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PAIN MEDICINE

Morphine-3-Glucuronide’s Neuro-Excitatory Effects Are Mediated via Indirect Activation of N-Methyl-D-Aspartic Acid Receptors: Mechanistic Studies in Embryonic Cultured Hippocampal Neurones

School of Pharmacy, The University of Queensland, St Lucia Campus, Brisbane, Australia

Address correspondence and reprint requests to Maree T. Smith, PhD, School of Pharmacy, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. Address e-mail to m.smith{at}pharmacy.uq.edu.au

Indirect evidence indicates that morphine-3-glucuronide (M3G) may contribute significantly to the neuro-excitatory side effects (myoclonus and allodynia) of large-dose systemic morphine. To gain insight into the mechanism underlying M3G’s excitatory behaviors, we used fluo-3 fluorescence digital imaging techniques to assess the acute effects of M3G (5–500 µM) on the cytosolic calcium concentration ([Ca²⁺]_CYT) in cultured embryonic hippocampal neurones. Acute (3 min) exposure of neurones to M3G evoked [Ca²⁺]_CYT transients that were typically either (a) transient oscillatory responses characterized by a rapid increase in [Ca²⁺]_CYT oscillation amplitude that was sustained for at least 30 s or (b) a sustained increase in [Ca²⁺]_CYT that slowly recovered to baseline. Naloxone-pretreatment decreased the proportion of M3G-responsive neurones by 10%–25%, implicating a predominantly non-opioidergic mechanism. Although the naloxone-insensitive M3G-induced increases in [Ca²⁺]_CYT were completely blocked by N-methyl-D-aspartic acid (NMDA) antagonists and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate antagonist), CNQX did not block the large increase in [Ca²⁺]_CYT evoked by NMDA (as expected), confirming that M3G indirectly activates the NMDA receptor. Additionally, tetrodotoxin (Na⁺ channel blocker), baclofen (-aminobutyric acid_B agonist), MVIIC (P/Q-type calcium channel blocker), and nifedipine (L-type calcium channel blocker) all abolished M3G-induced increases in [Ca²⁺]_CYT, suggesting that M3G may produce its neuro-excitatory effects by modulating neurotransmitter release. However, additional characterization is required.

IMPLICATIONS: Large systemic doses of morphine administered to some patients for cancer pain management have been reported to produce myoclonus and allodynia. Indirect evidence implicates the major morphine metabolite, morphine-3-glucuronide (M3G), in these neuro-excitatory side effects. Hence, this study was designed to gain insight into the cellular mechanism responsible for M3G’s neuro-excitatory actions.

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