Methadone's effects on pentylenetetrazole‐induced seizure threshold in mice: NMDA/opioid receptors and nitric oxide signaling

Abstract

Methadone is a synthetic opioid used to treat opiate withdrawal and addiction. Studies have demonstrated the impact of methadone on seizure susceptibility. This study investigated the modulatory impacts of acute and subchronic (three times daily for 5 days) intraperitoneal methadone treatment on pentylenetetrazole‐induced clonic seizure threshold (CST) in mice, as well as the involvement of the nitric oxide, N‐methyl‐d‐aspartate (NMDA), and µ‐opioid pathways. Acute administration of different doses of methadone (0.1, 0.3, 1, and 3 mg/kg) 45 min before CST significantly decreased the seizure threshold. Additionally, pretreatment with noneffective doses of an opioid receptor antagonist (naltrexone) and NMDA receptor antagonists (ketamine and MK‐801) inhibited methadone's proconvulsive activity in the acute phase, while l‐NAME (a nonspecific nitric oxide synthase (NOS) inhibitor) did not affect that activity. In the subchronic phase, methadone (3 mg/kg) demonstrated an anticonvulsive effect. Although subchronic pretreatment with noneffective doses of l‐NAME and 7‐nitroindazole (a specific neuronal NOS inhibitor) reversed methadone's anticonvulsive activity, aminoguanidine (a specific inducible NOS inhibitor), naltrexone, MK‐801, and ketamine did not change methadone's anticonvulsive characteristic. Our results suggest that NMDA and µ‐opioid receptors may be involved in methadone's proconvulsive activity in the acute phase, while methadone's anticonvulsive activity may be modulated by neuronal NOS in the subchronic phase.

The opioid antagonist naltrexone decreases seizure‐like activity in genetic and chemically induced epilepsy models

“…The role that opioid receptors play in seizures is complex. Low doses of morphine have an anticonvulsant impact, although high doses have the opposite effect 25–29 . Opioids worsen, and antagonists prevent absence‐like seizures, 30,31 and a polymorphism in the N‐terminal μ opioid receptor in humans confers genetic susceptibility to idiopathic absence epilepsy 32 .…”

“…Opioids worsen, and antagonists prevent absence‐like seizures, 30,31 and a polymorphism in the N‐terminal μ opioid receptor in humans confers genetic susceptibility to idiopathic absence epilepsy 32 . Low and ultra‐low doses of NTX potentiate the anticonvulsive effect of morphine and cannabinoids, 33–36 and NTX reverses the convulsive effect of acute methadone injections 29 . However, other studies indicate that NTX can potentiate seizures 37–39 .…”

“…Low doses of morphine have an anticonvulsant impact, although high doses have the opposite effect. [25][26][27][28][29] Opioids worsen, and antagonists prevent absence-like seizures, 30,31 and a polymorphism in the N-terminal μ opioid receptor in humans confers genetic susceptibility to idiopathic absence epilepsy. 32 Low and ultra-low doses of NTX potentiate the anticonvulsive effect of morphine and cannabinoids, [33][34][35][36] and NTX reverses the convulsive effect of acute methadone injections.…”

Clinical characteristics and time trends of hospitalized methadone exposures in the United States based on the Toxicology Investigators Consortium (ToxIC) case registry: 2010–2017

“…Animal studies showed that acute administration of methadone could substantially reduce the seizure threshold. NMDA and μ-opioid receptors may be involved in methadone's convulsive activity in the acute methadone overdose [25].…”

Clinical characteristics and time trends of hospitalized methadone exposures s in the United States based on the Toxicology Investigators Consortium (ToxIC) Case Registry: 2010-2017

“…Animal studies showed that acute administration of methadone could substantially reduce the seizure threshold. NMDA and µopioid receptors may be involved in methadone's convulsive activity in the acute methadone overdose [25].…”