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

. 2023 ; 16 () : 1188503. [epub] 20230622

Status PubMed-not-MEDLINE Language English Country Switzerland Media electronic-ecollection

Document type Journal Article

Transient receptor potential ion channel, vanilloid subfamily, type 1 (TRPV1) cation channel, and cannabinoid receptor 1 (CB1) are essential in the modulation of nociceptive signaling in the spinal cord dorsal horn that underlies different pathological pain states. TRPV1 and CB1 receptors share the endogenous agonist anandamide (AEA), produced from N-arachidonoylphosphatidylethanolamine (20:4-NAPE). We investigated the effect of the anandamide precursor 20:4-NAPE on synaptic activity in naive and inflammatory conditions. Patch-clamp recordings of miniature excitatory postsynaptic currents (mEPSCs) from superficial dorsal horn neurons in rat acute spinal cord slices were used. Peripheral inflammation was induced by subcutaneous injection of carrageenan. Under naive conditions, mEPSCs frequency (0.96 ± 0.11 Hz) was significantly decreased after 20 μM 20:4-NAPE application (55.3 ± 7.4%). This 20:4-NAPE-induced inhibition was blocked by anandamide-synthesizing enzyme N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor LEI-401. In addition, the inhibition was prevented by the CB1 receptor antagonist PF 514273 (0.2 μM) but not by the TRPV1 receptor antagonist SB 366791 (10 μM). Under inflammatory conditions, 20:4-NAPE (20 μM) also exhibited a significant inhibitory effect (74.5 ± 8.9%) on the mEPSCs frequency that was prevented by the TRPV1 receptor antagonist SB 366791 but not by PF 514273 application. Our results show that 20:4-NAPE application has a significant modulatory effect on spinal cord nociceptive signaling that is mediated by both TRPV1 and CB1 presynaptic receptors, whereas peripheral inflammation changes the underlying mechanism. The switch between TRPV1 and CB1 receptor activation by the AEA precursor 20:4-NAPE during inflammation may play an important role in nociceptive processing, hence the development of pathological pain.

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

Ahluwalia J., Urban L., Bevan S., Nagy I. (2003). Anandamide regulates neuropeptide release from capsaicin-sensitive primary sensory neurons by activating both the cannabinoid 1 receptor and the vanilloid receptor 1 in vitro. Eur. J. Neurosci. 17, 2611–2618. doi: 10.1046/j.1460-9568.2003.02703.x, PMID: PubMed DOI

Ahluwalia J., Urban L., Capogna M., Bevan S., Nagy I. (2000). Cannabinoid 1 receptors are expressed in nociceptive primary sensory neurons. Neuroscience 100, 685–688. doi: 10.1016/S0306-4522(00)00389-4 PubMed DOI

Amaya F., Shimosato G., Kawasaki Y., Hashimoto S., Tanaka Y., Ji R. R., et al. . (2006). Induction of CB1 cannabinoid receptor by inflammation in primary afferent neurons facilitates antihyperalgesic effect of peripheral CB1 agonist. Pain 124, 175–183. doi: 10.1016/j.pain.2006.04.001, PMID: PubMed DOI

Baccei M. L., Bardoni R., Fitzgerald M. (2003). Development of nociceptive synaptic inputs to the neonatal rat dorsal horn: glutamate release by capsaicin and menthol. J. Physiol. 549, 231–242. doi: 10.1113/jphysiol.2003.040451, PMID: PubMed DOI PMC

Bari M., Oddi S., De Simone C., Spagnolo P., Gasperi V., Battista N., et al. . (2008). Type-1 cannabinoid receptors colocalize with caveolin-1 in neuronal cells. Neuropharmacology 54, 45–50. doi: 10.1016/j.neuropharm.2007.06.030, PMID: PubMed DOI PMC

