Work

Metabolite–neuro–immune relay in chronic pain: spatial–temporal lactate, succinate and itaconate signalling as drivers of glial reprogramming and neuronal sensitisation

Year: 2026

Type: article

Abstract: Chronic pain is sustained by coupled neuronal hyperexcitability and neuroinflammation, yet prevailing frameworks incompletely explain why similar injuries diverge toward recovery or persistent sensitisation. Growing evidence indicates that lactate, succinate and itaconate act as signalling metabolites that shape glial state transitions and nociceptive circuit gain. Here, we synthesise preclinical and emerging clinical findings and propose a metabolite-neuro-immune relay model in which metabolic perturbations in astrocytes, microglia and peripheral immune cells generate characteristic lactate-succinate-itaconate patterns; glia decode these cues into pro-inflammatory or pro-resolving programs; and the resulting cytokines and physicochemical changes remodel dorsal root ganglion and spinal dorsal horn circuits. We highlight how spatially restricted metabolic microdomains and temporally phased shifts from transient bursts to stable immunometabolic reprogramming can sustain self-reinforcing neuroimmune loops. We then outline mechanism-guided therapeutic opportunities, including modulation of pathological glycolysis, lactate and acidosis-targeted microenvironment remodelling, succinate receptor 1 blockade and augmentation of the IRG1-itaconate-NRF2 axis using precision delivery approaches. This framework links molecular immunometabolism with circuit plasticity and offers testable targets for stage-aware analgesic development.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1786751