Chronic pain syndromes such as interstitial cystitis/bladder pain syndrome (IC/BPS), neuropathic pain, and fibromyalgia (FM) often exhibit overlapping features, particularly central sensitization (CS) — a heightened responsiveness of the central nervous system (CNS) that amplifies pain perception. IC/BPS, in particular, is a complex condition that often coexists with other chronic pain disorders, suggesting a shared dysregulation within central pain processing pathways. This systematic review is the first to examine the relationship between glial energy metabolism dysfunction and CS. While glial cells metabolism is thought to be regulated by glycolysis and the TCA cycle, its role in chronic pain and CS in IC/BPS still remain unclear.

A structured systematic literature review (n=20) was conducted following PRISMA guidelines using PubMed, ScienceDirect, and Scopus for peer-reviewed studies between 2018-2025, using the search terms “chronic pain”, “central sensitization”, “IC/BPS”, “gliosis”, “glial metabolism”, and “glial energy”. Inclusion criteria emphasized mechanistic depth, CNS involvement, and relevance to glial activation. Risk of bias was not formally assessed due to heterogeneity in study designs.

Studies have repeatedly highlighted the involvement of glial cells in the development and progression of chronic pain conditions. Disrupted glial energy metabolism, particularly mitochondrial dysfunction and impaired AMPK (adenosine monophosphate-activated protein kinase, an energy-sensing pathway) has been reported to initiate reactive gliosis. Additionally, astrocytes are shown to shift to aerobic glycolysis under inflammatory stress, producing excess lactate that heightens neuronal excitability and contributes to CS in chronic pain conditions (1). Reactive gliosis is characterized by proliferation, morphological changes, and increased synaptic remodeling. This process therefore contributes to chronic pain by strengthening nociceptive circuits, increasing central pain sensitivity and leading to persistent neuroinflammation and hypersensitivity (2). 
Neuroinflammation and CS was reported to play a primary role in symptom persistence in IC/BPS, even in the absence of ongoing peripheral inflammation (3). The BDNF in the CYP-induced cystitis model showed increased glial activation and IL-1β release, aggravating neuroinflammation and leading to mechanical allodynia (1).

Our analysis indicates that in chronic pain conditions, glial cell activation contributes to CS through reactive gliosis. This process not only alters neuronal-glial interactions but also leads to symptoms like allodynia, hyperalgesia, and widespread pain. A consistent finding across studies is energy dysfunction in glial cells, resulting in ATP depletion, oxidative stress, and an increase in pro-inflammatory cytokine production. Furthermore, the limitation of this study is that most studies were preclinical, and heterogeneity in models limited direct comparisons.

Evidence supports the involvement of glial-driven neuroinflammation and energy metabolism dysfunction, such as glycogenic and mitochondrial impairment in the pathophysiology in diseases associated with chronic pain. Based on these findings, a similar central mechanism may contribute to chronic pain in IC/BPS. The phenomenon of gliosis due to an energy deficit resulting in an energy imbalance and ultimately leading to CS warrants further investigation in IC/BPS, using neonatal maternal separation and water avoidance models that mimic the central form of the disease. Understanding the neurobiological basis of these conditions can lead to improved diagnostic and therapeutic strategies that target central and peripheral mechanisms, if required.

Akter M, Ma H, Hasan M, Karim A, Zhu X, Zhang L, Li Y. Exogenous L-lactate administration in rat hippocampus increases expression of key regulators of mitochondrial biogenesis and antioxidant defense. Front Mol Neurosci. 2023 Mar 16;16:1117146. doi: 10.3389/fnmol.2023.1117146. PMID: 37008779; PMCID: PMC10062455.
Donnelly CR, Andriessen AS, Chen G, Wang K, Jiang C, Maixner W, Ji RR. Central Nervous System Targets: Glial Cell Mechanisms in Chronic Pain. Neurotherapeutics. 2020 Jul;17(3):846-860. doi: 10.1007/s13311-020-00905-7. PMID: 32820378; PMCID: PMC7609632.
Nickel, J. C., & Tripp, D. A. (2021). Cognition, emotion, and the bladder: Psychosocial factors in the aetiology and management of interstitial cystitis/bladder pain syndrome. BJU International, 127(3), 257-267.