Binzen U., Greffrath W., Hennessy S., Bausen M., Saaler-Reinhardt S., Treede R. D. (2006). Co-expression of the voltage-gated potassium channel Kv1.4 with transient receptor potential channels (TRPV1 and TRPV2) and the cannabinoid receptor CB1 in rat dorsal root ganglion neurons. Neuroscience 142, 527–539. doi: 10.1016/j.neuroscience.2006.06.020, PMID: PubMed DOI

Chen J., Varga A., Selvarajah S., Jenes A., Dienes B., Sousa-Valente J., et al. . (2016). Spatial distribution of the cannabinoid type 1 and capsaicin receptors may contribute to the complexity of their crosstalk. Sci. Rep. 6:33307. doi: 10.1038/srep33307, PMID: PubMed DOI PMC

Comunanza V., Carbone E., Marcantoni A., Sher E., Ursu D. (2011). Calcium-dependent inhibition of T-type calcium channels by TRPV1 activation in rat sensory neurons. Pflugers Arch. 462, 709–722. doi: 10.1007/s00424-011-1023-5, PMID: PubMed DOI

Di Scala C., Fantini J., Yahi N., Barrantes F. J., Chahinian H. (2018). Anandamide revisited: how cholesterol and ceramides control receptor-dependent and receptor-independent signal transmission pathways of a lipid neurotransmitter. Biomol. Ther. 8:20031. doi: 10.3390/biom8020031, PMID: PubMed DOI PMC

Dow R. L., Carpino P. A., Hadcock J. R., Black S. C., Iredale P. A., DaSilva-Jardine P., et al. . (2009). Discovery of 2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropyl)-6,7-dihydro-2H-pyraz olo[3,4-f][1,4]oxazepin-8(5H)-one (PF-514273), a novel, bicyclic lactam-based cannabinoid-1 receptor antagonist for the treatment of obesity. J. Med. Chem. 52, 2652–2655. doi: 10.1021/jm900255t, PMID: PubMed DOI

Ermolyuk Y. S., Alder F. G., Surges R., Pavlov I. Y., Timofeeva Y., Kullmann D. M., et al. . (2013). Differential triggering of spontaneous glutamate release by P/Q-, N- and R-type Ca2+ channels. Nat. Neurosci. 16, 1754–1763. doi: 10.1038/nn.3563, PMID: PubMed DOI PMC

Farquhar-Smith W. P., Egertova M., Bradbury E. J., McMahon S. B., Rice A. S., Elphick M. R. (2000). Cannabinoid CB(1) receptor expression in rat spinal cord. Mol. Cell. Neurosci. 15, 510–521. doi: 10.1006/mcne.2000.0844 PubMed DOI

Goncalves Dos Santos G., Li R., Ng M. P. E., Lemes J. B. P., Vieira W. F., Nagy I., et al. . (2020). CB1 receptor-dependent desensitisation of TRPV1 channels contributes to the analgesic effect of dipyrone in sensitised primary sensory neurons. Br. J. Pharmacol. 177, 4615–4626. doi: 10.1111/bph.15170, PMID: PubMed DOI PMC

Gunthorpe M. J., Rami H. K., Jerman J. C., Smart D., Gill C. H., Soffin E. M., et al. . (2004). Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist. Neuropharmacology 46, 133–149. doi: 10.1016/S0028-3908(03)00305-8, PMID: PubMed DOI

Hegyi Z., Hollo K., Kis G., Mackie K., Antal M. (2012). Differential distribution of diacylglycerol lipase-alpha and N-acylphosphatidylethanolamine-specific phospholipase d immunoreactivity in the superficial spinal dorsal horn of rats. Glia 60, 1316–1329. doi: 10.1002/glia.22351, PMID: PubMed DOI PMC

Hegyi Z., Kis G., Hollo K., Ledent C., Antal M. (2009). Neuronal and glial localization of the cannabinoid-1 receptor in the superficial spinal dorsal horn of the rodent spinal cord. Eur. J. Neurosci. 30, 251–262. doi: 10.1111/j.1460-9568.2009.06816.x, PMID: PubMed DOI

