*ATP: Purinergic Receptors*

ATP acts as an extracellular signaling molecule that affects numerous downstream factors and signaling cascades. Signaling involving a purine nucleotide or nucleoside, such as ATP, is called purinergic signaling and is associated with multiple levels of nociception and immune responses in the oral system [132]. For example, P2X receptors (P2XRs) are expressed in the nociceptive TG cells [133,134] as well as in tooth pulp cells [35,135,136]. P2X positive nerve fibers have been detected in the subodontoblastic plexus close to odontoblasts [33,135,137]. P2XR2 and P2XR3 receptors have been found in both pulp nerves and a subpopulation of rat TG neurons [134,138–141]. In addition, a study showed that the presence of the P2X3 receptor and possibly the heteromeric P2X2/3 receptor in the trigeminal subnucleus caudalis (Vc) initiates and maintains the central sensitization in rat tooth pulp nociceptive neurons [142].

Recent studies suggest that P2X3 receptor activation by ATP induces tooth nociception in rat tooth pulp [33,139]. Importantly, an ATP derivative is sufficient to elicit behavioral pain sensation in tooth pulp [143] and odontoblasts contribute to the sensory function of teeth by releasing ATP in response to physical stimuli [19,66,129,144,145]. Furthermore, odontoblasts themselves express different P2XR subtypes (Figure 4) [34,146]. Since blocking extracellular ATP release results in the inhibition of interodontoblastic communication, ATP might regulate the physiology of odontoblasts via autocrine or paracrine mechanisms [19]. G-protein coupled P2Y ATP receptors are also present in pulp cells [136], TG neurons [147,148], trigeminal satellite glial cells [149], and odontoblasts [129,136].

**Figure 4.** Other types of ion channels such as ligand gated ion channels and voltage gated ion channels expressed in the dental sensory system. ATP molecules released by adjacent odontoblast or fibroblast cells in pulp by external stimuli and they induce activation of purinergic receptors in odontoblasts or DPA neurons. Various types of voltage gated ion channels are also expressed in dental pain sensory cells but their functions are not clearly revealed.
