Electroencephalographic and convulsant effects of the delta opioid agonist SNC80 in rhesus monkeys

Abstract

Non-peptidic delta opioid receptor agonists are being evaluated for a wide range of clinical applications; however, the clinical utility of piperazinyl benzamide delta agonists such as SNC80 may be limited by convulsant activity. The purpose of the present study was to evaluate the electroencephalographic and convulsant activity produced by a high dose of 10 mg/kg SNC80 IM in rhesus monkeys. EEG and behavioral activity were examined in four adult male rhesus monkeys after IM administration of SNC80. Monkeys were seated in a standard primate restraint chair, and EEG activity was recorded using an array of 16 needle electrodes implanted subcutaneously in the scalp in a bipolar (scalp-to scalp) montage in a longitudinal direction, with bilateral frontal, central, temporal, and occipital leads. Behavior was recorded using video monitoring equipment. Initially, all monkeys were tested with 10 mg/kg SNC80, which is a relatively high dose 3-10 fold greater than doses necessary to produce a variety of other behavioral effects. Behavioral convulsions and EEG seizures were observed in one of the four monkeys. In this monkey, neither behavioral convulsions nor EEG seizures were observed when a lower dose of 3.2 mg/kg was administered nine weeks later or when the same dose of 10 mg/kg SNC80 was administered one year later. These results suggest that IM administration of SNC80 is less potent in producing convulsant effects than in producing other, potentially useful behavioral effects (e.g. antinociception) in rhesus monkeys.

The delta opioid receptor tool box

“…SNC80 and (+)BW373U86 produce convulsions, however, most other systemically available agonists do not (Pradhan et al, 2011a). This deleterious effect is dependent on the activation of the delta opioid receptor (Comer et al, 1993; Broom et al, 2002b), and has been observed in mice, rats, and squirrel and rhesus monkeys (Dykstra et al, 1993; Broom et al, 2002a; Danielsson et al, 2006; Jutkiewicz et al, 2006). The convulsions produced by delta agonists like SNC80 or (+)BW373U86 are behaviorally similar, but weaker than those produced by 4 the epileptogenic drug pentylenetetrazol (Comer et al, 1993).…”

Delta opioid receptors expressed in forebrain GABAergic neurons are responsible for SNC80-induced seizures

“…The first non-peptidic agonists BW373U86 and SNC80 were described to mediate brief and non-lethal convulsions in rodents [5, 6]. In addition, pro-convulsive effects of SNC80 were also reported in rhesus monkeys [7]. New agonists were developed with less or no adverse effects on epileptic thresholds, such as ADL5859, ADL5747 [8, 9] or KNT-127 [10] for example.…”

From Acupuncture to Interaction betweenδ-Opioid Receptors and Na+Channels: A Potential Pathway to Inhibit Epileptic Hyperexcitability

“…Despite the demonstration of an antiepileptic effect following DOR activation in some studies [115–118], several other reports showed opposite results. For example, SNC80, a putative DOR agonist, is proconvulsive [119, 120] though it is reported to inhibit Na + channel activity [80]. The reasons for the complex and mixed effects of the δ -opioid system on seizures are not well clarified yet, but could be partially related to multiple factors like animal species (e.g., proconvulsive in rats but has little effect in rhesus monkeys) [119–121], seizure types, the methods of drug administration [122], dose used [123], target neurons, and so forth (also see [1]).…”

“…DOR activation in the granule cells inhibits voltage-gated Na + channels and thus lowers the excitability of granule neurons [80], which reduces excitatory transmission in the epileptic network and subsequently suppresses seizures. However, DOR activation in inhibitory interneurons leading to the inhibition of Na + channels, as observed by Remy et al [80] in granule neurons, may result in facilitation, rather than suppression, of seizures via postsynaptic deinhibition [126, 127], as has been observed [119, 120]. Therefore, selective activation/inhibition of the opioid system in certain locations of the epileptic networks with acupuncture therapy is critical but also challengeable for the therapeutic outcome.…”