Summary Polymodal nociceptors detect noxious stimuli including harsh touch, toxic chemicals, and extremes of heat and cold. The molecular mechanisms by which nociceptors are able to sense multiple qualitatively distinct stimuli are not well-understood. We show here that the C. elegans PVD neurons are mulitidendritic nociceptors that respond to harsh touch as well as cold temperatures. The harsh touch modality specifically requires the DEG/ENaC proteins MEC-10 and DEGT-1, which represent putative components of a harsh touch mechanotransduction complex. By contrast, responses to cold require the TRPA-1 channel and are MEC-10- and DEGT-1-independent. Heterologous expression of C. elegans TRPA-1 can confer cold responsiveness to other C. elegans neurons or to mammalian cells, indicating that TRPA-1 is itself a cold sensor. These results show that C. elegans nociceptors respond to thermal and mechanical stimuli using distinct sets of molecules, and identify DEG/ENaC channels as potential receptors for mechanical pain.
BACKGROUND AND PURPOSETemperature-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. EXPERIMENTAL APPROACHWe examined the effect of RvD1 on the six thermoTRPs using Ca 2+ imaging and whole cell electrophysiology experiments using the HEK cell heterologous expression system, cultured sensory neurons and HaCaT keratinocytes. We also checked changes in agonist-specific acute licking/flicking or flinching behaviours and TRP-related mechanical and thermal pain behaviours using Hargreaves, Randall-Selitto and von Frey assay systems with or without inflammation. KEY RESULTSRvD1 inhibited the activities of TRPA1, TRPV3 and TRPV4 at nanomolar and micromolar levels. Consistent attenuations in agonist-specific acute pain behaviours by immediate peripheral administration with RvD1 were also observed. Furthermore, local pretreatment with RvD1 significantly reversed mechanical and thermal hypersensitivity in inflamed tissues. CONCLUSIONS AND IMPLICATIONSRvD1 was a novel endogenous inhibitor for several sensory TRPs. The results of our behavioural studies suggest that RvD1 has an analgesic potential via these TRP-related mechanisms.
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 Ca 2؉ 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.Skin keratinocytes and sensory neurons express sensor ion channels that detect changes in the external or internal environments. TRPV3 channel has been found to be expressed in the skin keratinocytes of mice and humans and in the sensory neurons of humans and is activated by temperatures exceeding 33°C (1-3). Studies using TRPV3-knock-out mice or TRPV3-overexpressing transgenic mice have demonstrated that TRPV3 is involved in behavioral responses to innocuous and noxious heat (4 -5).Searching for pharmacological tools to modulate TRPV3 activity seems active (see review, Ref. 6). Several phytosubstances and synthetic compounds, such as camphor, menthol, carvacrol, citral, incensole acetate, and 2-aminoethoxydiphenyl borate (2-APB) 2 are shown to activate TRPV3 (4, 7-13). It has been reported that some of endogenous molecules are able to modulate TRPV3 activation. For example, unsaturated fatty acids potentiated TRPV3 activation by 2-APB (14). S-Nitrosylation of the channel protein activates TRPV3, as well as other TRPVs (15). Ca 2ϩ and calmodulin suppressed the sensitization of TRPV3 to recurrent stimuli (16). However, little is known about endogenous compounds that are able to directly and specifically activate TRPV3.A variety of metabolites are formed in the human body as a result of the diverse biochemical processes and some of the metabolites are potentially involved in pain development (17). Farnesyl pyrophosphate (FPP) is an intermediate molecule in the cholesterol synthesis pathway. In the present study, we examined whether FPP is an activator for TRPV3. We performed Ca 2ϩ ...
BACKGROUND AND PURPOSETransient 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. EXPERIMENTAL APPROACHWe examined the effect of 17R-RvD1 on sensory TRP channels using Ca 2+ imaging and whole cell electrophysiology experiments in a HEK cell heterologous expression system, cultured sensory neurons and keratinocytes. We also examined changes in sensory TRP agonist-specific acute licking/flicking or flinching behaviours and mechanical and thermal pain behaviours using Hargreaves, Randall-Selitto and von Frey assay systems in the absence and presence of inflammation. KEY RESULTSWe showed that 17R-RvD1 specifically suppresses TRPV3-mediated activity at nanomolar and micromolar concentrations. The voltage-dependence of TRPV3 activation by camphor was shifted rightwards by 17R-RvD1, which indicates its inhibitory mechanism is as a result of a shift in voltage-dependence. Consistently, TRPV3-specific acute pain behaviours were attenuated by locally injected 17R-RvD1. Moreover, the administration of 17R-RvD1 significantly reversed the thermal hypersensitivity that occurs during an inflammatory response. Knockdown of epidermal TRPV3 blunted these antinociceptive effects of 17R-RvD1. CONCLUSIONS AND IMPLICATIONS17R-RvD1 is a novel natural inhibitory substance specific for TRPV3. The results of our behavioural studies suggest that 17R-RvD1 has acute analgesic potential via TRPV3-specific mechanisms.
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