Abstract: The aim of this research was to assess the antinociceptive activity of the transient receptor potential (TRP) channel TRPV1, TRPM8, and TRPA1 antagonists in neurogenic, tonic, and neuropathic pain models in mice. For this purpose, TRP channel antagonists were administered into the dorsal surface of a hind paw 15 min before capsaicin, allyl isothiocyanate (AITC), or formalin. Their antiallodynic and antihyperalgesic efficacies after intraperitoneal administration were also assessed in a paclitaxel-induced neuropathic pain model. Motor coordination of paclitaxel-treated mice that received these TRP channel antagonists was investigated using the rotarod test. TRPV1 antagonists, capsazepine and SB-366791, attenuated capsaicin-induced nociceptive reaction in a concentration-dependent manner. At 8 µg/20 µl, this effect was 51% (P<0.001) for capsazepine and 37% (P<0.05) for SB-366791. A TRPA1 antagonist, A-967079, reduced pain reaction by 48% (P<0.05) in the AITC test and by 54% (P<0.001) in the early phase of the formalin test. The test compounds had no influence on the late phase of the formalin test. In paclitaxel-treated mice, they did not attenuate heat hyperalgesia but N-(3-aminopropyl)-2-{[(3-methylphenyl)methyl]oxy}-N-(2-thienylmethyl) benzamide hydrochloride salt (AMTB), a TRPM8 antagonist, reduced cold hyperalgesia and tactile allodynia by 31% (P<0.05) and 51% (P<0.01), respectively. HC-030031, a TRPA1 channel antagonist, attenuated tactile allodynia in the von Frey test (62%; P<0.001). In conclusion, distinct members of TRP channel family are involved in different pain models in mice. Antagonists of TRP channels attenuate nocifensive responses of neurogenic, tonic, and neuropathic pain, but their efficacies strongly depend on the pain model used.

瞬时受体电位通道TRPV1、TRPA1和TRPM8拮抗剂在小鼠神经源性和神经病理性疼痛模型中的镇痛作用

[1]Alessandri-Haber, N., Dina, O.A., Yeh, J.J., et al., 2004. Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. J. Neurosci., 24(18):4444-4452.

[2]Andoh, T., Sakamoto, A., Kuraishi, Y., 2013. Effects of xaliproden, a 5-HT_1A agonist, on mechanical allodynia caused by chemotherapeutic agents in mice. Eur. J. Pharmacol., 721(1-3):231-236.

[3]Authier, N., Balayssac, D., Marchand, F., et al., 2009. Animal models of chemotherapy-evoked painful peripheral neuropathies. Neurotherapeutics, 6(4):620-629.

[4]Bandell, M., Story, G.M., Hwang, S.W., et al., 2004. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron, 41(6):849-857.

[5]Bautista, D.M., Movahed, P., Hinman, A., et al., 2005. Pungent products from garlic activate the sensory ion channel TRPA1. PNAS, 102(34):12248-12252.

[6]Bautista, D.M., Jordt, S.E., Nikai, T., et al., 2006. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell, 124(6):1269-1282.

[7]Beltrán, L.R., Dawid, C., Beltrán, M., et al., 2013. The pungent substances piperine, capsaicin, 6-gingerol and polygodial inhibit the human two-pore domain potassium channels TASK-1, TASK-3 and TRESK. Front. Pharmacol., 4:141.

[8]Bennett, G.J., 2010. Pathophysiology and animal models of cancer-related painful peripheral neuropathy. Oncologist, 15(Suppl. 2):9-12.

[9]Brederson, J.D., Kym, P.R., Szallasi, A., 2013. Targeting TRP channels for pain relief. Eur. J. Pharmacol., 716(1-3):61-76.

[10]Callsen, M.G., Moller, A.T., Sorensen, K., et al., 2008. Cold hyposensitivity after topical application of capsaicin in humans. Exp. Brain Res., 191(4):447-452.

[11]Chen, Y., Yang, C., Wang, Z.J., 2011. Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain. Neuroscience, 193:440-451.

