Neuroimmune integration in chronic stress: mechanisms of TRPV1-CB2 crosstalk, inflammation, and neural resilience

Abstract

Under the relentless demands of contemporary life, stress orchestrates a sophisticated neurochemical cascade, engaging the hypothalamic-pituitary-adrenal axis and modulating key neurotransmitters-norepinephrine, serotonin, and dopamine-as though forcing a finely tuned thermostat beyond its limits. While acute stress can transiently sharpen adaptive responses, chronic exposure exacts an escalating allostatic burden, gradually compromising synaptic integrity and heightening vulnerability to psychiatric and neurological disorders. Guided by the Neuroimmune Integration Model, this review integrates foundational neurochemical paradigms with pioneering insights into TRPV1 and CB2 receptor dynamics, neuroinflammatory cascades, and oxidative stress signatures, each illuminated by cutting-edge tools such as CRISPR-Cas9 gene editing and single-cell RNA sequencing. The Neuroimmune Integration Model posits that stress responses operate through hierarchical biological organization, from molecular interactions to behavioral outcomes, characterized by dynamic reciprocity between central and peripheral neuroimmune systems. These emerging mediators converge on principal signaling hubs, notably the Mitogen-Activated Protein Kinase (MAPK) and cyclic AMP response element-binding (CREB) pathways, which govern synaptic plasticity and behavioral homeostasis yet are routinely derailed under sustained stress. To recalibrate these circuits, precision-medicine approaches-including CRHR1 antagonists, SIRT1 activators, individualized neurofeedback protocols, and pharmacogenomic profiling-have shown promising early results. Nevertheless, the intricate crosstalk among molecular networks, compounded by inequities in access to advanced therapies, underscores the urgent need for interdisciplinary research to unravel uncharted mechanisms and translate them into broadly accessible neuroprotective treatments.

Keywords: Glucocorticoids; Inflammation; Neurotransmitter agents; Oxidative stress; Signal transduction.