT-1 specific-inhibitor) significantly reversed CIBP-induced mechanical allodynia ( Ge et al, 2019 ). This suggests that the upregulation of GABAergic signaling has the potential to be an analgesic in CIBP.…”

Gamma aminobutyric acid (GABA) production using Lactobacillus sp. Makhdzir Naser‐1 (GQ451633) in the cherry‐kefir beverage

“…Moreover, GABA displays a significant effect on the proper release of hormones and therefore the regulation of insulin so the effective treatment of diabetes (Choat et al, 2019). As well as, the desired effect of GABA on preventing the accumulation and proliferation of cancer cells and improving the healing of cancer patients with GABA utilizing has been proven (Ge et al, 2019;Schuller, 2018).…”