Normalization of Neuroinflammation: A New Strategy for Treatment of Persistent Pain and Memory/Emotional Deficits in Chronic Pain

Abstract

Chronic pain, which affects around 1/3 of the world population and is often comorbid with memory deficit and mood depression, is a leading source of suffering and disability. Studies in past decades have shown that hyperexcitability of primary sensory neurons resulting from abnormal expression of ion channels and central sensitization mediated pathological synaptic plasticity, such as long-term potentiation in spinal dorsal horn, underlie the persistent pain. The memory/emotional deficits are associated with impaired synaptic connectivity in hippocampus. Dysregulation of numerous endogenous proteins including receptors and intracellular signaling molecules is involved in the pathological processes. However, increasing knowledge contributes little to clinical treatment. Emerging evidence has demonstrated that the neuroinflammation, characterized by overproduction of pro-inflammatory cytokines and glial activation, is reliably detected in humans and animals with chronic pain, and is sufficient to induce persistent pain and memory/emotional deficits. The abnormal expression of ion channels and pathological synaptic plasticity in spinal dorsal horn and in hippocampus are resulting from neuroinflammation. The neuroinflammation is initiated and maintained by the interactions of circulating monocytes, glial cells and neurons. Obviously, unlike infectious diseases and cancer, which are caused by pathogens or malignant cells, chronic pain is resulting from alterations of cells and molecules which have numerous physiological functions. Therefore, normalization (counterbalance) but not simple inhibition of the neuroinflammation is the right strategy for treating neuronal disorders. Currently, no such agent is available in clinic. While experimental studies have demonstrated that intracellular Mg 2+ deficiency is a common feature of chronic pain in animal models and supplement Mg 2+ are capable of normalizing the neuroinflammation, activation of upregulated proteins that promote recovery, such as translocator protein (18k Da) or liver X receptors, has a similar effect. In this article, relevant experimental and clinical evidence is reviewed and discussed.

Analgesic Effect of Perineural Injection of BoNT/A on Neuropathic Pain Induced by Chronic Constriction Injury of Sciatic Nerve in Rats

“…Emerging evidence has demonstrated that glial activation and overproduction of proin ammatory cytokines induce LTP and persistent pain [20]. In this study, we found that microglia were activated and proin ammatory cytokines IL-18 was upregulated in spinal cord after CCI surgery, which could be attenuated by perineural injection of BoNT/A.…”

“…The central sensitization is underlined primarily by long-lasting enhancement of synaptic transmission, called long-term potentiation (LTP) [20]. Peripheral nerve injury can induce LTP and manifested as the increased amplitude of C-ber evoked eld potential in spinal dorsal horn.…”

New Insights into Microglial Mechanisms of Memory Impairment in Alzheimer’s Disease

“…After activation, microglia further release pro-inflammatory factors, such as TNF-α and IL-1β. TNF-α aggravates the inflammatory response in AD [ 95 ] and disrupts the homeostasis of synaptic connections [ 96 ]. IL-1β can mediate the toxic effects of Aβ on synapses, causing changes in synaptic plasticity [ 97 ].…”

The core of maintaining neuropathic pain: Crosstalk between glial cells and neurons (neural cell crosstalk at spinal cord)

“…In addition to its role in learning and memory, the hippocampus and/or amygdala may also play a role in chronic pain and be influenced by pain‐induced plasticity (McCarberg & Peppin, 2019 ). Inflammatory cytokines modulate synaptic plasticity in a region‐dependent manner, that is, enhancing synaptic connections in the dorsal horn of the spinal cord and reducing synaptic connections in the hippocampus, respectively, leading to persistent pain and memory/emotion deficits (Liu, 2022 ). Overproduction of pro‐inflammatory cytokines and glial cell activation impairs long‐term potentiation (LTP) in the hippocampus and reduces excitatory synapses in the hippocampus (Cowley et al., 2012 ; Pickering & O'Connor, 2007 ).…”