In vitro and in vivo characterization of the bifunctional μ and δ opioid receptor ligand UFP-505
| Autor: | Dietis, Nikolas, Niwa, H., Tose, R., McDonald, J., Ruggieri, V., Filaferro, M., Vitale, G., Micheli, L., Ghelardini, C., Salvadori, S., Calo, G., Guerrini, R., Rowbotham, D. J., Lambert, D. G. |
|---|---|
| Přispěvatelé: | Dietis, Nikolas [0000-0002-8365-3837] |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist Male medicine.drug_class Receptors Opioid mu Pain Socio-culturale CHO Cells Pharmacology Ligands Partial agonist 03 medical and health sciences 0302 clinical medicine Cricetulus In vivo Opioid receptor Receptors Opioid delta medicine Arrestin Animals Rats Wistar Receptor Injections Spinal μ δ and μ /δ receptor Analgesics Chemistry Ligand (biochemistry) 030104 developmental biology Opioid Themed Section: Research Papers Oligopeptides 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | British Journal of Pharmacology |
| DOI: | 10.1111/bph.14199 |
| Popis: | Background and Purpose Targeting more than one opioid receptor type simultaneously may have analgesic advantages in reducing side-effects. We have evaluated the mixed μ opioid receptor agonist/ δ opioid receptor antagonist UFP-505 in vitro and in vivo. Experimental Approach We measured receptor density and function in single μ, δ and μ /δ receptor double expression systems. GTPγ35S binding, cAMP formation and arrestin recruitment were measured. Antinociceptive activity was measured in vivo using tail withdrawal and paw pressure tests following acute and chronic treatment. In some experiments, we collected tissues to measure receptor densities. Key Results UFP-505 bound to μ receptors with full agonist activity and to δ receptors as a low efficacy partial agonist At μ, but not δ receptors, UFP-505 binding recruited arrestin. Unlike morphine, UFP-505 treatment internalized μ receptors and there was some evidence for internalization of δ receptors. Similar data were obtained in a μ /δ receptor double expression system. In rats, acute UFP-505 or morphine, injected intrathecally, was antinociceptive. In tissues harvested from these experiments, μ and δ receptor density was decreased after UFP-505 but not morphine treatment, in agreement with in vitro data. Both morphine and UFP-505 induced significant tolerance. Conclusions and Implications In this study, UFP-505 behaved as a full agonist at μ receptors with variable activity at δ receptors. This bifunctional compound was antinociceptive in rats after intrathecal administration. In this model, dual targeting provided no advantages in terms of tolerance liability. Linked Articles This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc 175 14 2881 2896 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|