Pain is initiated when noxious thermal, mechanical, or chemical stimuli excite the peripheral terminals of specialized primary afferent neurons called nociceptors. Many different kinds of ionotropic and metabotropic receptors are known to be involved in this process. Capsaicin, the main ingredient in ‘hot’ chili peppers, elicits burning pain by activating specific (vanilloid) receptors on sensory nerve endings. The cloned capsaicin receptor (VR1) is a nonselective cation channel with six transmembrane domains. When expressed heterologously in HEK293 cells or Xenopus oocytes, VR1 is activated not only by capsaicin but also by heat in the noxious range (>43°C) or by protons. VR1 function as a detector of multiple pain-producing stimuli was verified by a behavioral study in mice lacking VR1. Thus, VR1 plays an important role in nociception.
It has been proposed that ATP, released from different cell types, initiates the sensation of pain by acting predominantly on nociceptive ionotropic purinoceptors located on sensory nerve terminals. We examined the effects of extracellular ATP on VR1 activity. In cells expressing VR1, ATP increased the currents evoked by capsaicin or protons through activation of metabotropic P2Y₁ receptors in a PKC-dependent pathway. The involvement of G_{q 11}-coupled metabotropic receptors in the potentiation of VR1 response was confirmed in cells expressing both VR1 and M1 muscarinic acetylcholine receptors. In the presence of ATP, the temperature threshold for VR1 ctivation was reduced from 42°C to 35°C, such that normally non-painful thermal stimuli (i.e. normal body temperature) were capable of activating VR1. This represents a novel mechanism through which the large amounts of ATP released from damaged cells in response to tissue trauma might trigger the sensation of pain.