Pharmacology of Morphine and Morphine‐3‐glucuronide at Opioid, Excitatory Amino Acid, GABA and Glycine Binding Sites

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Abstract
Morphine in high doses and its major metabolite, morphine‐3‐glucuronide, cause CNS excitation following intrathecal and intracerebroventricular administration by an unknown mechanism. This study investigated whether morphine and morphine‐3‐glucuronide interact at major excitatory (glutamate), major inhibitory (GABA or glycine), or opioid binding sites. Homogenate binding assays were performed using specific radioligands. At opioid receptors, morphine‐3‐glucuronide and morphine caused an equipotent sodium shift, consistent with morphine‐3‐glucuronide behaving as an agonist. This suggests that morphine‐3‐glucuronide‐mediated excitation is not caused by an interaction at opioid receptors. Morphine‐3‐glucuronide and morphine caused a weak inhibition of the binding of 3H‐MK801 (non‐competitive antagonist) and 125I‐ifenprodil (polyamine site antagonist), but at unphysiologically high concentrations. This suggests that CNS excitation would not result from an interaction of morphine‐3‐glucuronide and high‐dose morphine with these sites on the NMDA receptor. Morphine‐3‐glucuronide and morphine inhibited the binding of 3H‐muscimol (GABA receptor agonist), 3H‐diazepam and 3H‐flunitrazepam (benzodiazepine agonists) binding very weakly, suggesting the excitatory effects of morphine‐3‐glucuronide and high‐dose morphine are not elicited through GABAA, receptors. Mor‐phine‐3‐glucuronide and high‐dose morphine did not prevent re‐uptake of glutamate into presynaptic nerve terminals. In addition, morphine‐3‐glucuronide and morphine did not inhibit the binding of 3H‐strychnine (glycine receptor antagonist) to synaptic membranes prepared from bovine spinal cord. It is concluded that excitation caused by high‐dose morphine and morphine‐3‐glucuronide is not mediated by an interaction with postsynaptic amino acid receptors.