{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T23:48:14Z","timestamp":1790380094756,"version":"4.1.0"},"reference-count":60,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2018,5,31]],"date-time":"2018-05-31T00:00:00Z","timestamp":1527724800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Institute of Pharmacology Polish Academy of Sciences, Department of Pain Pharmacology","award":["-"],"award-info":[{"award-number":["-"]}]},{"name":"National Science Center, Poland","award":["DEC-2011\/02\/A\/NZ4\/00031"],"award-info":[{"award-number":["DEC-2011\/02\/A\/NZ4\/00031"]}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2018,7]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>The histaminergic system is a promising target for the development of new analgesics, as histamine H<jats:sub>3<\/jats:sub> and H<jats:sub>4<\/jats:sub> receptors are expressed in regions concerned with nociceptive transmission. Here we have determined the analgesic effects of new H<jats:sub>3<\/jats:sub> and H<jats:sub>4<\/jats:sub> receptor antagonists in naive and neuropathic mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We used chronic constriction injury (CCI) to the sciatic nerve in mice to model neuropathy. Effects of a new H<jats:sub>3<\/jats:sub> receptor antagonist, E\u2010162(1\u2010(5\u2010(naphthalen\u20101\u2010yloxy)pentyl)piperidine) and H<jats:sub>4<\/jats:sub> receptor antagonist, TR\u20107(4\u2010(4\u2010chlorophenyl)\u20106\u2010(4\u2010methylpiperazin\u20101\u2010yl)\u20101,3,5\u2010triazin\u20102\u2010amine) were assessed on mechanical (von Frey) and thermal (cold plate, tail flick) stimuli in mice with and without CCI (7\u00a0days after injury). Effects of these antagonists on morphine analgesia were also evaluated, along with the possible participation of H<jats:sub>1<\/jats:sub> receptors in their effects. We analysed the compounds in binding and functional cAMP assays at the H<jats:sub>3<\/jats:sub> and H<jats:sub>4<\/jats:sub> receptors and determined metabolic stability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>E\u2010162 and TR\u20107 attenuated nociceptive responses and profound morphine analgesia in males with CCI. These antagonists showed analgesia in naive mice (tail flick test) and produced prolonged analgesia in neuropathic females. E\u2010162\u2010induced analgesia was reversed by pyrilamine, an H<jats:sub>1<\/jats:sub> receptor antagonist. E\u2010162 bound potently to H<jats:sub>3<\/jats:sub> receptors (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>\u00a0=\u00a055\u00a0nM) and inhibited cAMP accumulation (IC<jats:sub>50<\/jats:sub>\u00a0=\u00a0165\u00a0nM). TR\u20107 showed lower affinity for H<jats:sub>4<\/jats:sub> receptors (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>\u00a0=\u00a0203\u00a0nM) and IC<jats:sub>50<\/jats:sub>\u00a0of 512\u00a0nM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>We describe a therapeutic use for new H<jats:sub>3<\/jats:sub> (E\u2010162) and H<jats:sub>4<\/jats:sub> receptor (TR\u20107) antagonists in neuropathy. Targeting H<jats:sub>3<\/jats:sub> and H<jats:sub>4<\/jats:sub> receptors enhanced morphine analgesia, consistent with multimodal pain therapy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14185","type":"journal-article","created":{"date-parts":[[2018,2,27]],"date-time":"2018-02-27T20:42:40Z","timestamp":1519764160000},"page":"2897-2910","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Antinociceptive effects of novel histamine H<sub>3<\/sub> and H<sub>4<\/sub> receptor antagonists and their influence on morphine analgesia of neuropathic pain in the mouse"],"prefix":"10.1111","volume":"175","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4366-6577","authenticated-orcid":false,"given":"Katarzyna","family":"Popiolek\u2010Barczyk","sequence":"first","affiliation":[{"name":"Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College  Krakow Poland"},{"name":"Department of Pain 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