[12]Coste, O., Möser, C.V., Sisignano, M., et al., 2012. The p21-activated kinase PAK 5 is involved in formalin-induced nociception through regulation of MAP-kinase signaling and formalin-specific receptors. Behav. Brain Res., 234(1):121-128.

[13]Docherty, R.J., Yeats, J.C., Piper, A.S., 1997. Capsazepine block of voltage-activated calcium channels in adult rat dorsal root ganglion neurones in culture. Br. J. Pharmacol., 121(7):1461-1467.

[14]Eddy, N.B., Leimbach, D., 1953. Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines. J. Pharmacol. Exp. Ther., 107(3):385-393.

[15]Eid, S.R., Crown, E.D., Moore, E.L., et al., 2008. HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity. Mol. Pain, 4:48.

[16]Hara, T., Chiba, T., Abe, K., et al., 2013. Effect of paclitaxel on transient receptor potential vanilloid 1 in rat dorsal root ganglion. Pain, 154(6):882-889.

[17]Islam, M.S., 2011. Transient Potential Receptor Channels. Advances in Experimental Medicine and Biology. Springer, Berlin, Germany, p.704-720.

[18]Kerstein, P.C., del Camino, D., Moran, M.M., et al., 2009. Pharmacological blockade of TRPA1 inhibits mechanical firing in nociceptors. Mol. Pain, 5:19.

[19]Lashinger, E.S., Steiginga, M.S., Hieble, J.P., et al., 2008. AMTB, a TRPM8 channel blocker: evidence in rats for activity in overactive bladder and painful bladder syndrome. Am. J. Physiol. Renal Physiol., 295(3):F803-F810.

[20]Laughlin, T.M., Tram, K.V., Wilcox, G.L., et al., 2002. Comparison of antiepileptic drugs tiagabine, lamotrigine, and gabapentin in mouse models of acute, prolonged, and chronic nociception. J. Pharmacol. Exp. Ther., 302(3):1168-1175.

[21]Levine, J.D., Alessandri-Haber, N., 2007. TRP channels: targets for the relief of pain. Biochim. Biophys. Acta, 1772(8):989-1003.

[22]Lopes, S.C., da Silva, A.V., Arruda, B.R., et al., 2013. Peripheral antinociceptive action of mangiferin in mouse models of experimental pain: role of endogenous opioids, K_ATP-channels and adenosine. Pharmacol. Biochem. Behav., 110:19-26.

[23]Materazzi, S., Fusi, C., Benemei, S., et al., 2012. TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism. Pflugers Arch., 463(4):561-569.

[24]McNamara, C.R., Mandel-Brehm, J., Bautista, D.M., et al., 2007. TRPA1 mediates formalin-induced pain. PNAS, 104(33):13525-13530.

[25]Merrill, A.W., Cuellar, J.M., Judd, J.H., et al., 2008. Effects of TRPA1 agonists mustard oil and cinnamaldehyde on lumbar spinal wide-dynamic range neuronal responses to innocuous and noxious cutaneous stimuli in rats. J. Neurophysiol., 99(2):415-425.

[26]Nieto, F.R., Cendán, C.M., Sánchez-Fernández, C., et al., 2012. Role of sigma-1 receptors in paclitaxel-induced neuropathic pain in mice. J. Pain, 13(11):1107-1121.

[27]Niiyama, Y., Kawamata, T., Yamamoto, J., et al., 2009. SB366791, a TRPV1 antagonist, potentiates analgesic effects of systemic morphine in a murine model of bone cancer pain. Br. J. Anaesthesiol., 102(2):251-258.

[28]Oh, G.S., Pae, H.O., Seo, W.G., et al., 2001. Capsazepine, a vanilloid receptor antagonist, inhibits the expression of inducible nitric oxide synthase gene in lipopolysaccharide-stimulated RAW264.7 macrophages through the inactivation of nuclear transcription factor-kappa B. Int. Immunopharmacol., 1(4):777-784.

