Transient receptor potential vanilloid 1 (TRPV1) channels contribute to the development of several chronic pain states and represent a possible therapeutic target in many painful disease treatment. Proinflammatory mediator bradykinin (BK) sensitizes TRPV1, whereas noxious peripheral stimulation increases BK level in the spinal cord. Here, we investigated the involvement of spinal TRPV1 in thermal and mechanical hypersensitivity, evoked by intrathecal (i.t.) administration of BK and an endogenous agonist of TRPV1, N-oleoyldopamine (OLDA), using behavioral tests and i.t. catheter implantation, and administration of BK-induced transient thermal and mechanical hyperalgesia and mechanical allodynia. All these hypersensitive states were enhanced by co-administration of a low dose of OLDA (0.42 µg i.t.), which was ineffective only under the control conditions. Intrathecal pretreatment with TRPV1 selective antagonist SB366791 prevented hypersensitivity induced by i.t. co-administration of BK and OLDA. Our results demonstrate that both thermal and mechanical hypersensitivity evoked by co-administration of BK and OLDA is mediated by the activation of spinal TRPV1 channels.

Department of Anaesthesiology Resuscitation and Critical Care Institute for Clinical and Experimental Medicine Videnska 1958 9 14021 Prague Czech Republic

Laboratory of Pain Research Institute of Physiology Czech Academy of Sciences Videnska 1083 14220 Prague Czech Republic

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Mou J., Paillard F., Turnbull B., Trudeau J., Stoker M., Katz N.P. Efficacy of Qutenza(R) (capsaicin) 8% patch for neuropathic pain: A meta-analysis of the Qutenza Clinical Trials Database. Pain. 2013;154:1632–1639. doi: 10.1016/j.pain.2013.04.044. PubMed DOI

Schumacher M., Pasvankas G. Topical capsaicin formulations in the management of neuropathic pain. Prog. Drug Res. 2014;68:105–128. PubMed

Smith H., Brooks J.R. Capsaicin-based therapies for pain control. Prog. Drug Res. 2014;68:129–146. PubMed

Pospisilova E., Palecek J. Post-operative pain behavior in rats is reduced after single high-concentration capsaicin application. Pain. 2006;125:233–243. doi: 10.1016/j.pain.2006.05.021. PubMed DOI

Uchytilova E., Spicarova D., Palecek J. TRPV1 antagonist attenuates postoperative hypersensitivity by central and peripheral mechanisms. Mol. Pain. 2014;10:67. doi: 10.1186/1744-8069-10-67. PubMed DOI PMC

Moran M.M., Szallasi A. Targeting nociceptive transient receptor potential channels to treat chronic pain: Current state of the field. Br. J. Pharmacol. 2018;175:2185–2203. doi: 10.1111/bph.14044. PubMed DOI PMC

Treede R.D., Wagner T., Kern K.U., Husstedt I.W., Arendt G., Birklein F., Cegla T., Freynhagen R., Gockel H.H., Heskamp M.L., et al. Mechanism- and experience-based strategies to optimize treatment response to the capsaicin 8% cutaneous patch in patients with localized neuropathic pain. Curr. Med. Res. Opin. 2013;29:527–538. doi: 10.1185/03007995.2013.781019. PubMed DOI

Anand P., Bley K. Topical capsaicin for pain management: Therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br. J. Anaesth. 2011;107:490–502. doi: 10.1093/bja/aer260. PubMed DOI PMC

Iadarola M.J., Mannes A.J. The vanilloid agonist resiniferatoxin for interventional-based pain control. Curr. Top. Med. Chem. 2011;11:2171–2179. doi: 10.2174/156802611796904942. PubMed DOI PMC

Spicarova D., Nerandzic V., Palecek J. Update on the role of spinal cord TRPV1 receptors in pain modulation. Physiol. Res. 2014;63(Suppl. S1):S225–S236. doi: 10.33549/physiolres.932713. PubMed DOI

