Cellular and molecular mechanisms driving neuropathic pain: recent advancements and challenges

Abstract

Current pharmacotherapeutics for neuropathic pain offer only symptomatic relief without treating the underlying pathophysiology. Additionally, they are associated with various dose-limiting side effects. Pain research in the past few decades has revolved around the role of oxidative-nitrosative stress, protein kinases, glial cell activation, and inflammatory signaling cascades but has failed to produce specific and effective therapies. Areas covered: This review focuses on recent advances in cellular and molecular mechanisms of neuropathic pain that may be translated into future therapies. We discuss emerging targets such as WNT signaling mechanisms, the tetrahydrobiopterin pathway, Mrg receptors, endogenous lipid mediators, micro-RNAs and their roles in pain regulation. Recent evidence is also presented regarding genetic and epigenetic mechanisms of pain modulation. Expert opinion: During chronic neuropathic pain, maladaptation occurs in the peripheral and central nervous systems, including a shift in microglial phenotype from a surveillance state to an activated state. Microglial activation leads to an altered expression of cell surface proteins, growth factors, and intracellular signaling molecules that contribute to development of a neuroinflammatory cascade and chronic pain sensitization. Specific targeting of these cellular and molecular mechanisms may provide the key to development of effective neuropathic pain therapies that have minimal side effects.

Quantitative sensory profiles of upper extremity chemotherapy induced peripheral neuropathy: Are there differences in sensory profiles for neuropathic versus nociceptive pain?

“…Microglia and mast cell activation along with the recruitment of astrocytes incite and maintain neuroinflammation. [27][28][29][30] Neuroimmune changes may not primarily affect the cutaneous receptors that are involved in QST measurement. Neuropathic pain may primarily impact higher order processing and interpretation of pain in the central nervous system.…”

Necrostatin-1 Ameliorates Peripheral Nerve Injury-Induced Neuropathic Pain by Inhibiting the RIP1/RIP3 Pathway

“…Current analgesic drugs, such as non-steroidal anti-inflammatory drugs, tricyclic antidepressants, and opioids, lack satisfactory efficacy in controlling disease progression, and most of them alleviate symptoms by inhibiting neuronal activity. In addition, these drugs are associated with serious toxicity and dose-limiting side effects, such as dependence, addiction, dizziness, constipation, and blurred vision (Ji et al, 2014; Fernandes et al, 2018). Therefore, it is crucial to elucidate the mechanisms of neuropathic pain and to explore better therapeutic interventions.…”

Small RNA sequencing reveals microRNAs related to neuropathic pain in rats

“…An increasing number of studies revealed that the Wnt signaling pathway, including the canonical Wnt/β-catenin signaling and non-canonical Wnt/Ryk signaling, contributes to neuropathic pain (13,23). During the nerve injury process, Wnt binds to its receptor and inhibits β-catenin phosphorylation by GSK-3, and the elevated levels of β-catenin associate with TCF4 to promote the induction of the Wnt target genes, which are responsible for neuropathic pain (24). Moreover, a number of drugs have been demonstrated to alleviate neuropathic pain via the Wnt pathway.…”