Novel hybrid compounds, opioid agonist+melanocortin 4 receptor antagonist, as efficient analgesics in mouse chronic constriction injury model of neuropathic pain. (1st November 2020)

• Record Type: Journal Article
• Authors: Starnowska-Sokół, Joanna; Piotrowska, Anna; Bogacka, Joanna; Makuch, Wioletta; Mika, Joanna; Witkowska, Ewa; Godlewska, Magda; Osiejuk, Jowita; Gątarz, Sandra; Misicka, Aleksandra; Przewłocka, Barbara
• Is Part Of: Neuropharmacology. Volume 178(2020)
• Publication Date: 2020-11-01
• Subjects: Neuropathic pain -- SHU9119 -- Enkephalin -- Opioids -- Melanocortin system -- Bifunctional hybrid analgesics; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2020.108232
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: When the nerve tissue is injured, endogenous agonist of melanocortin type 4 (MC4) receptor, α-MSH, exerts tonic pronociceptive action in the central nervous system, contributing to sustaining the neuropathic pain state and counteracting the analgesic effects of exogenous opioids. With the intent of enhancing opioid analgesia in neuropathy by blocking the MC4 activation, so-called parent compounds (opioid agonist, MC4 antagonist) were joined together using various linkers to create novel bifunctional hybrid compounds. Analgesic action of four hybrids was tested after intrathecal (i.t.) administration in mouse models of acute and neuropathic pain (chronic constriction injury model, CCI). Under nerve injury conditions, one of the hybrids, UW3, induced analgesia in 1500 times lower i.t. dose than the opioid parent (ED50: 0.0002 nmol for the hybrid, 0.3 nmol for the opioid parent) and in an over 16000 times lower dose than the MC4 parent (ED50: 3.33 nmol) as measured by the von Frey test. Two selected hybrids were tested for analgesic properties in CCI mice after intravenous (i.v.) and intraperitoneal (i.p.) administration. Opioid receptor antagonists and MC4 receptor agonists diminished the analgesic action of these two hybrids studied, though the extent of this effect differed between the hybrids; this suggests that linker is of key importance here. Further results indicate a significant advantage of hybrid compounds over the physical mixture of individual pharmacophores in their analgesic effect. All this evidence justifies the idea of synthesizing a bifunctional opioid agonist-linker-MC4 antagonist compound, as such structure may bring important benefits in neuropathic pain treatment. Graphical abstract: Image 1 Highlights: OP-linker-MC4 hybrids bring better analgesia in CCI mice than a two-component mixture OP-linker-MC4 hybrids can provide efficient analgesia in relatively low doses Selected hybrids cause analgesia after central as well as peripheral injection OP-antagonists and MC4-agonists pre-treatment lowers hybrid-induced analgesia OP-linker-MC4 hybrids can be a promising option of the neuropathic pain treatment