Spicarova D., Nerandzic V., Palecek J. Modulation of spinal cord synaptic activity by tumor necrosis factor alpha in a model of peripheral neuropathy. J. Neuroinflamm. 2011;8:177. doi: 10.1186/1742-2094-8-177. PubMed DOI PMC

Spicarova D., Adamek P., Kalynovska N., Mrozkova P., Palecek J. TRPV1 receptor inhibition decreases CCL2-induced hyperalgesia. Neuropharmacology. 2014;81:75–84. doi: 10.1016/j.neuropharm.2014.01.041. PubMed DOI

Nerandzic V., Mrozkova P., Adamek P., Spicarova D., Nagy I., Palecek J. Peripheral inflammation affects modulation of nociceptive synaptic transmission in the spinal cord induced by N-arachidonoylphosphatidylethanolamine. Br. J. Pharmacol. 2018;175:2322–2336. doi: 10.1111/bph.13849. PubMed DOI PMC

Li Y., Adamek P., Zhang H., Tatsui C.E., Rhines L.D., Mrozkova P., Li Q., Kosturakis A.K., Cassidy R.M., Harrison D.S., et al. The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4. J. Neurosci. Off. J. Soc. Neurosci. 2015;35:13487–13500. doi: 10.1523/JNEUROSCI.1956-15.2015. PubMed DOI PMC

Adamek P., Heles M., Palecek J. Mechanical allodynia and enhanced responses to capsaicin are mediated by PI3K in a paclitaxel model of peripheral neuropathy. Neuropharmacology. 2019;146:163–174. doi: 10.1016/j.neuropharm.2018.11.027. PubMed DOI

Mrozkova P., Spicarova D., Palecek J. Spinal PAR2 Activation Contributes to Hypersensitivity Induced by Peripheral Inflammation in Rats. Int. J. Mol. Sci. 2021;22:991. doi: 10.3390/ijms22030991. PubMed DOI PMC

Szolcsanyi J., Pinter E. Transient receptor potential vanilloid 1 as a therapeutic target in analgesia. Expert Opin. Ther. Targets. 2013;17:641–657. doi: 10.1517/14728222.2013.772580. PubMed DOI

Mrozkova P., Spicarova D., Palecek J. Hypersensitivity Induced by Activation of Spinal Cord PAR2 Receptors Is Partially Mediated by TRPV1 Receptors. PLoS ONE. 2016;11:e0163991. doi: 10.1371/journal.pone.0163991. PubMed DOI PMC

Spicarova D., Palecek J. Tumor necrosis factor alpha sensitizes spinal cord TRPV1 receptors to the endogenous agonist N-oleoyldopamine. J. Neuroinflamm. 2010;7:49. doi: 10.1186/1742-2094-7-49. PubMed DOI PMC

Spicarova D., Palecek J. The role of the TRPV1 endogenous agonist N-Oleoyldopamine in modulation of nociceptive signaling at the spinal cord level. J. Neurophysiol. 2009;102:234–243. doi: 10.1152/jn.00024.2009. PubMed DOI

Couture R., Harrisson M., Vianna R.M., Cloutier F. Kinin receptors in pain and inflammation. Eur. J. Pharmacol. 2001;429:161–176. doi: 10.1016/S0014-2999(01)01318-8. PubMed DOI

Lopes P., Kar S., Chretien L., Regoli D., Quirion R., Couture R. Quantitative autoradiographic localization of [125I-Tyr8]bradykinin receptor binding sites in the rat spinal cord: Effects of neonatal capsaicin, noradrenergic deafferentation, dorsal rhizotomy and peripheral axotomy. Neuroscience. 1995;68:867–881. doi: 10.1016/0306-4522(95)00161-B. PubMed DOI

Wang H., Kohno T., Amaya F., Brenner G.J., Ito N., Allchorne A., Ji R.R., Woolf C.J. Bradykinin produces pain hypersensitivity by potentiating spinal cord glutamatergic synaptic transmission. J. Neurosci. Off. J. Soc. Neurosci. 2005;25:7986–7992. doi: 10.1523/JNEUROSCI.2393-05.2005. PubMed DOI PMC

