Marc López-Cano1,2, Joan Font3,4, Ester Aso1,2, Kristoffer Sahlholm1,2,5,6, Gisela Cabré7, Jesús Giraldo8,9,10, Yves De Koninck11,12, Jordi Hernando7, Amadeu Llebaria3, Víctor Fernández-Dueñas1,2, Francisco Ciruela1,2. 1. Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, , University of Barcelona, L'Hospitalet de Llobregat, Spain. 2. Neuropharmacology & Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Spain. 3. MCS, Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain. 4. Institut de Génomique Fonctionnelle (IGF), University of Montpellier, CNRS, INSERM, Montpellier, France. 5. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. 6. Department of Integrative Medical Biology, Umeå University, Umeå, Sweden. 7. Departament de Química, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain. 8. Laboratory of Molecular Neuropharmacology and Bioinformatics, Unitat de Bioestadística and Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain. 9. Unitat de Neurociència Traslacional, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí (I3PT), Institut de Neurociències, Universitat Autònoma de Barcelona, Spain. 10. Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain. 11. Institut Universitaire en Santé Mentale de Québec, Québec, Canada. 12. Department of Psychiatry and Neuroscience, Université Laval, Québec, Canada.
Abstract
BACKGROUND AND PURPOSE: Opioid-based drugs are the gold standard medicines for pain relief. However, tolerance and several side effects (i.e., constipation, dependence) may occur upon chronic opioid administration. Photopharmacology is a promising approach to improve the benefit/risk profiles of these drugs. Thus, opioids can be locally activated with high spatiotemporal resolution, potentially minimizing systemic-mediated adverse effects. Here, we aimed at developing a morphine photo-derivative (photocaged morphine, pc-Mor), which can be activated upon light irradiation both in vitro and in vivo. EXPERIMENTAL APPROACH: Light-dependent activity of pc-Mor was assessed in cell-based assays (intracellular calcium accumulation and electrophysiology) and in mice (formalin animal model of pain). In addition, tolerance, constipation, and dependence were investigated in vivo using experimental paradigms. KEY RESULTS: In mice, pc-Mor was able to elicit antinociceptive effects, both using external light-irradiation (hind paw) and spinal cord implanted fibre-optics. In addition, remote morphine photoactivation was devoid of common systemic opioid-related undesired effects, namely constipation, tolerance to the analgesic effects, rewarding effects, and naloxone-induced withdrawal. CONCLUSION AND IMPLICATIONS: Light-dependent opioid-based drugs may allow effective analgesia without the occurrence of tolerance or the associated and severe opioid-related undesired effects. This article is protected by copyright. All rights reserved.
BACKGROUND AND PURPOSE: Opioid-based drugs are the gold standard medicines for pain relief. However, tolerance and several side effects (i.e., constipation, dependence) may occur upon chronic opioid administration. Photopharmacology is a promising approach to improve the benefit/risk profiles of these drugs. Thus, opioids can be locally activated with high spatiotemporal resolution, potentially minimizing systemic-mediated adverse effects. Here, we aimed at developing a morphine photo-derivative (photocaged morphine, pc-Mor), which can be activated upon light irradiation both in vitro and in vivo. EXPERIMENTAL APPROACH: Light-dependent activity of pc-Mor was assessed in cell-based assays (intracellular calcium accumulation and electrophysiology) and in mice (formalin animal model of pain). In addition, tolerance, constipation, and dependence were investigated in vivo using experimental paradigms. KEY RESULTS: In mice, pc-Mor was able to elicit antinociceptive effects, both using external light-irradiation (hind paw) and spinal cord implanted fibre-optics. In addition, remote morphine photoactivation was devoid of common systemic opioid-related undesired effects, namely constipation, tolerance to the analgesic effects, rewarding effects, and naloxone-induced withdrawal. CONCLUSION AND IMPLICATIONS: Light-dependent opioid-based drugs may allow effective analgesia without the occurrence of tolerance or the associated and severe opioid-related undesired effects. This article is protected by copyright. All rights reserved.