Toothache trees

In traditional folk medicine, xanthoxylum plants are referred to as toothache trees because their anesthetic or counter-irritant properties render them useful in the treatment of pain. Pshychophysical studies have identified hydroxyl- α-sanshool as the compound most responsible for the unique tingling and buzzing sensations produced by Szechuan peppercorns. Although it is generally agreed that sanshool eleicts its effects by activating somatosensory neurons, the underlying cellular and molecular mechanisms remain a matter of debate.

….. Sanshool activates a constellation of sensory neurons that include specific subpopulations of small and large diameter cells, which together represent a unique subset of nociceptors and presumptive light-touch receptors. ….we find that sanshool excites these neurons by inhibiting background potassium conductances. Specifically, we identify three members of the pH-sensitive two-pore KCNK channel family as being molecular targets for sanshool action. Notably, these channels are targeted by volatile anaesthetics, perhaps accounting for the numbing properties elicited by sanshool compounds and for the use of Xanthoxylum extracts in traditional folk medicine for treating toothache and other types of orofacial pain.

Nature, Neuroscience; Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels, vol 11 no 7 July 2008

Interest in nociceptive channels is thus likely to remain high and not just among basic researchers. "At this stage, any new targets are interesting for pain." This is because the most commonly used pain medications, such as opioids and non-steroidal inflammatory agents, also act on receptors outside the pain pathway, causing unwanted side effects. According to Jesus Gonzalez, of Vertex Pharmaceuticals, his company and others are placing "significant emphasis on targeting peripheral mechanisms for pain," hoping to come up with new, side-effect-free methods for controlling pain.

Although nociceptors have been known about for more than a century, only in the last decade have researchers identified the specific ion channels that respond to noxious, potentially tissue-damaging stimuli. This is our "first molecular insight into the detection of stimuli under normal, acute pain conditions," says David Julius, of the University of California, San Francisco, whose group discovered transient receptor potential V1 (TRPV1), one of the first channels implicated in nociception.

http://www.the-scientist.com/2005/03/28/S20/1/

neurons were cultured from trigeminal or dorsal root ganglia of the mouse and responses assessed using live-cell calcium imaging as a functional readout
According to John Wood, who leads the molecular nociception group at University College London, there are two classes of channels involved in nociception. One class is responsible for detecting noxious stimuli and the products of tissue damage. Of the 20 to 30 TRP channels identified, at least nine are involved in these functions, in addition to members of the acid-sensing channel, or ASIC, family, and the adenosine triphosphate (ATP)-gated P2X receptor family.

Nociceptors reach into every tissue of the body, from the skin to the gastro intestinal tract. They arise from clusters of sensory neuron cell bodies, known as dorsal root ganglia, located at the junction between the spinal cord and the peripheral nervous system. When nociceptors are activated by painful stimuli, these neurons generate an action potential, resulting in synaptic transmission to "second-order" neurons buried in the spinal cord's grey matter. These second-order neurons in turn transmit the sensation of pain to the brain for processing and interpretation at a conscious level.

http://www.the-scientist.com/2005/03/28/S20/1/