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Comparison of the transport of QX-314 through TRPA1, TRPM8, and TRPV1 channels

1 , 2

Journal of Pain Research

Dove Medical Press

anesthetics, capsaicin, AITC, menthol, capsazepine, behavioral tests

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      Abstract

      BackgroundIt has been demonstrated that N-ethyl-lidocaine (QX-314) can target the transient receptor protein vanilloid 1 (TRPV1) nociceptors when coadministered with capsaicin, resulting in a selective block of the nociceptors. Capsaicin is problematic in therapeutic use because it induces firing of nociceptors. The present study aimed to search for substitutes for capsaicin. We also examined the transportability of QX-314 into nociceptive neurons, through the pores of transient receptor potential ankyrin 1 (TRPA1), transient receptor potential melastatin-8 (TRPM8), and TRPV1.MethodsTo investigate the effect on TRPA1, injections of a vehicle, allyl isothiocyanate (AITC), QX-314, or AITC/QX-314 were made into the hind paws of rats. The effects of menthol and capsaicin on the opening of TRPM8 and TRPV1 were also examined and compared with the potency of QX-314. To examine inhibition of the antinociceptive effect by capsaicin/ QX-314, capsazepine (50 μg/mL; 10 μL) was injected 30 minutes prior to capsaicin/QX-314 (10 μL) injection. Thermal sensitivity was investigated by the Hargreaves method. 5(6)-carboxyfluorescein (FAM)-conjugated QX-314 was used as a tracer to examine how many and which kind of dorsal root ganglia accumulate this molecule. QX-314-FAM, capsaicin/QX-314-FAM, AITC/QX-314-FAM, and menthol/QX-314-FAM were injected into the paw. Two weeks after injections, dorsal root ganglia were removed and sectioned with a cryostat.ResultsThe capsaicin/QX-314 group induced longer withdrawal-response latency at 60 to 300 minutes after injection than the control. Both menthol only and menthol/QX-314 injections showed analgesia 10 to 60 minutes after injection. No significant difference was seen between the capsazepine/capsaicin/QX-314 group and the vehicle group. The fluorescence in small- and medium-sized neurons was conspicuous in only the dorsal root ganglia injected with capsaicin/ QX-314-FAM.ConclusionThese results indicate that TRPA1 and TRPM8 are ineffective in the transport of QX-314 compared with TRPV1.

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      Most cited references 39

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      The capsaicin receptor: a heat-activated ion channel in the pain pathway.

      Capsaicin, the main pungent ingredient in 'hot' chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons. This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels. The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.
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        A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.

        A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia. Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
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          Identification of a cold receptor reveals a general role for TRP channels in thermosensation.

          The cellular and molecular mechanisms that enable us to sense cold are not well understood. Insights into this process have come from the use of pharmacological agents, such as menthol, that elicit a cooling sensation. Here we have characterized and cloned a menthol receptor from trigeminal sensory neurons that is also activated by thermal stimuli in the cool to cold range. This cold- and menthol-sensitive receptor, CMR1, is a member of the TRP family of excitatory ion channels, and we propose that it functions as a transducer of cold stimuli in the somatosensory system. These findings, together with our previous identification of the heat-sensitive channels VR1 and VRL-1, demonstrate that TRP channels detect temperatures over a wide range and are the principal sensors of thermal stimuli in the mammalian peripheral nervous system.
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            Author and article information

            Affiliations
            [1 ]Dentistry for Persons with Disability, Tokushima University Hospital, Tokushima, Japan
            [2 ]Department of Oral Histology, School of Dentistry, University of Tokushima, Tokushima, Japan
            Author notes
            Correspondence: Hiroshi Nakagawa Dentistry for Persons with Disability, Tokushima University Hospital, 3-18-15 Kuramoto cho, Tokushima 770, Japan Tel +81 88 633 7970 Fax +81 88 633 7970 Email nakagawa@ 123456dent.tokushima-u.ac.jp
            Journal
            J Pain Res
            J Pain Res
            Journal of Pain Research
            Dove Medical Press
            1178-7090
            2013
            16 March 2013
            : 6
            : 223-230
            23525210
            3604974
            10.2147/JPR.S41614
            jpr-6-223
            © 2013 Nakagawa and Hiura, publisher and licensee Dove Medical Press Ltd

            This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

            Categories
            Original Research

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