From glial cells to pain pathways: ICAM-1 as a central player in neuroinflammation and neuropathy

Chronic neuropathic pain (NeP) involves somatosensory system dysfunction, which contributes to altered pain perception and is commonly associated with allodynia and hyperalgesia. In NeP, conditions like diabetes, trauma, spinal cord injury, and cancer result in damage to both central and peripheral nerves. Despite advances in understanding its mechanisms, effective therapies for NeP remain elusive. Current treatments—such as opioids, NSAIDs, antidepressants, and gabapentinoids—provide limited relief and fail to target underlying neuroinflammation, highlighting the need for novel therapeutic strategies. Intercellular adhesion molecule-1 (ICAM-1) has emerged as a promising target for NeP management. It is a cell surface glycoprotein expressed in neurons, glia, and endothelial cells. ICAM-1 plays a crucial role in leukocyte adhesion and immune responses. In the central nervous system, nerve injury or infection leads to the upregulation of ICAM-1. This upregulation activates resident immune cells, such as microglia and astrocytes. These immune cells then release pro-inflammatory mediators. The mediators initiate neuroinflammation and central sensitization. This process results in the hyperexcitability of spinal cord neurons and amplifies pain signals. Research suggests that inhibiting ICAM-1 signaling can reduce microglial activation, cytokine release, and pain perception. These findings highlight ICAM-1’s potential as a therapeutic target. This review explores the role of ICAM-1 in the molecular and cellular mechanisms involved in NeP development. It attempts to emphasize the potential of ICAM-1 as a therapeutic target. Further, the modulation of ICAM-1 by phytoconstituents in inflammatory conditions has been discussed. Finally, we incorporated the updated information on the ICAM-1-based clinical studies.