Table 1.
Preclinical studies promoting inhibitory tone for SCI-NP
| Approach and route | SCI model | Mechanism and conclusion | |
|---|---|---|---|
| Enhancing GAD expression | |||
| HFV vector expressing GAD67 (s.c. inoculation) | Male SD rats (hemisection model) | Attenuated mechanical allodynia and thermal hyperalgesia through GAD mediated GABA release [61] | |
| HSV vector expressing GAD67 (s.c. inoculation) | Male SD rats (hemisection model) | Attenuated mechanical allodynia and thermal hyperalgesia through GAD mediated GABA release [62] | |
| Reducing hyperexcitability | |||
| Riluzole (i.t.) | Male SD rats (static compression) | Significant antinociceptive on below-level pain by blocking sodium channels [77] | |
| Huperzine A (i.t.) | Female SD rats (static compression) | Safe and effective for NP antagonizing NMDA receptors [137] | |
| Gabapentinoids | |||
| Gabapentin+Pregabalin (i.p.) | Female ddY-strain mice (contusion model) | Reduction of mechanical hypersensitivity in a dose-dependent manner by GABA modulation [138] | |
| Inhibiting GABA uptake | |||
| Tiagabine | Male FVB gad1: GFP mice (contusion model) | Diminished SCI-induced NP by inhibiting GABA transporter [34] | |
| GABA agonists | |||
| Muscimol (i.t.) | Male Wistar rats (compression model) | GABAA agonist reduced NP (effects decrease after 15 min) call for combination therapies [139] | |
| Muscimol+Endomorphin-1 (i.t.) | (Compression model) | GABAA agonist increased pain threshold significantly (approach for combination therapy) [95] | |
| Baclofen+Ketamine (i.t.) | Male SD rats (compression model) | Additive effect of GABAB agonist+NMDA antagonist (approach for combination therapy) [40] | |
| Cell therapy | |||
| Mesenchymal stem cells (intraspinal) | Male Wistar rats (compression model) | Alleviated NP and promoted motor recovery by restoring GABAergic tone [140] | |
| Exercise+GABAergic neural progenitor cell transplants (intraspinal) | Male SD rats (compression model) | Significant pain reduction by restoring GABAergic tone (mutually beneficial) [105] | |
| Human ESC derived interneuron precursors (intraspinal) | Female B6.CB17-Prkdcscid/SzJ mice (contusion model) | Cells differentiate into GABAergic neuron subtype and restore GABAergic tone [141] | |
| Human neuronal cell line [h NT2.17] (subarachnoid space) | Male Wistar-Furth rats (excitotoxic SCI pain model) | Reversal of tactile allodynia and thermal hyperalgesia by release of GABA and glycine [103] | |
| Mouse ESC derived GABAergic neurons (subarachnoid space) | Male SD rats (spinal hemisection model) | Long-term attenuation of tactile hypersensitivity and neuronal hyperexcitability by restoring GABAergic tone [102] | |
| (i.t) | Male SD rats (contusion model) | Attenuated SCI-CNP by restoring GABAergic tone [7] | |
| KCC2 enhancer | |||
| CLP290 (i.p.) | Female C57BL/6 WT mouse and Vgatires-Cre VGlut2-ires Cre, ChAT-ires Cre strains (double lateral hemisection) | KCC2 agonist promoted functional recovery [57] | |
SCI, spinal cord injury; NP, neuropathic pain; CNP, chronic neuropathic pain; HFV, human foamy virus; s.c., subcutaneous; GAD, glutamate acid decarboxylase; SD, sprague Dawley; GABA, gamma-aminobutyric acid; HSV, herpes simplex virus; i.t., intrathecal; NMDA, N-methyl-Daspartate; FVB, FV-1b allele friend leukemia virus B sensitive; GFP, green fluorescent protein; ESC, embryonic stem cells; i.p., intraperitoneal; WT, wild-type.