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Tramadol and its metabolite m1 selectively suppress transient receptor potential ankyrin 1 activity, but not transient receptor potential vanilloid 1 activity.
Anesth Analg. 2015 Apr; 120(4):790-8.A&A

Abstract

BACKGROUND

The transient receptor potential vanilloid 1 (TRPV1) and the transient receptor potential ankyrin 1 (TRPA1), which are expressed in sensory neurons, are polymodal nonselective cation channels that sense noxious stimuli. Recent reports showed that these channels play important roles in inflammatory, neuropathic, or cancer pain, suggesting that they may serve as attractive analgesic pharmacological targets. Tramadol is an effective analgesic that is widely used in clinical practice. Reportedly, tramadol and its metabolite (M1) bind to μ-opioid receptors and/or inhibit reuptake of monoamines in the central nervous system, resulting in the activation of the descending inhibitory system. However, the fundamental mechanisms of tramadol in pain control remain unclear. TRPV1 and TRPA1 may be targets of tramadol; however, they have not been studied extensively.

METHODS

We examined whether and how tramadol and M1 act on human embryonic kidney 293 (HEK293) cells expressing human TRPV1 (hTRPV1) or hTRPA1 by using a Ca imaging assay and whole-cell patch-clamp recording.

RESULTS

Tramadol and M1 (0.01-10 μM) alone did not increase in intracellular Ca concentration ([Ca]i) in HEK293 cells expressing hTRPV1 or hTRPA1 compared with capsaicin (a TRPV1 agonist) or the allyl isothiocyanate (AITC, a TRPA1 agonist), respectively. Furthermore, in HEK293 cells expressing hTRPV1, pretreatment with tramadol or M1 for 5 minutes did not change the increase in [Ca]i induced by capsaicin. Conversely, pretreatment with tramadol (0.1-10 μM) and M1 (1-10 μM) significantly suppressed the AITC-induced [Ca]i increases in HEK293 cells expressing hTRPA1. In addition, the patch-clamp study showed that pretreatment with tramadol and M1 (10 μM) decreased the inward currents induced by AITC.

CONCLUSIONS

These data indicate that tramadol and M1 selectively inhibit the function of hTRPA1, but not that of hTRPV1, and that hTRPA1 may play a role in the analgesic effects of these compounds.

Authors+Show Affiliations

From the *Division of Cancer Pathophysiology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan; †Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan; ‡Tsumura Research Labs, Tumura & Co., Inashiki-gun, Ibaraki, Japan; §Division of Biostatistics, Tohoku University Graduate School of Medicine, Clinical Research Data Center, Tohoku University Hospital, Sendai, Miyagi, Japan; ∥Department of Palliative Medicine, Seirei Sakura Citizen Hospital, Sakura-shi, Chiba, Japan; and ¶Department of Palliative Medicine, Aomori Prefectural Central Hospital, Aomori-city, Aomori, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25642661

Citation

Miyano, Kanako, et al. "Tramadol and Its Metabolite M1 Selectively Suppress Transient Receptor Potential Ankyrin 1 Activity, but Not Transient Receptor Potential Vanilloid 1 Activity." Anesthesia and Analgesia, vol. 120, no. 4, 2015, pp. 790-8.
Miyano K, Minami K, Yokoyama T, et al. Tramadol and its metabolite m1 selectively suppress transient receptor potential ankyrin 1 activity, but not transient receptor potential vanilloid 1 activity. Anesth Analg. 2015;120(4):790-8.
Miyano, K., Minami, K., Yokoyama, T., Ohbuchi, K., Yamaguchi, T., Murakami, S., Shiraishi, S., Yamamoto, M., Matoba, M., & Uezono, Y. (2015). Tramadol and its metabolite m1 selectively suppress transient receptor potential ankyrin 1 activity, but not transient receptor potential vanilloid 1 activity. Anesthesia and Analgesia, 120(4), 790-8. https://doi.org/10.1213/ANE.0000000000000625
Miyano K, et al. Tramadol and Its Metabolite M1 Selectively Suppress Transient Receptor Potential Ankyrin 1 Activity, but Not Transient Receptor Potential Vanilloid 1 Activity. Anesth Analg. 2015;120(4):790-8. PubMed PMID: 25642661.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tramadol and its metabolite m1 selectively suppress transient receptor potential ankyrin 1 activity, but not transient receptor potential vanilloid 1 activity. AU - Miyano,Kanako, AU - Minami,Kouichiro, AU - Yokoyama,Toru, AU - Ohbuchi,Katsuya, AU - Yamaguchi,Takuhiro, AU - Murakami,Satoshi, AU - Shiraishi,Seiji, AU - Yamamoto,Masahiro, AU - Matoba,Motohiro, AU - Uezono,Yasuhito, PY - 2015/2/3/entrez PY - 2015/2/3/pubmed PY - 2015/6/16/medline SP - 790 EP - 8 JF - Anesthesia and analgesia JO - Anesth Analg VL - 120 IS - 4 N2 - BACKGROUND: The transient receptor potential vanilloid 1 (TRPV1) and the transient receptor potential ankyrin 1 (TRPA1), which are expressed in sensory neurons, are polymodal nonselective cation channels that sense noxious stimuli. Recent reports showed that these channels play important roles in inflammatory, neuropathic, or cancer pain, suggesting that they may serve as attractive analgesic pharmacological targets. Tramadol is an effective analgesic that is widely used in clinical practice. Reportedly, tramadol and its metabolite (M1) bind to μ-opioid receptors and/or inhibit reuptake of monoamines in the central nervous system, resulting in the activation of the descending inhibitory system. However, the fundamental mechanisms of tramadol in pain control remain unclear. TRPV1 and TRPA1 may be targets of tramadol; however, they have not been studied extensively. METHODS: We examined whether and how tramadol and M1 act on human embryonic kidney 293 (HEK293) cells expressing human TRPV1 (hTRPV1) or hTRPA1 by using a Ca imaging assay and whole-cell patch-clamp recording. RESULTS: Tramadol and M1 (0.01-10 μM) alone did not increase in intracellular Ca concentration ([Ca]i) in HEK293 cells expressing hTRPV1 or hTRPA1 compared with capsaicin (a TRPV1 agonist) or the allyl isothiocyanate (AITC, a TRPA1 agonist), respectively. Furthermore, in HEK293 cells expressing hTRPV1, pretreatment with tramadol or M1 for 5 minutes did not change the increase in [Ca]i induced by capsaicin. Conversely, pretreatment with tramadol (0.1-10 μM) and M1 (1-10 μM) significantly suppressed the AITC-induced [Ca]i increases in HEK293 cells expressing hTRPA1. In addition, the patch-clamp study showed that pretreatment with tramadol and M1 (10 μM) decreased the inward currents induced by AITC. CONCLUSIONS: These data indicate that tramadol and M1 selectively inhibit the function of hTRPA1, but not that of hTRPV1, and that hTRPA1 may play a role in the analgesic effects of these compounds. SN - 1526-7598 UR - https://www.unboundmedicine.com/medline/citation/25642661/Tramadol_and_its_metabolite_m1_selectively_suppress_transient_receptor_potential_ankyrin_1_activity_but_not_transient_receptor_potential_vanilloid_1_activity_ L2 - https://doi.org/10.1213/ANE.0000000000000625 DB - PRIME DP - Unbound Medicine ER -