TABLE 3.
M3G pharmacological targets and effects.
| References | Specie/Model | Experiment type | M3G effects |
| Pasternak et al., 1987 | Bovine brain membranes | In vitro | M3G has a low affinity for MOR |
| Christensen and Jorgensen, 1987 | Bovine brain membranes | In vitro | |
| Chen et al., 1991 | Rat brain membranes | In vitro | |
| Bartlett and Smith, 1995 | Sheep brain membranes | In vitro | |
| Roeckel et al., 2017 | Mouse brain membranes | In vitro | |
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| Labella et al., 1979 | SD male rats | In vivo | M3G-induced hyperalgesia/allodynia is enhanced by naloxone/naltrexone treatment |
| Woolf, 1981 | SD rats | In vivo | |
| Yaksh et al., 1986 | Rats | In vivo | |
| Yaksh and Harty, 1988 | Rats | In vivo | |
| Halliday et al., 1999 | SD male rats | In vivo | |
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| Roeckel et al., 2017 | MOR–/– mice | In vivo | MOR is required for M3G-induced hyperalgesia following i.p. injection |
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| Lewis et al., 2010 | SD male rats | In vivo, in vitro and in silico | TLR4 is required for M3G-induced hyperalgesia. M3G activates TLR4 signaling. M3G induces the release of proinflammatory cytokines. |
| Due et al., 2012 | TLR4–/– male mice and SD female rats | In vivo and in vitro | |
| Grace et al., 2014 | SD and lewis male rats | In vivo, in vitro and in silico | |
| Xie et al., 2017 | HEK cells | In vitro | |
| Allette et al., 2017 | SD rats | In vivo and in vitro | |
| Doyle and Murphy, 2018 | SD male and female rats | In vivo | |
| Iqbal et al., 2020 | PC12 cells | In vitro | |
| Wang et al., 2021 | C57BL/6 mice and human lung cancer cell lines | In vivo and in vitro | |
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| Sullivan et al., 1989 | SD male rats | In vivo electrophysiologi-cal recording | M3G does not affect basal or morphine-induced inhibition of C-fiber-evoked responses of convergent dorsal horn neurons, neither on membrane currents or action potential firing in locus coeruleus neurons |
| Hewett et al., 1993 | SD male rats | In vivo electrophysiologi-cal recording | |
| Osborne et al., 2000 | SD male rats | In situ electrophysiologi-cal recording | |
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| Bartlett et al., 1994a | SD male rats | In vivo | M3G-induced behavioral excitation involves the indirect activation of NMDA receptors. |
| Hemstapat et al., 2003 | Primary cultures of embryonic rat hippocampal neurones | In vitro | |
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| Bartlett et al., 1994b | SD male rats | In vitro | M3G does not interact with opioid, GABAA, AMPA, NMDA, kaïnate or glycinergic receptors, nor alters GABA or glutamate release from synaptosomes. |
| Bartlett and Smith, 1996 | SD male rats | In vitro | |
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| Moran and Smith, 2002 | SD rats | In vitro | M3G reduces the amplitude of GABAerbic and glycinergic inhibitory post-synaptic currents in the rat substantia gelatinosa through a presynaptic mechanism |
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| Komatsu et al., 2009 | ddY male mice | In vivo | i.t. M3G-induced behavioral excitation involves the ERK-NO-cGMP-PKG pathway and is blocked by coadministration of naltriben, a selective δ2-opioid receptor antagonist |
| Komatsu et al., 2016 | ddY male mice | In vivo | |
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| Due et al., 2014 | SD male and female rats | In vitro | M3G-induced increase of sensory neurons excitability is blocked by carbamazepine, an inhibitor of several voltage-dependent sodium channels |
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| Arout et al., 2014 | CD-1 male mice | In vivo | i.p. injection of M3G induces c-Fos activation in the PAG |
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| Juni et al., 2006 | CD-1 male mice | In vivo | M3G induces hyperalgesia following chronic treatment with high doses but not low doses of morphine |
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| Blomqvist et al., 2020 | SD male rats | In vivo | Chronic i.t. injections of M3G causes antinociceptive cross-tolerance to morphine and increases substance P expression in the dorsal horn of the spinal cord |
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| Igawa et al., 1993 | SD female rats | In vivo | i.t. M3G injection has excitatory effects on micturition |
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| Thomas et al., 1995 | Female B6C3F1 mouse cells | In vitro | M3G modulates B cell proliferation |
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| Hashiguchi et al., 1995 | SD male rats | In vivo | M3G enhance the hyperglycemic effects of M6G |
AMPA, α-amino-3-hydroxy-5-methylisoxazole-4-propionate; CNS, central nervous system; ddY, Deutschland, Denken, and Yoken mice; DOR, δ-opioid receptor; DRG, dorsal root ganglion; ERK, extracellular signal-regulated kinase; GABA, γ–aminobutyric acid; GABAA, GABA receptor A; HEK, human embryonic kidney cells; KO, knock-out; KOR, κ-opioid receptor; LC, locus coeruleus; LPS, lipopolysaccharide; M3G, morphine-3-glucuronide; M6G, morphine-6-glucuronide; MD-2, myeloid differentiation factor 2; MOR, μ-opioid receptor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA, N-methyl-D-aspartate; NO-cGMP-PKG, nitric oxide–cyclic guanosine monophosphate–protein kinase G signaling pathway; OIH, opioid-induced hyperalgesia; PAG, periaqueductal gray; PD-L1, programmed death-ligand 1; SD, Sprague-Dawley; TLR4, Toll-like receptor 4; vl-PAG, ventrolateral periaqueductal gray.