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. 2020 Aug;57(8):3376-3389.
doi: 10.1007/s12035-020-01975-6. Epub 2020 Jun 10.

Morphine Induces Apoptosis, Inflammation, and Mitochondrial Oxidative Stress via Activation of TRPM2 Channel and Nitric Oxide Signaling Pathways in the Hippocampus

Haci Ömer Osmanlıoğlu  1 , Mustafa Kemal Yıldırım  1 , Yener Akyuva  2 , Kenan Yıldızhan  3 , Mustafa Nazıroğlu  4   5   6
Affiliations

Morphine Induces Apoptosis, Inflammation, and Mitochondrial Oxidative Stress via Activation of TRPM2 Channel and Nitric Oxide Signaling Pathways in the Hippocampus

Haci Ömer Osmanlıoğlu et al. Mol Neurobiol. 2020 Aug.

Erratum in

Abstract

Morphine as an opioid is an important drug in the treatment of moderate to severe pain. Several stress factors via generation of nitric oxide (NO) and oxidative stress (OS) are responsible for the adverse effects of morphine-induced analgesia, addiction, and antinociceptive tolerance, including altered Ca2+ concentration, inflammation, OS, and release of apoptotic factors. TRPM2 is a Ca2+-permeable cation channel and it is activated by OS and NO. Hence, adverse effect of morphine addiction may occur via the OS and NO-induced TRPM2 activation. Because of the unclear etiology of morphine-induced adverse effects in the hippocampus, investigating the involvement of TRPM2 and NO synthetase (NOS) activations in the treatment of morphine-induced OS, apoptosis, and neuroinflammation is a major challenge. The hippocampal neuron of TRPM2 wild-type (TRPM2-WT) and knockout (TRPM2-KO) mice were divided into control, morphine, NOS inhibitor (L-NAME) + morphine, and TRPM2 channel blockers (ACA and 2-APB) + morphine. The morphine-induced increases of apoptosis, neuron death, OS, lipid peroxidation, caspase-3 and caspase-9, neuroinflammatory cytokines (IL-1β, TNF-α, IL-6), and Ca2+ levels in the hippocampal neuron of TRPM2-WT mouse were decreased by the L-NAME, ACA, and 2-APB treatments, although cell viability, neuron count, and reduced glutathione and glutathione peroxidase levels were increased by the treatments. However, the effects of morphine were not observed in the hippocampus of TRPM2-KO mice. Taken together, our data show that neurodegeneration adverse effects of morphine were induced by activation of TRPM2, and excessive generations of NO and OS. Thus, inhibition of TRPM2 may modulate morphine-induced neurodegeneration in the hippocampus.

Keywords: Apoptosis; Mitochondria; Morphine; Nitric oxide; TRPM2 channel.

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