{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T12:45:59Z","timestamp":1789908359288,"version":"4.0.1"},"reference-count":65,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2016,3,10]],"date-time":"2016-03-10T00:00:00Z","timestamp":1457568000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>The synthetic peptide PnPP\u201019 has been studied as a new drug candidate to treat erectile dysfunction. However, PnTx2\u20136, the spider toxin from which the peptide was designed, induces hyperalgesia. Therefore, we intended to investigate the role of PnPP\u201019 in the nociceptive pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Nociceptive thresholds were measured by paw pressure test. PnPP\u201019 was administered intraplantarly alone or with selective cannabinoid or opioid receptor antagonists. The hydrolysis of PnPP\u201019 by neutral endopeptidase (NEP) (EC 3.4.24.11), an enzyme that cleaves enkephalin, was monitored by HPLC and the cleavage sites were deduced by LC\u2013MS. Inhibition by PnPP\u201019 and Leu\u2010enkephalin of NEP enzyme activity was determined spectrofluorimetrically.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>PnPP\u201019 (5, 10 and 20\u00a0\u03bcg per paw) induced peripheral antinociception in rats. Specific antagonists of \u03bc opioid receptors (clocinnamox), \u03b4 opioid receptors (naltrindole) and CB<jats:sub>1<\/jats:sub>receptors (AM251) partly inhibited the antinociceptive effect of PnPP\u201019. Inhibition of fatty acid amide hydrolase by MAFP or of anandamide uptake by VDM11 enhanced PnPP\u201019\u2010induced antinociception. NEP cleaved PnPP\u201019 only after a long incubation, and<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>values of 35.6\u00a0\u00b1\u00a01.4 and 14.6\u00a0\u00a0\u00b1\u00a00.44 \u03bcmol\u00b7L<jats:sup>\u22121<\/jats:sup>\u00a0were determined for PnPP\u201019 and Leu\u2010enkephalin respectively as inhibitors of NEP activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Antinociception induced by PnPP\u201019 appears to involve the inhibition of NEP and activation of CB<jats:sub>1<\/jats:sub>, \u03bc and \u03b4 opioid receptors. Our data provide a greater understanding of the antinociceptive effects of PnPP\u201019. This peptide could be useful as a new antinociceptive drug candidate.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13448","type":"journal-article","created":{"date-parts":[[2016,3,7]],"date-time":"2016-03-07T05:18:38Z","timestamp":1457327918000},"page":"1491-1501","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["PnPP\u201019, a spider toxin peptide, induces peripheral antinociception through opioid and cannabinoid receptors and inhibition of neutral endopeptidase"],"prefix":"10.1111","volume":"173","author":[{"given":"A C N","family":"Freitas","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica e Imunologia Universidade Federal de Minas Gerais Belo Horizonte MG Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D F","family":"Pacheco","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica e Imunologia Universidade Federal de Minas Gerais Belo 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