**1. Introduction**

The tooth is a unique sensory system that senses external stimuli predominantly as nociception. Most of the nerves innervating tooth pulp have been presumed to be nociceptors since most axons in tooth pulp are unmyelinated or small fibers that are myelinated [1]. However, this belief was challenged by multiple observations that pulpal nerves possess physical and chemical properties of large myelinated Aβ fibers. Due to these paradoxical findings, a new concept of "algoneurons" was introduced [2,3].

The structure of the tooth is comprised of densely vascularized and innervated tooth pulp covered by two layers of hard tissue—the dentin and enamel [3,4]. The dentin and enamel are distinguished by their microstructure and mineral content. The outermost enamel layer is the hardest tissue in the body, with minerals forming 97% of its weight. The dentin layer lies between the tooth pulp and the enamel layer and has an intermediate hardness with a mineral content slightly higher than that of bone, providing resilience to the enamel. The most notable property of dentin is its microstructure. Dentin is made of thousands of microtubules—dentinal tubules—filled with dentin tubular fluid. Odontoblasts are the cells that deposit the calcium matrix to form dentin and constitute a cellular single layer at the

inter-surface of the dentin and the tooth pulp. Each odontoblast possesses a process that protrudes into the dentinal tubules (Figure 1).

**Figure 1.** Anatomical features of the dental pain sensory system. Odontoblasts comprise the outermost cell layer of dental pulp tissue, which is advantageous to odontoblasts playing the role of a sensory transducer. Some nerve endings of dental primary afferents (DPAs) spread into the dentinal tubule. This structural nature establishes a distinctive sensory mechanism for the tooth.

The structure of teeth results in a unique pattern of nociception. One example is a special condition known as dentin hypersensitivity—the exaggerated nociception in teeth caused by non-noxious mechanical, chemical, or thermal stimuli without the pulpal inflammation predisposed or the nerve damage in the adjacent tissue [5–8]. While the molecular mechanisms underlying dentin hypersensitivity have not been fully elucidated, one promising hypothesis—the hydrodynamic theory—states that external stimuli cause the movement of the dentin tubular fluid to, ultimately, excite nerve fibers in the pulp to initiate pain. This provides the most plausible explanation for dental cold hypersensitivity of all the hypotheses that have been proposed, although not without controversy [9–20]. Another example is the pulsating nature of tooth pain often described by chronic pulpitis patients. This phenomenon is presumed to be caused by hydrostatic pressure applied to the edematous tooth pulp in the restricted space within the dentin and enamel. Both the pulsating pain associated with pulpal inflammation and the hydrodynamic theory of dental hypersensitivity require a mechanosensitive receptor as a key molecule. However, understanding such a receptor and its associated mechanism of action only began not long ago. This review summarizes the most recent advances in the understanding of the molecular and cellular mechanisms of mechanotransduction in the context of tooth pain.

The tooth is exposed to drastic temperature changes of the oral cavity. Although the harsh thermal conditions from food consumption hardly induce tooth pain under normal circumstances because of the excellent thermal insulating of the enamel tissue [21–24], mild temperature changes can induce intense pain with exposed dentin or pulpal inflammation. For example, noxious cold induces sharp and transient pain while noxious heat induces dull and lasting pain [25,26]. To elucidate the molecular mechanisms associated with temperature-driven tooth pain, the expression and physiology of molecular thermosensor candidates, such as the transient receptor potential (TRP) channel superfamily, have been investigated. A large variety of temperature receptors that may play critical roles in the transduction of tooth pain are expressed in dental primary afferent nerves [22,27] and odontoblasts [5,6,8–10,18].

In addition, voltage-gated and ligand-gated ion channels take important roles in tooth pain. Not only are various types of voltage-gated ion channels expressed in the trigeminal sensory nerve on common nerve cells, but they are also expressed in odontoblast cells [22,28–32]. Previous studies have indicated that small molecules, such as adenosine 5 -triphosphate (ATP), and their ionotropic receptors, the P2X family, play an important role in the sensory system for tooth pain [19,33–35]. In this review, we summarize the research on temperature-sensitive, mechanosensitive, ligand-gated, and voltage-gated ion channels and their role in the sensory system for tooth pain.
