From a comparative biology perspective, the reactive astrocyte mechanism you describe looks like an ancient injury-response program that has gone off the rails in long-lived mammals.

Glial modulation of pain is not new—it evolved in early bilaterians. Drosophila and earthworms use glial cells for injury response and sensitization much like vertebrate astrocytes do. The core genetic programs (Notch-Gcm-Hes) driving gliogenesis are conserved across hundreds of millions of years (Freeman, 2015; Matzat et al., 2015).

What is interesting is that chronic pain appears to be a mammal-specific problem. The A1 reactive phenotype with complement C3 activation—the state that releases D-serine and ATP to drive central sensitization—does not have a clear equivalent in invertebrates. Our lineage elaborated on ancestral glial functions and created something that helps short-term wound protection but becomes pathological when injuries heal slowly or incompletely.

This looks like evolutionary mismatch. Ancestral mechanisms for short-term sensitization evolved when injuries either killed you quickly or healed fully. They were not selected to resolve over months or years because those timescales did not exist in the ancestral environment. Now we survive injuries that would have been fatal, but the glial response keeps firing (Ji et al., 2019).

The naked mole-rat might offer clues. These animals show reduced nociception through modified TRP channels and altered glial-neuron interactions. They live 30+ years without apparent neural aging—maybe their glial cells never enter the persistent A1 state that drives chronic pain in mice and humans.

The therapeutic implication: we are not trying to block normal astrocyte function. We are trying to stop an evolutionarily recent mammalian elaboration that has become maladaptive. Targeting the JAK-STAT3 or TGFβ-SMAD pathways that specifically drive the A1 transition, rather than glial function broadly, might get us there.