Sangsu Bang

Resolvin D1 attenuates activation of sensory transient receptor potential channels leading to multiple anti-nociception

BACKGROUND AND PURPOSE Temperature‐sensitive transient receptor potential ion channels (thermoTRPs) expressed in primary sensory neurons and skin keratinocytes play a crucial role as peripheral pain detectors. Many natural and synthetic ligands have been found to act on thermoTRPs, but little is known about endogenous compounds that inhibit these TRPs. Here, we asked whether resolvin D1 (RvD1), a naturally occurring anti‐inflammatory and pro‐resolving lipid molecule is able to affect the TRP channel activation.

Transient receptor potential A1 mediates acetaldehyde‐evoked pain sensation

Six transient receptor potential (TRP) ion channels expressed in the sensory afferents play an important role as body thermosensors and also as peripheral pain detectors. It is known that a number of natural compounds specifically activate those sensory neuronal TRP channels, and a well‐known example is cinnamaldehyde for TRPA1. Here we show that human and mouse TRPA1 are activated by acetaldehyde, an intermediate substance of ethanol metabolism, in the HEK293T cell heterologous expression system and in cultured mouse trigeminal neurons. Acetaldehyde failed to activate other temperature‐sensitive TRP channels expressed in sensory neurons. TRPA1 antagonists camphor and gadolinium, and a general TRP blocker ruthenium red inhibited TRPA1 activation by acetaldehyde. Camphor, gadolinium and ruthenium red also suppressed the acute nociceptive behaviors induced by the intradermal administration of acetaldehyde into the mouse footpads. Intradermal co‐application of prostaglandin E2 and acetaldehyde greatly potentiated the acetaldehyde‐induced nociceptive responses, and this effect was reversed by treatment with the TRPA1 antagonist camphor. These results suggest that acetaldehyde causes nociception via TRPA1 activation. Our data may also help elucidate the mechanisms underlying acetaldehyde‐related pathological symptoms such as hangover pain.

Transient receptor potential V2 expressed in sensory neurons is activated by probenecid

Temperature-activated transient receptor potential ion channels (thermoTRPs) are known to function as ambient temperature sensors and are also involved in peripheral pain sensation. The thermoTRPs are activated by a variety of chemicals, of which specific activators have been utilized to explore the physiology of particular channels and sensory nerve subtypes. The use of capsaicin for TRPV1 is an exemplary case for nociceptor studies. In contrast, specific agents for another vanilloid subtype channel, TRPV2 have been lacking. Here, we show that probenecid is able to activate TRPV2 using electrophysiological and calcium imaging techniques with TRPV2-expressing HEK293T cells. Five other sensory thermoTRPs-TRPV1, TRPV3, TRPV4, TRPM8 and TRPA1-failed to show a response to this drug in the same heterologous expression system, suggesting that probenecid is a specific activator for TRPV2. Probenecid-evoked responses were also reproduced in a distinct subset of cultured trigeminal neurons that were responsive to 2-aminoethoxydiphenyl borate, a TRPV1-3 activator. The probenecid-sensitive neurons were mainly distributed in a medium to large-diameter population, in agreement with previous observations with TRPV2 immunolocalization. Under inflammation, probenecid elicited nociceptive behaviors in in vivo assays. These results suggest that TRPV2 is specifically activated by probenecid and that this chemical might be useful for investigation of pain-related TRPV2 function.

Farnesyl pyrophosphate is a novel pain-producing molecule via specific activation of TRPV3.

Temperature-sensitive transient receptor potential ion channels (thermoTRPs) expressed in epidermal keratinocytes and sensory afferents play an important role as peripheral pain detectors for our body. Many natural and synthetic compounds have been found to act on the thermoTRPs leading to altered nociception, but little is known about endogenous painful molecules activating TRPV3. Here, we show that farnesyl pyrophosphate (FPP), an intermediate metabolite in the mevalonate pathway, specifically activates TRPV3 among six thermoTRPs using Ca2+ imaging and electrophysiology with cultured keratinocytes and TRPV3-overexpressing cells. Agonistic potencies of related compounds in the FPP metabolism were ignorable. Voltage-dependence of TRPV3 was shifted by FPP, which appears to be the activation mechanism. An intraplantar injection of FPP acutely elicits nociceptive behaviors in inflamed animals, indicating that FPP is a novel endogenous pain-producing substance via TRPV3 activation. Co-culture experiments demonstrated that this FPP-evoked signal in the keratinocytes is transmitted to sensory neurons. In addition, FPP reduced TRPV3 heat threshold resulting in heightened behavioral sensitivity to noxious heat. Taken together, our data suggest that FPP is the firstly identified endogenous TRPV3 activator that causes nociception. Our results may provide useful chemical information to elucidate TRPV3 physiology and novel pain-related metabolisms.

17(R)-resolvin D1 specifically inhibits transient receptor potential ion channel vanilloid 3 leading to peripheral antinociception

BACKGROUND AND PURPOSE Transient receptor potential ion channel vanilloid 3 (TRPV3) is expressed in skin keratinocytes and plays an important role in thermal and chemical nociceptions in the periphery. The presence of TRPV3 inhibitors would improve our understanding of TRPV3 function and help to develop receptor‐specific analgesics. However, little is known about physiological substances that specifically inhibit TRPV3 activity. Here, we investigated whether 17(R)‐resolvin D1 (17R‐RvD1), a naturally occurring pro‐resolving lipid specifically affects TRPV3 activity.

Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade

Mechanical allodynia, induced by normally innocuous low-threshold mechanical stimulation, represents a cardinal feature of neuropathic pain. Blockade or ablation of high-threshold, small-diameter unmyelinated group C nerve fibers (C-fibers) has limited effects on mechanical allodynia. Although large, myelinated group A fibers, in particular Aβ-fibers, have previously been implicated in mechanical allodynia, an A-fiber–selective pharmacological blocker is still lacking. Here we report a new method for targeted silencing of A-fibers in neuropathic pain. We found that Toll-like receptor 5 (TLR5) is co-expressed with neurofilament-200 in large-diameter A-fiber neurons in the dorsal root ganglion (DRG). Activation of TLR5 with its ligand flagellin results in neuronal entry of the membrane-impermeable lidocaine derivative QX-314, leading to TLR5-dependent blockade of sodium currents, predominantly in A-fiber neurons of mouse DRGs. Intraplantar co-application of flagellin and QX-314 (flagellin/QX-314) dose-dependently suppresses mechanical allodynia after chemotherapy, nerve injury, and diabetic neuropathy, but this blockade is abrogated in Tlr5-deficient mice. In vivo electrophysiology demonstrated that co-application of flagellin/QX-314 selectively suppressed Aβ-fiber conduction in naive and chemotherapy-treated mice. TLR5-mediated Aβ-fiber blockade, but not capsaicin-mediated C-fiber blockade, also reduced chemotherapy-induced ongoing pain without impairing motor function. Finally, flagellin/QX-314 co-application suppressed sodium currents in large-diameter human DRG neurons. Thus, our findings provide a new tool for targeted silencing of Aβ-fibers and neuropathic pain treatment.

tmc-1 encodes a sodium-sensitive channel required for salt chemosensation in C. elegans

Transmembrane channel-like (TMC) genes encode a broadly conserved family of multipass integral membrane proteins in animals. Human TMC1 and TMC2 genes are linked to human deafness and required for hair-cell mechanotransduction; however, the molecular functions of these and other TMC proteins have not been determined. Here we show that the Caenorhabditis elegans tmc-1 gene encodes a sodium sensor that functions specifically in salt taste chemosensation. tmc-1 is expressed in the ASH polymodal avoidance neurons, where it is required for salt-evoked neuronal activity and behavioural avoidance of high concentrations of NaCl. However, tmc-1 has no effect on responses to other stimuli sensed by the ASH neurons including high osmolarity and chemical repellents, indicating a specific role in salt sensation. When expressed in mammalian cell culture, C. elegans TMC-1 generates a predominantly cationic conductance activated by high extracellular sodium but not by other cations or uncharged small molecules. Thus, TMC-1 is both necessary for salt sensation in vivo and sufficient to generate a sodium-sensitive channel in vitro, identifying it as a probable ionotropic sensory receptor.

Isopentenyl pyrophosphate is a novel antinociceptive substance that inhibits TRPV3 and TRPA1 ion channels

&NA; Transient receptor potential ion channels (TRPs) expressed in the periphery sense and electrically transduce noxious stimuli to transmit the signals to the brain. Many natural and synthetic ligands for the sensory TRPs have been found, but little is known about endogenous inhibitors of these TRP channels. Recently, we reported that farnesyl pyrophosphate, an endogenous substance produced in the mevalonate pathway, is a specific activator for TRPV3. Here, we show that isopentenyl pyrophosphate (IPP), an upstream metabolite in the same pathway, is a dual inhibitor for TRPA1 and TRPV3. By using Ca2+ imaging and voltage clamp experiments with human embryo kidney cell heterologous expression system, cultured sensory neurons, and epidermal keratinocytes, we demonstrate that micromolar IPP suppressed responses to specific agonists of TRPA1 and TRPV3. Consistently, peripheral IPP administration attenuated TRPA1 and TRPV3 agonist‐specific acute pain behaviors. Furthermore, local IPP pretreatment significantly reversed mechanical and thermal hypersensitivity of inflamed animals. Taken together, the present study suggests that IPP is a novel endogenous TRPA1 and TRPV3 inhibitor that causes local antinociception. Our results may provide useful chemical information to elucidate TRP physiology in peripheral pain sensation. Isopentenyl pyrophosphate, a substance generated in the mevalonate metabolism, inhibits TRPA1 and TRPV3, and it results in peripheral antinociception in a receptor‐dependent manner.

Polymodal ligand sensitivity of TRPA1 and its modes of interactions

Understanding the mechanism of peripheral pain sensation has progressed remarkably in recent years, in part thanks to the discovery of transient receptor potential (TRP) ion channels in sensory neurons. Among these ion channels, the TRPA1 subtype is attracting attention because of its ability to

Nociceptive and pro‐inflammatory effects of dimethylallyl pyrophosphate via TRPV4 activation

BACKGROUND AND PURPOSE Sensory neuronal and epidermal transient receptor potential ion channels (TRPs) serve an important role as pain sensor molecules. While many natural and synthetic ligands for sensory TRPs have been identified, little is known about the endogenous activator for TRPV4. Recently, we reported that endogenous metabolites produced by the mevalonate pathway regulate the activities of sensory neuronal TRPs. Here, we show that dimethylallyl pyrophosphate (DMAPP), a substance produced by the same pathway is an activator of TRPV4.