Heles M., Mrozkova P., Sulcova D., Adamek P., Spicarova D., Palecek J. (2021). Chemokine CCL2 prevents opioid-induced inhibition of nociceptive synaptic transmission in spinal cord dorsal horn. J. Neuroinflammation 18:279. doi: 10.1186/s12974-021-02335-4, PMID: PubMed DOI PMC

Howlett A. C., Barth F., Bonner T. I., Cabral G., Casellas P., Devane W. A., et al. . (2002). International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev. 54, 161–202. doi: 10.1124/pr.54.2.161, PMID: PubMed DOI

Katona I., Freund T. F. (2008). Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat. Med. 14, 923–930. doi: 10.1038/nm.f.1869, PMID: PubMed DOI

Katona I., Urban G. M., Wallace M., Ledent C., Jung K. M., Piomelli D., et al. . (2006). Molecular composition of the endocannabinoid system at glutamatergic synapses. J. Neurosci. 26, 5628–5637. doi: 10.1523/JNEUROSCI.0309-06.2006, PMID: PubMed DOI PMC

Kim C., Jun K., Lee T., Kim S. S., McEnery M. W., Chin H., et al. . (2001). Altered nociceptive response in mice deficient in the alpha(1B) subunit of the voltage-dependent calcium channel. Mol. Cell. Neurosci. 18, 235–245. doi: 10.1006/mcne.2001.1013, PMID: PubMed DOI

La Porta C., Bura S. A., Aracil-Fernandez A., Manzanares J., Maldonado R. (2013). Role of CB1 and CB2 cannabinoid receptors in the development of joint pain induced by monosodium iodoacetate. Pain 154, 160–174. doi: 10.1016/j.pain.2012.10.009, PMID: PubMed DOI

Li Y., Adamek P., Zhang H., Tatsui C. E., Rhines L. D., Mrozkova P., et al. . (2015). The cancer chemotherapeutic paclitaxel increases human and rodent sensory neuron responses to TRPV1 by activation of TLR4. J. Neurosci. 35, 13487–13500. doi: 10.1523/JNEUROSCI.1956-15.2015, PMID: PubMed DOI PMC

Mahmud A., Santha P., Paule C. C., Nagy I. (2009). Cannabinoid 1 receptor activation inhibits transient receptor potential vanilloid type 1 receptor-mediated cationic influx into rat cultured primary sensory neurons. Neuroscience 162, 1202–1211. doi: 10.1016/j.neuroscience.2009.05.024, PMID: PubMed DOI

Mrozkova P., Spicarova D., Palecek J. (2021). Spinal PAR2 activation contributes to hypersensitivity induced by peripheral inflammation in rats. Int. J. Mol. Sci. 22:991. doi: 10.3390/ijms22030991, PMID: PubMed DOI PMC

Nagy I., Fedonidis C., Paule C. C., Wahba J., Andrew P., Austin J., et al. . (2009). NAPE-PLD is involved in Anandamide synthesis in capsaicin-sensitive primary sensory neurons. J. Physiol. Sci. 59:422.

Nagy B., Fedonidis C., Photiou A., Wahba J., Paule C. C., Ma D., et al. . (2009). Capsaicin-sensitive primary sensory neurons in the mouse express N-Acyl phosphatidylethanolamine phospholipase D. Neuroscience 161, 572–577. doi: 10.1016/j.neuroscience.2009.03.047, PMID: PubMed DOI PMC

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

Nichols R. A., Suplick G. R., Brown J. M. (1994). Calcineurin-mediated protein dephosphorylation in brain nerve terminals regulates the release of glutamate. J. Biol. Chem. 269, 23817–23823. doi: 10.1016/S0021-9258(17)31588-0, PMID: PubMed DOI

Nyilas R., Gregg L. C., Mackie K., Watanabe M., Zimmer A., Hohmann A. G., et al. . (2009). Molecular architecture of endocannabinoid signaling at nociceptive synapses mediating analgesia. Eur. J. Neurosci. 29, 1964–1978. doi: 10.1111/j.1460-9568.2009.06751.x, PMID: PubMed DOI PMC

