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Neurotransmitter release from the terminals of DRG neurons is regulated by cannabinoid receptor 1 (CB<jats:sub>1<\/jats:sub>) and transient receptor potential vanilloid 1 (TRPV1), both activated by anandamide (AEA). In our experiments, the AEA precursor N-arachidonoylphosphatidylethanolamine (20:4-NAPE) was used to study the modulation of nociceptive DRG neurons excitability using K<jats:sup>+<\/jats:sup>-evoked Ca<jats:sup>2+<\/jats:sup> transients. Intrathecal administration was used to evaluate in vivo effects. Application of 20:4-NAPE at lower concentrations (10 nM \u2212\u20091 \u00b5M) decreased the excitability of DRG neurons, whereas the higher (10 \u00b5M) increased it. Both effects of 20:4-NAPE were blocked by the N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor LEI-401. Similarly, lower concentrations of externally applied AEA (1 nM \u2212\u200910 nM) inhibited DRG neurons, whereas higher concentration (100 nM) did not change it. High AEA concentration (10 \u00b5M) evoked Ca<jats:sup>2+<\/jats:sup> transients dependent on TRPV1 activation in separate experiments. Inhibition of the CB<jats:sub>1<\/jats:sub> receptor by PF514273 (400 nM) prevented the 20:4-NAPE- and AEA-induced inhibition, whereas TRPV1 inhibition by SB366791 (1 \u00b5M) prevented the increased DRG neuron excitability. In behavioral tests, lower 20:4-NAPE concentration caused hyposensitivity, while higher evoked mechanical allodynia. Intrathecal LEI-401 prevented both in vivo effects of 20:4-NAPE. These results highlight anti- and pro-nociceptive effects of 20:4-NAPE mediated by CB<jats:sub>1<\/jats:sub> and TRPV1 in concentration-dependent manner. Our study underscores the complexity of endocannabinoid signaling in pain transmission modulation and highlights 20:4-NAPE as a potential therapeutic target, offering new insights for developing analgesic strategies.<\/jats:p>","DOI":"10.1038\/s41598-025-98567-y","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T11:15:18Z","timestamp":1745406918000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["20:4-NAPE induced changes of mechanical sensitivity and DRG neurons excitability are concentration dependent and mediated via NAPE-PLD"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1077-2082","authenticated-orcid":false,"given":"Anirban","family":"Bhattacharyya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Vasconcelos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4268-2831","authenticated-orcid":false,"given":"Diana","family":"Spicarova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0609-8542","authenticated-orcid":false,"given":"Jiri","family":"Palecek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"issue":"5090","key":"98567_CR1","doi-asserted-by":"publisher","first-page":"1946","DOI":"10.1126\/science.1470919","volume":"258","author":"WA Devane","year":"1992","unstructured":"Devane, W. 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