Remote local photoactivation of morphine produces analgesia without opioid‐related adverse effects

Abstract

Background and Purpose: Opioid-based drugs are the gold standard medicines for pain relief. However, tolerance and several side effects (i.e. constipation and 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 photoderivative (photocaged morphine), which can be activated upon light irradiation both in vitro and in vivo.Experimental Approach: Light-dependent activity of pc-morphine 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-morphine was able to elicit antinociceptive effects, both using external light-irradiation (hind paw) and spinal cord implanted fibre-optics.

Photoremovable Protecting Groups

“…Since the 1970s, a considerable effort has been dedicated both to the development of novel photoactivatable chemical probes and their applications in various experimental studies. Regarding the scope of PPG applications, the caged substrate could be as Encyclopedia 2022, 2 1227 simple as a proton or an inorganic species or ion (e.g., Ca 2+ [15], Zn 2+ [16], CO [17], NO [18], H 2 S [19]), it could be a small molecule (e.g., second messenger (such as inositol-1,4,5-triphosphate (IP 3 ) [20]), neurotransmitter (notably GABA and glutamate [21,22]), nucleotide [23], peptide [24], drug molecule [25] (such as antibiotics [26], analgesics [27] or anticancer agents [28]) or a more complex biomolecule (e.g., enzymes [29], RNA [30] or DNA [31]) (Figure 3).…”

“…Since the 1970s, a considerable effort has been dedicated both to the development of novel photoactivatable chemical probes and their applications in various experimental studies. Regarding the scope of PPG applications, the caged substrate could be as simple as a proton or an inorganic species or ion (e.g., Ca 2+ [15], Zn 2+ [16], CO [17], NO [18], H2S [19]), it could be a small molecule (e.g., second messenger (such as inositol-1,4,5-triphosphate (IP3) [20]), neurotransmitter (notably GABA and glutamate [21,22]), nucleotide [23], peptide [24], drug molecule [25] (such as antibiotics [26], analgesics [27] or anticancer agents [28]) or a more complex biomolecule (e.g., enzymes [29], RNA [30] or DNA [31]) (Figure 3). Examples of PPG applications for small molecules/inorganic species: (A) calcium caging with photoactivatable EGTA [32], (B) neurotransmitter glutamate caging with MNI [21], (C) caging the anticancer agent vemurafenib with a nitrobenzyl PPG [33], (D) a coumarin PPG-caged antibiotic agent [34], (E) a coumarin PPG-caged analgesic [27].…”

“…Regarding the scope of PPG applications, the caged substrate could be as simple as a proton or an inorganic species or ion (e.g., Ca 2+ [15], Zn 2+ [16], CO [17], NO [18], H2S [19]), it could be a small molecule (e.g., second messenger (such as inositol-1,4,5-triphosphate (IP3) [20]), neurotransmitter (notably GABA and glutamate [21,22]), nucleotide [23], peptide [24], drug molecule [25] (such as antibiotics [26], analgesics [27] or anticancer agents [28]) or a more complex biomolecule (e.g., enzymes [29], RNA [30] or DNA [31]) (Figure 3). Examples of PPG applications for small molecules/inorganic species: (A) calcium caging with photoactivatable EGTA [32], (B) neurotransmitter glutamate caging with MNI [21], (C) caging the anticancer agent vemurafenib with a nitrobenzyl PPG [33], (D) a coumarin PPG-caged antibiotic agent [34], (E) a coumarin PPG-caged analgesic [27]. Examples of PPG applications for small molecules/inorganic species: (A) calcium caging with photoactivatable EGTA [32], (B) neurotransmitter glutamate caging with MNI [21], (C) caging the anticancer agent vemurafenib with a nitrobenzyl PPG [33], (D) a coumarin PPG-caged antibiotic agent [34], (E) a coumarin PPG-caged analgesic [27].…”

“…Examples of PPG applications for small molecules/inorganic species: (A) calcium caging with photoactivatable EGTA [32], (B) neurotransmitter glutamate caging with MNI [21], (C) caging the anticancer agent vemurafenib with a nitrobenzyl PPG [33], (D) a coumarin PPG-caged antibiotic agent [34], (E) a coumarin PPG-caged analgesic [27]. Examples of PPG applications for small molecules/inorganic species: (A) calcium caging with photoactivatable EGTA [32], (B) neurotransmitter glutamate caging with MNI [21], (C) caging the anticancer agent vemurafenib with a nitrobenzyl PPG [33], (D) a coumarin PPG-caged antibiotic agent [34], (E) a coumarin PPG-caged analgesic [27].…”

“…Figure 3.Examples of PPG applications for small molecules/inorganic species: (A) calcium caging with photoactivatable EGTA[32], (B) neurotransmitter glutamate caging with MNI[21], (C) caging the anticancer agent vemurafenib with a nitrobenzyl PPG[33], (D) a coumarin PPG-caged antibiotic agent[34], (E) a coumarin PPG-caged analgesic[27].…”