The GABA-B – Substance P–Histamine Axis: A Unifying Mechanism for Neurogenic Inflammation

Neurogenic inflammation—the process by which sensory neurones release neuropeptides that activate immune cells—is increasingly recognised as a pathogenic mechanism in a range of chronic inflammatory conditions, including rosacea, chronic pruritus, and mast cell-mediated dermatoses. Despite its clinical significance, the mechanisms that regulate neurogenic inflammation remain incompletely understood, particularly the pathways that modulate Substance P release and mast cell histamine release. We propose that the GABA-B receptor plays a critical regulatory role in neurogenic inflammation through a dual mechanism: (i) presynaptic inhibition of Substance P release from sensory neurones, and (ii) direct inhibition of histamine release from mast cells. This GABA-B–Substance P–histamine axis functions as a key control point in the neurogenic inflammatory cascade, and its dysregulation—whether through GABA-B receptor withdrawal, antagonism, or functional impairment—may contribute to pathological neurogenic inflammation. Two clinical phenomena illustrate the axis in action. First, baclofen (GABA-B agonist) withdrawal produces severe pruritus, attributed to rebound Substance P release and subsequent mast cell histamine release. Second, GABA derivatives such as gabapentin and pregabalin have shown efficacy in neurogenic rosacea, a condition driven by Substance P-mediated mast cell activation. We argue that both phenomena are manifestations of the same underlying mechanism: modulation of the GABA-B–Substance P–histamine axis. This paper forms the third part of a trilogy: the first defined the destabilised neuroimmune feedback loop, the second identified CREB as the gain-setting amplifier, and the present work characterises the inhibitory brake mediated by the GABA-B–Substance P–histamine axis. Together, these papers outline a complete control-theoretic model of neurogenic inflammation: a destabilised loop, a gain-setting amplifier, and an inhibitory brake. This unified framework provides a mechanistic foundation for future therapeutic strategies targeting loop gain, loop sensitivity, or inhibitory tone.