Fox A., Wotherspoon G., McNair K., Hudson L., Patel S., Gentry C., Winter J. Regulation and function of spinal and peripheral neuronal B1 bradykinin receptors in inflammatory mechanical hyperalgesia. Pain. 2003;104:683–691. doi: 10.1016/S0304-3959(03)00141-6. PubMed DOI

Kohno T., Wang H., Amaya F., Brenner G.J., Cheng J.K., Ji R.R., Woolf C.J. Bradykinin enhances AMPA and NMDA receptor activity in spinal cord dorsal horn neurons by activating multiple kinases to produce pain hypersensitivity. J. Neurosci. Off. J. Soc. Neurosci. 2008;28:4533–4540. doi: 10.1523/JNEUROSCI.5349-07.2008. PubMed DOI PMC

Chuang H.H., Prescott E.D., Kong H., Shields S., Jordt S.E., Basbaum A.I., Chao M.V., Julius D. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature. 2001;411:957–962. doi: 10.1038/35082088. PubMed DOI

Cao E., Cordero-Morales J.F., Liu B., Qin F., Julius D. TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids. Neuron. 2013;77:667–679. doi: 10.1016/j.neuron.2012.12.016. PubMed DOI PMC

Lukacs V., Yudin Y., Hammond G.R., Sharma E., Fukami K., Rohacs T. Distinctive changes in plasma membrane phosphoinositides underlie differential regulation of TRPV1 in nociceptive neurons. J. Neurosci. Off. J. Soc. Neurosci. 2013;33:11451–11463. doi: 10.1523/JNEUROSCI.5637-12.2013. PubMed DOI PMC

Talbot S., Dias J.P., Lahjouji K., Bogo M.R., Campos M.M., Gaudreau P., Couture R. Activation of TRPV1 by capsaicin induces functional kinin B(1) receptor in rat spinal cord microglia. J. Neuroinflamm. 2012;9:16. doi: 10.1186/1742-2094-9-16. PubMed DOI PMC

Cernit V., Senecal J., Othman R., Couture R. Reciprocal Regulatory Interaction between TRPV1 and Kinin B1 Receptor in a Rat Neuropathic Pain Model. Int. J. Mol. Sci. 2020;21:821. doi: 10.3390/ijms21030821. PubMed DOI PMC

Chu C.J., Huang S.M., De Petrocellis L., Bisogno T., Ewing S.A., Miller J.D., Zipkin R.E., Daddario N., Appendino G., Di Marzo V., et al. N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia. J. Biol. Chem. 2003;278:13633–13639. doi: 10.1074/jbc.M211231200. PubMed DOI

Laneuville O., Reader T.A., Couture R. Intrathecal bradykinin acts presynaptically on spinal noradrenergic terminals to produce antinociception in the rat. Eur. J. Pharmacol. 1989;159:273–283. doi: 10.1016/0014-2999(89)90158-1. PubMed DOI

Kariya K., Yamauchi A., Hattori S., Tsuda Y., Okada Y. The disappearance rate of intraventricular bradykinin in the brain of the conscious rat. Biochem. Biophys. Res. Commun. 1982;107:1461–1466. doi: 10.1016/S0006-291X(82)80163-0. PubMed DOI

Retamal J.S., Ramirez-Garcia P.D., Shenoy P.A., Poole D.P., Veldhuis N.A. Internalized GPCRs as Potential Therapeutic Targets for the Management of Pain. Front. Mol. Neurosci. 2019;12:273. doi: 10.3389/fnmol.2019.00273. PubMed DOI PMC

Zimmerman B., Simaan M., Akoume M.Y., Houri N., Chevallier S., Seguela P., Laporte S.A. Role of ssarrestins in bradykinin B2 receptor-mediated signalling. Cell. Signal. 2011;23:648–659. doi: 10.1016/j.cellsig.2010.11.016. PubMed DOI

