The activation of spinal cord glial cells has been implicated in the development of neuropathic pain upon peripheral nerve injury. The molecular mechanisms underlying glial cell activation, however, have not been clearly elucidated. In this study, we found that damaged sensory neurons induce the expression of tumor necrosis factor-α, interleukin-1β, interleukin-6, and inducible nitric-oxide synthase genes in spinal cord glial cells, which is implicated in the development of neuropathic pain. Studies using primary glial cells isolated from toll-like receptor 2 knock-out mice indicate that damaged sensory neurons activate glial cells via toll-like receptor 2. In addition, behavioral studies using toll-like receptor 2 knock-out mice demonstrate that the expression of toll-like receptor 2 is required for the induction of mechanical allodynia and thermal hyperalgesia due to spinal nerve axotomy. The nerve injury-induced spinal cord microglia and astrocyte activation is reduced in the toll-like receptor 2 knock-out mice. Similarly, the nerve injury-induced pro-inflammatory gene expression in the spinal cord is also reduced in the toll-like receptor 2 knock-out mice. These data demonstrate that toll-like receptor 2 contributes to the nerve injury-induced spinal cord glial cell activation and subsequent pain hypersensitivity.

Sensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved. We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons. Infiltration of cytotoxic NK cells into the sciatic nerve by extravasation occurs within 3 days following crush injury. Using a combination of genetic cell ablation and cytokine-antibody complex stimulation, we show that NK cell function correlates with loss of sensation due to degeneration of injured afferents and reduced incidence of post-injury hypersensitivity. This neuro-immune mechanism of selective NK cell-mediated degeneration of damaged but intact sensory axons complements Wallerian degeneration and suggests the therapeutic potential of modulating NK cell function to resolve painful neuropathy through the clearance of partially damaged nerves.

Curcumin has diverse therapeutic effects, such as anti-inflammatory, anti-oxidant, anti-cancer, and antimicrobial activities. The vanilloid moiety of curcumin is considered important for activation of the transient receptor potential vanilloid 1 (TRPV1), which plays an important role in nociception. However, very little is known about the effects of curcumin on nociception. In the present study, we investigated whether the anti-nociceptive effects of curcumin are mediated via TRPV1 by using nociceptive behavioral studies and in vitro whole-cell patch-clamp recordings in the trigeminal system. Subcutaneous injection of capsaicin in the vibrissa pad area of rats induced thermal hyperalgesia. Intraperitoneally administered curcumin blocked capsaicin-induced thermal hyperalgesia in a dose-dependent manner. Whereas curcumin reduced capsaicin-induced currents in a dose-dependent manner in both trigeminal ganglion neurons and TRPV1-expressing HEK 293 cells, curcumin did not affect heat-induced TRPV1 currents. Taken together, our results indicate that curcumin blocks capsaicin-induced TRPV1 activation and thereby inhibits TRPV1-mediated pain hypersensitivity.

Although eugenol is widely used in dentistry, little is known about the molecular mechanisms responsible for its anesthetic properties. In addition to calcium channels, recently demonstrated by our group, there could be another molecular target for eugenol. Using a whole-cell patch-clamp technique, we investigated the effect of eugenol on voltage-gated sodium channel currents ( I_Na) in rat dental primary afferent neurons identified by retrograde labeling with a fluorescent dye in maxillary molars. Eugenol inhibited action potentials and I_Nain both capsaicin-sensitive and capsaicin-insensitive neurons. The pre-treatment with capsazepine, a competitive antagonist of transient receptor potential vanilloid 1 (TRPV1), failed to block the inhibitory effect of eugenol on I_Na, suggesting no involvement of TRPV1. Two types of I_Na, tetrodotoxin (TTX)-resistant and TTX-sensitive I_Na, were inhibited by eugenol. Our results demonstrated that eugenol inhibits I_Nain a TRPV1-independent manner. We suggest that I_Nainhibition by eugenol contributes to its analgesic effect.

Due, in part, to the unique structure of the tooth, dental pain is initiated via distinct mechanisms. Here we review recent advances in our understanding of inflammatory tooth pain and discuss 3 hypotheses proposed to explain dentinal hypersensitivity: The first hypothesis, supported by functional expression of temperature-sensitive transient receptor potential channels, emphasizes the direct transduction of noxious temperatures by dental primary afferent neurons. The second hypothesis, known as hydrodynamic theory, attributes dental pain to fluid movement within dentinal tubules, and we discuss several candidate cellular mechanical transducers for the detection of fluid movement. The third hypothesis focuses on the potential sensory function of odontoblasts in the detection of thermal or mechanical stimuli, and we discuss the accumulating evidence that supports their excitability. We also briefly update on a novel strategy for local nociceptive anesthesia via nociceptive transducer molecules in dental primary afferents with the potential to specifically silence pain fibers during dental treatment. Further understanding of the molecular mechanisms of dental pain would greatly enhance the development of therapeutics that target dental pain.