Résumé
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.