Shin J., Cho H., Hwang S.W., Jung J., Shin C.Y., Lee S.Y., Kim S.H., Lee M.G., Choi Y.H., Kim J., et al. Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia. Proc. Natl. Acad. Sci. USA. 2002;99:10150–10155. doi: 10.1073/pnas.152002699. PubMed DOI PMC

Ferreira J., da Silva G.L., Calixto J.B. Contribution of vanilloid receptors to the overt nociception induced by B2 kinin receptor activation in mice. Br. J. Pharmacol. 2004;141:787–794. doi: 10.1038/sj.bjp.0705546. PubMed DOI PMC

Katanosaka K., Banik R.K., Giron R., Higashi T., Tominaga M., Mizumura K. Contribution of TRPV1 to the bradykinin-evoked nociceptive behavior and excitation of cutaneous sensory neurons. Neurosci. Res. 2008;62:168–175. doi: 10.1016/j.neures.2008.08.004. PubMed DOI

Kollarik M., Undem B.J. Activation of bronchopulmonary vagal afferent nerves with bradykinin, acid and vanilloid receptor agonists in wild-type and TRPV1-/- mice. J. Physiol. 2004;555:115–123. doi: 10.1113/jphysiol.2003.054890. PubMed DOI PMC

Rong W., Hillsley K., Davis J.B., Hicks G., Winchester W.J., Grundy D. Jejunal afferent nerve sensitivity in wild-type and TRPV1 knockout mice. J. Physiol. 2004;560:867–881. doi: 10.1113/jphysiol.2004.071746. PubMed DOI PMC

Dickenson A.H., Dray A. Selective antagonism of capsaicin by capsazepine: Evidence for a spinal receptor site in capsaicin-induced antinociception. Br. J. Pharmacol. 1991;104:1045–1049. doi: 10.1111/j.1476-5381.1991.tb12547.x. PubMed DOI PMC

Zahner M.R., Li D.P., Chen S.R., Pan H.L. Cardiac vanilloid receptor 1-expressing afferent nerves and their role in the cardiogenic sympathetic reflex in rats. J. Physiol. 2003;551:515–523. doi: 10.1113/jphysiol.2003.048207. PubMed DOI PMC

Petho G., Reeh P.W. Sensory and signaling mechanisms of bradykinin, eicosanoids, platelet-activating factor, and nitric oxide in peripheral nociceptors. Physiol. Rev. 2012;92:1699–1775. doi: 10.1152/physrev.00048.2010. PubMed DOI

Mizumura K., Sugiura T., Katanosaka K., Banik R.K., Kozaki Y. Excitation and sensitization of nociceptors by bradykinin: What do we know? Exp. Brain Res. 2009;196:53–65. doi: 10.1007/s00221-009-1814-5. PubMed DOI

Huang J., Zhang X., McNaughton P.A. Inflammatory pain: The cellular basis of heat hyperalgesia. Curr. Neuropharmacol. 2006;4:197–206. doi: 10.2174/157015906778019554. PubMed DOI PMC

Sugiura T., Tominaga M., Katsuya H., Mizumura K. Bradykinin lowers the threshold temperature for heat activation of vanilloid receptor 1. J. Neurophysiol. 2002;88:544–548. doi: 10.1152/jn.2002.88.1.544. PubMed DOI

Kumar R., Geron M., Hazan A., Priel A. Endogenous and Exogenous Vanilloids Evoke Disparate TRPV1 Activation to Produce Distinct Neuronal Responses. Front. Pharmacol. 2020;11:903. doi: 10.3389/fphar.2020.00903. PubMed DOI PMC

Inhibition of synaptic transmission by anandamide precursor 20:4-NAPE is mediated by TRPV1 receptors under inflammatory conditions

Chemokine CCL2 prevents opioid-induced inhibition of nociceptive synaptic transmission in spinal cord dorsal horn