Can Src protein tyrosine kinase inhibitors be combined with opioid analgesics? Src and opioid-induced tolerance, hyperalgesia and addiction

Li, Yaoyuan; Bao, Yanju; Zheng, Hongliang; Qin, Yinggang; Bai, Hua

doi:10.1016/j.biopha.2021.111653

Cited by 2 publications

(1 citation statement)

References 117 publications

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“…At the cellular level, several postulated mechanisms have been proposed for opioid analgesic tolerance, as described in Table 1, though the exact mechanisms responsible are poorly understood. With respect to receptor desensitization and opioid analgesic tolerance development, several mechanisms have been proposed, including one that relies on the activation of NMDARs [23][24][25]. This mechanism is supported by the fact that MK-801, a highly potent and selective noncompetitive NMDAR antagonist, attenuates the development of morphine analgesic tolerance in mice [12,26].…”

Section: N-methyl-d-aspartate Acid Glutamate Receptors As Key Players...mentioning

confidence: 99%

Glycine Transporter 1 Inhibitors: Predictions on Their Possible Mechanisms in the Development of Opioid Analgesic Tolerance

Galambos,

Papp,

Boldizsár

et al. 2024

Biomedicines

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The development of opioid tolerance in patients on long-term opioid analgesic treatment is an unsolved matter in clinical practice thus far. Dose escalation is required to restore analgesic efficacy, but at the price of side effects. Intensive research is ongoing to elucidate the underlying mechanisms of opioid analgesic tolerance in the hope of maintaining opioid analgesic efficacy. N-Methyl-D-aspartate receptor (NMDAR) antagonists have shown promising effects regarding opioid analgesic tolerance; however, their use is limited by side effects (memory dysfunction). Nevertheless, the GluN2B receptor remains a future target for the discovery of drugs to restore opioid efficacy. Mechanistically, the long-term activation of µ-opioid receptors (MORs) initiates receptor phosphorylation, which triggers β-arrestin-MAPKs and NOS-GC-PKG pathway activation, which ultimately ends with GluN2B receptor overactivation and glutamate release. The presence of glutamate and glycine as co-agonists is a prerequisite for GluN2B receptor activation. The extrasynaptic localization of the GluN2B receptor means it is influenced by the glycine level, which is regulated by astrocytic glycine transporter 1 (GlyT1). Enhanced astrocytic glycine release by reverse transporter mechanisms as a consequence of high glutamate levels or unconventional MOR activation on astrocytes could further activate the GluN2B receptor. GlyT1 inhibitors might inhibit this condition, thereby reducing opioid tolerance.

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Section: N-methyl-d-aspartate Acid Glutamate Receptors As Key Players...mentioning

confidence: 99%

Glycine Transporter 1 Inhibitors: Predictions on Their Possible Mechanisms in the Development of Opioid Analgesic Tolerance

Galambos,

Papp,

Boldizsár

et al. 2024

Biomedicines

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Glycine Transporter 1 Inhibitors Minimize the Analgesic Tolerance to Morphine

Galambos,

Essmat,

Lakatos

et al. 2024

IJMS

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Opioid analgesic tolerance (OAT), among other central side effects, limits opioids’ indispensable clinical use for managing chronic pain. Therefore, there is an existing unmet medical need to prevent OAT. Extrasynaptic N-methyl D-aspartate receptors (NMDARs) containing GluN2B subunit blockers delay OAT, indicating the involvement of glutamate in OAT. Glycine acts as a co-agonist on NMDARs, and glycine transporters (GlyTs), particularly GlyT-1 inhibitors, could affect the NMDAR pathways related to OAT. Chronic subcutaneous treatments with morphine and NFPS, a GlyT-1 inhibitor, reduced morphine antinociceptive tolerance (MAT) in the rat tail-flick assay, a thermal pain model. In spinal tissues of rats treated with a morphine–NFPS combination, NFPS alone, or vehicle-comparable changes in µ-opioid receptor activation, protein and mRNA expressions were seen. Yet, no changes were observed in GluN2B mRNA levels. An increase was observed in glycine and glutamate contents of cerebrospinal fluids from animals treated with a morphine–NFPS combination and morphine, respectively. Finally, GlyT-1 inhibitors are likely to delay MAT by mechanisms relying on NMDARs functioning rather than an increase in opioid efficacy. This study, to the best of our knowledge, shows for the first time the impact of GlyT-1 inhibitors on MAT. Nevertheless, future studies are required to decipher the exact mechanisms.

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Can Src protein tyrosine kinase inhibitors be combined with opioid analgesics? Src and opioid-induced tolerance, hyperalgesia and addiction

Cited by 2 publications

References 117 publications

Glycine Transporter 1 Inhibitors: Predictions on Their Possible Mechanisms in the Development of Opioid Analgesic Tolerance

Glycine Transporter 1 Inhibitors: Predictions on Their Possible Mechanisms in the Development of Opioid Analgesic Tolerance

Glycine Transporter 1 Inhibitors Minimize the Analgesic Tolerance to Morphine

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