The long‐term effects of neonatal morphine administration on the pentylenetetrazol seizure model in rats: The role of hippocampal cholinergic receptors in adulthood

Abstract

Early life exposure to opiates may affect neuropathological conditions, such as epilepsy, during adulthood. We investigated whether neonatal morphine exposure affects pentylenetetrazol (PTZ)-induced seizures in adulthood. Male rats were subcutaneously injected with morphine or saline on postnatal days 8-14. During adulthood, each rat was assigned to 1 of the following 10 sub-groups: saline, nicotine (0.1, 0.5, or 1 μg), atropine (0.25 or 1 μg), oxotremorine M (0.1 or 1 μg), or mecamylamine (2 or 8 μg). An intrahippocampal infusion of the indicated compound was administered 30 min before seizure induction (80 mg/kg PTZ). Compared with the saline/oxotremorine (1 μg), saline/saline, and morphine/saline groups, the morphine/oxotremorine (1 μg) group showed a significantly increased latency to the first epileptic behavior. The duration of tonic-clonic seizures was significantly lower in the morphine/oxotremorine (1 μg) group compared to the saline/saline and morphine/saline groups. The severity of seizure was significantly decreased in the morphine/atropine (1 μg) group than in the saline/atropine (1 μg). Seizure severity was also decreased in the morphine/mecamylamine (2 μg) group than in the saline/mecamylamine (2 μg) group. Latency for death was significantly lower in the morphine/mecamylamine (2 μg) group compared with the saline/mecamylamine (2 μg) group. Mortality rates in the morphine/atropine (1 μg) and morphine/mecamylamine (2 μg) groups were significantly lower than those in the saline/atropine (1 μg) and saline/mecamylamine (2 μg) groups, respectively. Chronic neonatal morphine administration attenuated PTZ-induced seizures, reduced the mortality rate, and decreased the impact of the hippocampal cholinergic system on seizures and mortality rate in adult rats. Neonatal morphine exposure induces changes to μ-receptors that may lead to activation of GABAergic neurons in the hippocampus. This pathway may explain the anti-convulsant effects of morphine observed in our study.

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

“…On the other hand, there is a large body of evidence indicating diverse features of opioid agonists like morphine in seizure susceptibility in various models (kindling and PTZ‐induced) and phases (acute and chronic). Several studies have reported that low doses of morphine have an anticonvulsive impact in acute and chronic administrations, although high doses lower the seizure threshold . In line with previous studies, some paradoxical effects of opioid agonists were observed in our experiments.…”

Behavioral effects of perinatal opioid exposure

“…Controversially, the postnatal treatment of male rats with morphine reduced the development of pentylenetetrazol (PTZ)-induced seizures and the mortality rate in adulthood, possibly through the activation of GABAergic neurons in the hippocampus (Saboory et al, 2014). This effect was very similar to the consequences of prenatal morphine treatment, with decreased susceptibility to GABA-regulated seizures (Vathy, 2001).…”

The effect of selective opioid receptor agonists and antagonists on epileptiform activity in morphine‐dependent infant mice hippocampal slices

“…In a model of morphine sensitization in rats, autoradiography revealed a significant increase in the number of MORs in the hippocampus (Vigano et al, 2003) that making this system one of the predominant endogenous modulatory mechanisms that affect seizure susceptibility. Although the hippocampal formation is a structure that expresses significant densities of opioid receptors, morphine and other neurotransmitters including glutamate, acetylcholine, GABA, and nitric oxide appear to have a functional relationships (Saboory et al, 2014). The co‐localization between hippocampal MOR and GABAergic interneurons is observed in CA1, CA3, and dentate gyrus regions in rats, suggesting that these receptors can directly control hippocampal GABAergic neuronal activity (Kalyuzhny and Wessendorf, 1998).…”

“…Opioids appear to have a complex influence on neuronal excitability. The pro‐ or anti‐convulsant activity of an opioid compound depends not only on its affinity to specific opioid receptor, but also on the dose, route of administration, and animal model (Saboory et al, 2007; Saboory et al, 2014). Generally, opioids tend to inhibit neuronal activity.…”