{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T11:45:18Z","timestamp":1759664718888},"reference-count":47,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2009,2,17]],"date-time":"2009-02-17T00:00:00Z","timestamp":1234828800000},"content-version":"vor","delay-in-days":1569,"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":[[2004,11]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Naloxone benzoylhydrazone (NalBzoH) has initially been developed as an agonist of the pharmacologically defined <jats:italic>\u03ba<\/jats:italic><jats:sub>3<\/jats:sub>\u2010opioid receptor and has recently been employed as an antagonist at the opioid receptor\u2010like (ORL1) receptor. In the present study, we investigated the ability of NalBzoH to elicit agonist\u2010like effects on receptor signalling in distinct layers of rat olfactory bulb, a brain region where we have demonstrated the presence of opioid and ORL1 receptors coupled to both stimulation and inhibition of cyclic AMP formation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In membranes of the olfactory nerve\u2010glomerular layer (ON\u2010GL), external plexiform layer (EPL) and granule cell layer (GRL), NalBzoH elicited a concentration\u2010dependent stimulation of guanosine\u20105\u2032\u2010<jats:italic>O<\/jats:italic>\u2010(3\u2010[<jats:sup>35<\/jats:sup>S]\u2010thio)triphosphate ([<jats:sup>35<\/jats:sup>S]GTP<jats:italic>\u03b3<\/jats:italic>S) binding with pEC<jats:sub>50<\/jats:sub> values ranging from 7.36 to 7.86, whereas the <jats:italic>\u03ba<\/jats:italic><jats:sub>1<\/jats:sub>\u2010opioid receptor agonists (\u2212)\u2010U\u201050,488 and U\u201069,593 were inactive.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In membranes of GRL, but not ON\u2010GL and EPL, NalBzoH stimulated basal adenylyl cyclase activity by 40% with a pEC<jats:sub>50<\/jats:sub> of 8.14, and significantly potentiated the net enzyme stimulation elicited by corticotropin\u2010releasing hormone and pituitary adenylate cyclase\u2010activating peptide 38. Pertussis toxin prevented the NalBzoH stimulations of [<jats:sup>35<\/jats:sup>S]GTP<jats:italic>\u03b3<\/jats:italic>S binding and adenylyl cyclase activity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In membranes of EPL and GRL, but not ON\u2010GL, NalBzoH elicited a concentration\u2010dependent inhibition of forskolin\u2010stimulated adenylyl cyclase activity with pEC<jats:sub>50<\/jats:sub> values of 8.07 and 8.08, respectively.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>At concentrations that completely blocked the actions of nociceptin\/orphanin FQ (N\/OFQ), the ORL1 receptor antagonists CompB and [Nphe<jats:sup>1<\/jats:sup>]N\/OFQ(1\u201313)NH<jats:sub>2<\/jats:sub> failed to antagonize either the stimulatory or the inhibitory effect of NalBzoH on cyclic AMP formation. Similarly, the <jats:italic>\u03ba<\/jats:italic><jats:sub>1<\/jats:sub>\u2010opioid receptor antagonist nor\u2010binaltorphimine counteracted the NalBzoH effects with relatively low potencies (p<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> values=7.67\u20138.09).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Conversely, the selective <jats:italic>\u03b4<\/jats:italic>\u2010opioid receptor antagonist TIPP (p<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>=9.10) and the selective <jats:italic>\u03bc<\/jats:italic>\u2010opioid receptor antagonist CTAP (p<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>=8.27) reduced the inhibitory effect of NalBzoH by 70 and 30%, respectively. Moreover, TIPP and CTAP potently inhibited the NalBzoH stimulation of cyclic AMP, each antagonist maximally causing 50% blockade of the agonist response.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These data demonstrate that in the olfactory bulb NalBzoH activates receptor signalling by acting through <jats:italic>\u03b4<\/jats:italic>\u2010 and <jats:italic>\u03bc<\/jats:italic>\u2010opioid receptors and independently of ORL1 and <jats:italic>\u03ba<\/jats:italic><jats:sub>1<\/jats:sub>\u2010opioid receptors.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2004) <jats:bold>143<\/jats:bold>, 638\u2013648. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0705951\">10.1038\/sj.bjp.0705951<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0705951","type":"journal-article","created":{"date-parts":[[2004,10,28]],"date-time":"2004-10-28T22:33:50Z","timestamp":1099002830000},"page":"638-648","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["G protein activation and cyclic AMP modulation by naloxone benzoylhydrazone in distinct layers of rat olfactory bulb"],"prefix":"10.1111","volume":"143","author":[{"given":"Pierluigi","family":"Onali","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria C","family":"Olianas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,2,17]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-22-08721.1997"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(95)00088-3"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1139\/y02-040"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(76)90527-3"},{"key":"e_1_2_6_6_1","first-page":"376","article-title":"3H\u2010Naloxone benzoylhydrazone binding in MOR\u20101\u2010transfected Chinese hamster ovary cells: evidence for G\u2010protein\u2010dependent antagonist binding","volume":"286","author":"BROWN G.P.","year":"1998","journal-title":"J. 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