mice than in humans, such studies unnecessarily muddled a finding that local inflammation can result in the local release of adenosine with analgesic effect." the anti-nociceptive effect of acupuncture may be mediated by the adenosine a1 receptor. electroacupuncture may inhibit pain by the activation of a variety of bioactive chemicals through peripheral, spinal, and supraspinal mechanisms of the nervous system. anti-inflammatory drugs methotrexate, which has strong anti-inflammatory properties, inhibits the action of dihydrofolate reductase, leading to an accumulation of adenosine. on the other hand, the adenosine-receptor antagonist caffeine reverses the anti-inflammatory effects of methotrexate. anti-platelet drugs many anti-platelet drugs such as prasugrel, ticagrelor, and ticlopidine are adenosine diphosphate (adp) receptor inhibitors. before the expiry of its patent, the p2y12 receptor antagonist clopidogrel (trade name: plavix) was the second most prescribed drug in the world. in 2010 alone, it generated over us$9 billion in global sales. bronchodilators theophylline was originally used as a bronchodilator, although its usage has declined due to several side effects such as seizures and cardiac arrhythmias caused by adenosine a1 receptor antagonism. herbal medicine several herbs used in traditional chinese medicine contain drug compounds that are antagonists of p2x purinoreceptors. the following table provides an overview of these drug compounds and their interaction with purinergic receptors. herbdrug compoundphysiologic effects on purinergic receptors many tetramethylpyrazine attenuation of acute nociception in dorsal root ganglia via p2rx3 antagonism modulation of p2rx3 expression on sensory nerve terminals of burned skin ligusticum wallichii sodium ferulate reduction of thermal and mechanical hyperalgesia via p2rx3 antagonism kudzu puerarin reduction of chronic neuropathic pain via p2rx3 and p2x2/3 antagonism rheum officinale emodin inhibition of cancer growth via p2rx7 antagonism rhubarb chrysophanol induction of necrosis in human liver cancer cells via a decrease in atp levels. vasodilators regadenoson, a vasodilator which acts on the adenosine a2a receptor, was approved by the united states food and drug administration in 2008 and is currently widely used in the field of cardiology. both adenosine and dipyridamole, which act on the a2a receptor, are used in myocardial perfusion imaging. proposed purinergic signalling is an important regulatory mechanism in a wide range of inflammatory diseases. it is understood that shifting the balance between purinergic p1 and p2 signalling is an emerging therapeutic concept that aims to dampen pathologic inflammation and promote healing. the following list of proposed medications is based on the workings of the purinergic signalling system: diquafosol - agonist of the p2y2 receptor used in the treatment of dry eye disease. istradefylline - antagonist of the adenosine a2a receptor, used in the treatment of parkinson's disease as an adjunct to l-dopa. history the earliest reports of purinergic signalling date back to 1929, when the hungarian physiologist albert szent-györgyi observed that purified adenine compounds produced a temporary reduction in heart rate when injected into animals. in the 1960s, the classical view of autonomic smooth muscle control was based upon dale's principle, which asserts that each nerve cell can synthesize, store, and release only one neurotransmitter. it was therefore assumed that a sympathetic neuron releases noradrenaline only, while an antagonistic parasympathetic neuron releases acetylcholine only. although the concept of cotransmission gradually gained acceptance in the 1980s, the belief that a single neuron acts via a single type of neurotransmitter continued to dominate the field of neurotransmission throughout the 1970s. beginning in 1972, geoffrey burnstock ignited decades of controversy after he proposed the existence of a non-adrenergic, non-cholinergic (nanc) neurotransmitter, which he identified as atp after observing the cellular responses in a number of systems exposed to the presence of cholinergic and adrenergic blockers. burnstock's proposal was met with criticism, since atp is an ubiquitous intracellular molecular energy source so it seemed counter-intuitive that cells might also actively release this vital molecule as a neurotransmitter. after years of prolonged scepticism, however, the concept of purinergic signalling was gradually accepted by the scientific community. today, purinergic signalling is no longer considered to be confined to neurotransmission, but is regarded as a general intercellular communication system of many, if not all, tissues.