Spinal Cord Injury Provoked Neuropathic Pain and Spasticity, and Their GABAergic Connection

Abstract

Traumatic spinal cord injury (SCI) is the devastating neurological damage to the spinal cord that becomes more complicated in the secondary phase. The secondary injury comes with inevitable long-lasting complications, such as chronic neuropathic pain (CNP) and spasticity which interfere with day to day activities of SCI patients. Mechanisms underlying CNP post-SCI are complex and remain refractory to current medical treatment. Due to the damage, extensive inhibitory, excitatory tone dysregulation causes maladaptive synaptic transmissions, further altering the nociceptive and nonnociceptive pathways. Excitotoxicity mediated GABAergic cell loss, downregulation of glutamate acid decarboxylase enzyme, upregulation of gamma-aminobutyric acid (GABA) transporters, overactivation of glutamate receptors are some of the key evidence for hypoactive inhibitory tone contributing to CNP and spasticity post-SCI. Restoring the inhibitory GABAergic tone and preventing damage-induced excitotoxicity by employing various strategies provide neuroprotective and analgesic effects. The present article will discuss CNP and spasticity post-SCI, understanding their pathophysiological mechanisms, especially GABA-glutamate-related mechanisms, therapeutic interventions targeting them, and progress regarding how regulating the excitatory-inhibitory tone may lead to more targeted treatments for these distressing complications. Taking background knowledge of GABAergic analgesia and recent advancements, we aim to highlight how far we have reached in promoting inhibitory GABAergic tone for SCI-CNP and spasticity.

The Role of Exercise in the Alleviation of Neuropathic Pain Following Traumatic Spinal Cord Injuries: A Systematic Review and Meta-analysis

“…The development of neuropathic pain is a consequence of nerve injury, either in the periphery or the CNS [ 51 ]. Even though a multitude of factors have been suggested to provoke the pathological pathways that lead to neuropathic pain, the distinct molecular and cellular alterations involved in the process remain understudied [ 52 , 53 ]. The underlying mechanisms of neuropathic pain can be categorized into the alterations of pain threshold in the primary afferent nociceptive neurons, activation of nonnociceptive receptors, changes in neurotransmitter transduction, and rewiring of neurons in the pain perception pathways of the CNS [ 54 , 55 ].…”

Different Ways to Die: Cell Death Pathways and Their Association With Spinal Cord Injury

“…Initial tissue injury results in secondary injury, which further damages the spinal tissues chemically and mechanically, causes neuronal excitotoxicity because the calcium level in the cells is too high, and increases reactive oxygen and glutamate levels. 15 These events result in brain/spinal cord dysfunction by harming the underlying proteins, phospholipids, and nucleic acids. 16 The secondary injury phase, which follows the main damage phase and lasts several weeks, reflects multifeatured pathological processes.…”

Therapeutic potential of luteolin-loaded poly(lactic-co-glycolic acid)/modified magnesium hydroxide microsphere in functional thermosensitive hydrogel for treating neuropathic pain

“… 3 , 4 The primary pathological mechanisms of NP mainly involve central and peripheral nerve sensitization, inflammation, oxidative stress, and release of pro-inflammatory cytokines. 5 – 8 Activated microglia and macrophages contribute to the production of interleukins and tumor necrosis factor-alpha (TNF-α), culminating in inflammation and cellular apoptosis. However, current therapeutic approaches, such as non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, suffer from limited specificity and are associated with a wide range of side effects, including nausea, constipation, gastric and intestinal ulcers, bleeding, and perforation.…”