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Herein, a novel peptide\u2010drug conjugate FENPFF01, incorporating the neuropeptide FF (NPFF) and fentanyl pharmacophores, was synthesised and pharmacologically characterised.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      The agonist activities of FENPFF01 at opioid and NPFF receptors were characterised in\n                      <jats:italic>in vitro<\/jats:italic>\n                      functional assays. Antinociceptive effects and underlying pharmacological mechanisms of FENPFF01 were assessed in multiple mouse pain models. The side effects of FENPFF01 were further investigated through antinociceptive tolerance, respiratory function, addiction potential and gastrointestinal transit tests.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      FENPFF01 functioned as a mixed partial agonist at the \u03bc\u2010opioid and NPFF\n                      <jats:sub>2<\/jats:sub>\n                      receptors, and a full agonist at NPFF\n                      <jats:sub>1<\/jats:sub>\n                      receptor. Subcutaneous FENPFF01 produced potent antinociception in acute, inflammatory and post\u2010operative pain, which was mediated by the \u03bc receptor. The\n                      <jats:italic>in vivo<\/jats:italic>\n                      pharmacological and pharmacokinetic data demonstrated that FENPFF01 could penetrate the blood\u2013brain barrier (BBB) and activate the \u03bc receptor in the brain to elicit antinociception. Importantly, chronic administration of FENPFF01 did not induce antinociceptive tolerance or observable effects on spinal microglial activation, which may be partly attributable to the activation of the NPFF\n                      <jats:sub>2<\/jats:sub>\n                      receptor. FENPFF01 also did not affect arterial gas parameters, respiratory rate, locomotor activity, conditioned place preference response, physical dependence and gastrointestinal transit.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>The newly developed peptide\u2010drug conjugate FENPFF01 exhibited strong antinociception with reduced opioid\u2010like side effects. It represents an interesting candidate for developing novel analgesics with multi\u2010targeted agonist properties, aiming to address the widespread issues associated with opioid misuse.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70178","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T22:39:12Z","timestamp":1756161552000},"page":"6136-6157","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A novel peptide\u2010fentanyl conjugate with \u03bc\u2010opioid and neuropeptide FF receptor agonism produces antinociception with limited side effects in male mice"],"prefix":"10.1111","volume":"182","author":[{"given":"Ning","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Preclinical Study for New Drugs of Gansu Province and School of Basic Medical Sciences Lanzhou University  Lanzhou 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