Park J., Luo Z. D. (2010). Calcium channel functions in pain processing. Channels (Austin) 4, 510–517. doi: 10.4161/chan.4.6.12869, PMID: PubMed DOI PMC

Pertwee R. G. (2006). The pharmacology of cannabinoid receptors and their ligands: an overview. Int. J. Obes. 30, S13–S18. doi: 10.1038/sj.ijo.0803272 PubMed DOI

Pertwee R. G. (2009). Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br. J. Pharmacol. 156, 397–411. doi: 10.1111/j.1476-5381.2008.00048.x, PMID: PubMed DOI PMC

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

Rimmerman N., Hughes H. V., Bradshaw H. B., Pazos M. X., Mackie K., Prieto A. L., et al. . (2008). Compartmentalization of endocannabinoids into lipid rafts in a dorsal root ganglion cell line. Br. J. Pharmacol. 153, 380–389. doi: 10.1038/sj.bjp.0707561, PMID: PubMed DOI PMC

Santha P., Jenes A., Somogyi C., Nagy I. (2010). The endogenous cannabinoid anandamide inhibits transient receptor potential vanilloid type 1 receptor-mediated currents in rat cultured primary sensory neurons. Acta Physiol. Hung. 97, 149–158. doi: 10.1556/APhysiol.97.2010.2.1, PMID: PubMed DOI

Sihra T. S., Nairn A. C., Kloppenburg P., Lin Z., Pouzat C. (1995). A role for calcineurin (protein phosphatase-2B) in the regulation of glutamate release. Biochem. Biophys. Res. Commun. 212, 609–616. doi: 10.1006/bbrc.1995.2013, PMID: PubMed DOI

Snider N. T., Walker V. J., Hollenberg P. F. (2010). Oxidation of the endogenous cannabinoid arachidonoyl ethanolamide by the cytochrome P450 monooxygenases: physiological and pharmacological implications. Pharmacol. Rev. 62, 136–154. doi: 10.1124/pr.109.001081, PMID: PubMed DOI PMC

Sousa-Valente J., Andreou A. P., Urban L., Nagy I. (2014). Transient receptor potential ion channels in primary sensory neurons as targets for novel analgesics. Br. J. Pharmacol. 171, 2508–2527. doi: 10.1111/bph.12532, PMID: PubMed DOI PMC

Sousa-Valente J., Varga A., Torres-Perez J. V., Jenes A., Wahba J., Mackie K., et al. . (2017). Inflammation of peripheral tissues and injury to peripheral nerves induce differing effects in the expression of the calcium-sensitive N-arachydonoylethanolamine-synthesizing enzyme and related molecules in rat primary sensory neurons. J. Comp. Neurol. 525, 1778–1796. doi: 10.1002/cne.24154, PMID: PubMed DOI

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

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

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

Spicarova D., Palecek J. (2008). The role of spinal cord vanilloid (TRPV1) receptors in pain modulation. Physiol. Res. 57, S69–S77. doi: 10.33549/physiolres.931601 PubMed DOI

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

Storti B., Di Rienzo C., Cardarelli F., Bizzarri R., Beltram F. (2015). Unveiling TRPV1 spatio-temporal organization in live cell membranes. PLoS One 10:e0116900. doi: 10.1371/journal.pone.0116900, PMID: PubMed DOI PMC

Tominaga M., Caterina M. J., Malmberg A. B., Rosen T. A., Gilbert H., Skinner K., et al. . (1998). The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21, 531–543. doi: 10.1016/s0896-6273(00)80564-4, PMID: PubMed DOI

Uchytilova E., Spicarova D., Palecek J. (2021). Hypersensitivity induced by intrathecal bradykinin administration is enhanced by N-oleoyldopamine (OLDA) and prevented by TRPV1 antagonist. Int. J. Mol. Sci. 22:712. doi: 10.3390/ijms22073712, PMID: PubMed DOI PMC

van der Stelt M., Trevisani M., Vellani V., De Petrocellis L., Schiano Moriello A., Campi B., et al. . (2005). Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels. EMBO J. 24, 3026–3037. doi: 10.1038/sj.emboj.7600784, PMID: PubMed DOI PMC

