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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

          Background

          It 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.

          Methods

          To 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.

          Results

          The 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.

          Conclusion

          These results indicate that TRPA1 and TRPM8 are ineffective in the transport of QX-314 compared with TRPV1.

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          Most cited references 37

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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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            • Article: not found

            A TRP channel that senses cold stimuli and menthol.

            A distinct subset of sensory neurons are thought to directly sense changes in thermal energy through their termini in the skin. Very little is known about the molecules that mediate thermoreception by these neurons. Vanilloid Receptor 1 (VR1), a member of the TRP family of channels, is activated by noxious heat. Here we describe the cloning and characterization of TRPM8, a distant relative of VR1. TRPM8 is specifically expressed in a subset of pain- and temperature-sensing neurons. Cells overexpressing the TRPM8 channel can be activated by cold temperatures and by a cooling agent, menthol. Our identification of a cold-sensing TRP channel in a distinct subpopulation of sensory neurons implicates an expanded role for this family of ion channels in somatic sensory detection.
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              • Record: found
              • Abstract: found
              • Article: not found

              ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures.

              Mammals detect temperature with specialized neurons in the peripheral nervous system. Four TRPV-class channels have been implicated in sensing heat, and one TRPM-class channel in sensing cold. The combined range of temperatures that activate these channels covers a majority of the relevant physiological spectrum sensed by most mammals, with a significant gap in the noxious cold range. Here, we describe the characterization of ANKTM1, a cold-activated channel with a lower activation temperature compared to the cold and menthol receptor, TRPM8. ANKTM1 is a distant family member of TRP channels with very little amino acid similarity to TRPM8. It is found in a subset of nociceptive sensory neurons where it is coexpressed with TRPV1/VR1 (the capsaicin/heat receptor) but not TRPM8. Consistent with the expression of ANKTM1, we identify noxious cold-sensitive sensory neurons that also respond to capsaicin but not to menthol.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2013
                16 March 2013
                : 6
                : 223-230
                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
                Article
                jpr-6-223
                10.2147/JPR.S41614
                3604974
                23525210
                © 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

                Anesthesiology & Pain management

                anesthetics, behavioral tests, capsazepine, menthol, aitc, capsaicin

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