[29]O'Neill, J., Brock, C., Olesen, A.E., et al., 2012. Unravelling the mystery of capsaicin: a tool to understand and treat pain. Pharmacol. Rev., 64(4):939-971.

[30]Pascual, D., Goicoechea, C., Burgos, E., et al., 2010. Antinociceptive effect of three common analgesic drugs on peripheral neuropathy induced by paclitaxel in rats. Pharmacol. Biochem. Behav., 95(3):331-337.

[31]Pevida, M., Lastra, A., Hidalgo, A., et al., 2013. Spinal CCL2 and microglial activation are involved in paclitaxel-evoked cold hyperalgesia. Brain Res. Bull., 95:21-27.

[32]Ray, A.M., Benham, C.D., Roberts, J.C., et al., 2003. Capsazepine protects against neuronal injury caused by oxygen glucose deprivation by inhibiting I_h. J. Neurosci., 23(31):10146-10153.

[33]Ren, K., Dubner, R., 1999. Inflammatory models of pain and hyperalgesia. ILAR J., 40(3):111-118.

[34]Rigo, F.K., Dalmolin, G.D., Trevisan, G., et al., 2013. Effect of ω-conotoxin MVIIA and Phα1β on paclitaxel-induced acute and chronic pain. Pharmacol. Biochem. Behav., 114-115:16-22.

[35]Rios, E.R., Rocha, N.F., Carvalho, A.M., et al., 2013. TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Chem. Biol. Interact., 203(3):573-579.

[36]Sałat, K., Filipek, B., Wieckowski, K., et al., 2009. Analgesic activity of 3-mono-substituted derivatives of dihydrofuran-2-one in experimental rodent models of pain. Pharmacol. Rep., 61(5):807-818.

[37]Salat, K., Librowski, T., Moniczewski, A., et al., 2012a. Analgesic, antioedematous and antioxidant activity of γ-butyrolactone derivatives in rodents. Behav. Pharmacol., 23(4):407-416.

[38]Salat, K., Moniczewski, A., Salat, R., et al., 2012b. Analgesic, anticonvulsant and antioxidant activities of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride in mice. Pharmacol. Biochem. Behav., 101(1):138-147.

[39]Sałat, K., Gawlik, K., Witalis, J., et al., 2013a. Evaluation of antinociceptive and antioxidant properties of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one in mice. Naunyn Schmiedeberg’s Arch. Pharmacol., 386(6):493-505.

[40]Sałat, K., Moniczewski, A., Librowski, T., 2013b. Transient receptor potential channels—emerging novel drug targets for the treatment of pain. Curr. Med. Chem., 20(11):1409-1436.

[41]Sandkühler, J., 2009. Models and mechanisms of hyperalgesia and allodynia. Physiol. Rev., 89(2):707-758.

[42]Santos, A.R., Calixto, J.B., 1997. Ruthenium red and capsazepine antinociceptive effect in formalin and capsaicin models of pain in mice. Neurosci. Lett., 235(1-2):73-76.

[43]Sawynok, J., Liu, X.J., 2003. The formalin test: characteristics and usefulness of the model. Rev. Analg., 7(2):145-163.

[44]Walker, K.M., Urban, L., Medhurst, S.J., et al., 2003. The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain. J. Pharmacol. Exp. Ther., 304(1):56-62.

[45]Westlund, K.N., Kochuko, M.Y., Lu, Y., et al., 2010. Impact of central and peripheral TRPV1 and ROS levels on proinflammatory mediators and nociceptive behavior. Mol. Pain, 6:46.

[46]Xiao, W.H., Zheng, H., Bennett, G.J., 2012. Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel. Neuroscience, 203:194-206.

[47]Zhao, M., Isami, K., Nakamura, S., et al., 2012. Acute cold hypersensitivity characteristically induced by oxaliplatin is caused by the enhanced responsiveness of TRPA1 in mice. Mol. Pain, 8:55.