The Concept of Cotransmission: Focus on ATP as a Cotransmitter and its Significance in Health and Disease

The concept of cotransmission, including sympathetic nerve release of noradrenaline and ATP, was formalised in 1976, which challenged the accepted view known as ‘Dale's Principle’ that one nerve released only one transmitter. ATP was also shown to be a cotransmitter with acetylcholine in parasympathetic nerves supplying the urinary bladder and as a cotransmitter with nitric oxide in non-adrenergic, non-cholinergic inhibitory nerves supplying the intestine. It is now recognised that ATP is a cotransmitter in most, if not all, nerves in the peripheral and central nervous systems. The physiological significance of cotransmission will be considered. In pathophysiology, the role of ATP as a cotransmitter appears to increase as shown, for example, in the parasympathetic nerves supplying the diseased human bladder and in sympathetic nerves in spontaneously hypertensive rats. ATP is likely to be involved in sympathetic pain, causalgia and reflex sympathetic dystrophy. Purinergic signalling also appears to be enhanced in inflammatory and stress conditions.