Varga A., Jenes A., Marczylo T. H., Sousa-Valente J., Chen J., Austin J., et al. . (2014). Anandamide produced by Ca(2+)-insensitive enzymes induces excitation in primary sensory neurons. Pflugers Arch. 466, 1421–1435. doi: 10.1007/s00424-013-1360-7, PMID: PubMed DOI

Vellani V., Petrosino S., De Petrocellis L., Valenti M., Prandini M., Magherini P. C., et al. . (2008). Functional lipidomics. Calcium-independent activation of endocannabinoid/endovanilloid lipid signalling in sensory neurons by protein kinases C and A and thrombin. Neuropharmacology 55, 1274–1279. doi: 10.1016/j.neuropharm.2008.01.010, PMID: PubMed DOI

Veress G., Meszar Z., Muszil D., Avelino A., Matesz K., Mackie K., et al. . (2013). Characterisation of cannabinoid 1 receptor expression in the perikarya, and peripheral and spinal processes of primary sensory neurons. Brain Struct. Funct. 218, 733–750. doi: 10.1007/s00429-012-0425-2, PMID: PubMed DOI PMC

Wang J., Okamoto Y., Morishita J., Tsuboi K., Miyatake A., Ueda N. (2006). Functional analysis of the purified anandamide-generating phospholipase D as a member of the metallo-beta-lactamase family. J. Biol. Chem. 281, 12325–12335. doi: 10.1074/jbc.M512359200, PMID: PubMed DOI

Wang J., Ueda N. (2009). Biology of endocannabinoid synthesis system. Prostaglandins Other Lipid Mediat. 89, 112–119. doi: 10.1016/j.prostaglandins.2008.12.002 PubMed DOI

Woodhams S. G., Wong A., Barrett D. A., Bennett A. J., Chapman V., Alexander S. P. (2012). Spinal administration of the monoacylglycerol lipase inhibitor JZL184 produces robust inhibitory effects on nociceptive processing and the development of central sensitization in the rat. Br. J. Pharmacol. 167, 1609–1619. doi: 10.1111/j.1476-5381.2012.02179.x, PMID: PubMed DOI PMC

Wu Z. Z., Chen S. R., Pan H. L. (2005). Transient receptor potential vanilloid type 1 activation down-regulates voltage-gated calcium channels through calcium-dependent calcineurin in sensory neurons. J. Biol. Chem. 280, 18142–18151. doi: 10.1074/jbc.M501229200, PMID: PubMed DOI

Wu Z. Z., Chen S. R., Pan H. L. (2006). Signaling mechanisms of down-regulation of voltage-activated Ca2+ channels by transient receptor potential vanilloid type 1 stimulation with olvanil in primary sensory neurons. Neuroscience 141, 407–419. doi: 10.1016/j.neuroscience.2006.03.023, PMID: PubMed DOI

Wu Y., Liu Y., Hou P., Yan Z., Kong W., Liu B., et al. . (2013). TRPV1 channels are functionally coupled with BK(mSlo1) channels in rat dorsal root ganglion (DRG) neurons. PLoS One 8:e78203. doi: 10.1371/journal.pone.0078203, PMID: PubMed DOI PMC

Yu L., Yang F., Luo H., Liu F. Y., Han J. S., Xing G. G., et al. . (2008). The role of TRPV1 in different subtypes of dorsal root ganglion neurons in rat chronic inflammatory nociception induced by complete Freund's adjuvant. Mol. Pain 4:61. doi: 10.1186/1744-8069-4-61, PMID: PubMed DOI PMC

Zygmunt P. M., Petersson J., Andersson D. A., Chuang H., Sorgard M., Di Marzo V., et al. . (1999). Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452–457. doi: 10.1038/22761, PMID: PubMed DOI

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