Hydrocephalus-associated persistent pain: a preclinical investigation correlating brain fluid imbalance and sensory...

Hydrocephalus is a neurological disorder characterized by ventricular enlargement, elevated intracranial pressure and long-term complications, including cognitive dysfunction, motor deficits and pain. Despite the relevance of hydrocephalus-associated pain (characterized by peripheral sensory disturbances and central sensitization) this aspect is neglected both in clinical practice and animal studies.

We characterized persistent pain in a rat model of kaolin-induced hydrocephalus, investigating behavioural, pharmacological, molecular, and cellular aspects, to improve translational relevance. A particular focus was placed on the role of glial cells in the underlying pathophysiology: astrocytes and astrocytic protein aquaporin-4 (AQP4) and microglia. Analyses were conducted separately in male and female rats as an exploratory approach to examine potential sex-related differences in hydrocephalus-associated pain, an aspect that has been largely overlooked in previous preclinical studies.

Induction of hydrocephalus resulted in a significant reduction in pain threshold, as evidenced by the development of peripheral and cephalic hypersensitivity, and spontaneous pain. This pain phenotype is of mixed origin, encompassing both nociceptive and neuropathic components, and shows limited responsiveness to conventional pain therapy. Histological analysis revealed activation of ependymal cells, likely triggered by increased intraventricular pressure. In brain regions implicated in pain processing, particularly the periaqueductal gray (PAG), astrocytes are altered in terms of quantity, simplified morphology, and diminished AQP4 expression, while microglial cells switched to an activated phenotype, suggesting primary mechanical compression damage leading to cellular distress. In downstream areas, in the dorsal horns of the spinal cord, both astrocytes and microglia displayed overt activation, suggestive of secondary reactive changes at spinal level, in line with the hypothesis of central sensitization.

The regional specificity of these alterations underscores the complexity of hydrocephalus-related pain mechanisms and emphasizes the urgent need for novel therapeutic options to manage pain in hydrocephalus, a clinical challenge that remains inadequately addressed.