Decoding visceral pain: Molecular pathways and translational targets in gaseous signalling and pharmacology

Visceral pain, a hallmark of many gastrointestinal (GI) disorders, remains a persistent clinical challenge due to its multifactorial pathophysiology and limited treatment options. Recent advances highlight the role of endogenous gaseous signalling molecules, hydrogen sulphide (H₂S), nitric oxide (NO) and carbon monoxide (CO) in maintaining GI mucosal integrity. Notably, their involvement in neurosignalling and pain modulation, including within the enteric nervous system, has also been suggested. However, their contribution to visceral nociception remains incompletely understood. These gasotransmitters exhibit both anti- and pro-nociceptive properties in a context-dependent manner, influenced by factors such as dose, tissue specificity, experimental model and the complex interplay between opposing nociceptive pathways. This review brings together current, though still relatively limited, evidence to rationally explore the role of gaseous mediators in visceral pain. We highlight underexplored mechanisms and conceptual gaps that may underlie the dual and context-specific roles of gaseous mediators in nociceptive signalling. In addition to endogenous molecules, we discuss the therapeutic potential of pharmacological agents engineered to release these gases in a controlled manner, based on recent advances in medicinal chemistry. Particular emphasis is placed on these approaches not only as promising therapeutic strategies but also as fundamental contributors to the pathogenesis of visceral pain.