Prior morphine exposure enhances ibogaine antagonism of morphine-induced locomotor stimulation

Abstract

Ibogaine is currently being investigated for its potential use as an anti-addictive agent. In the present study we sought to determine whether prior morphine exposure influences the ability of ibogaine to inhibit morphine-induced locomotor stimulation. Female Sprague-Dawley rats were pretreated once a day for 1-4 days with morphine (5, 10, 20 or 30 mg/kg, i.p.) or saline and then received ibogaine (40 mg/kg, i.p.) 5 h after the last morphine pretreatment dose. Compared to rats pretreated with saline, rats pretreated with morphine (10, 20 or 30 mg/kg, i.p.) before ibogaine (40 mg/kg, i.p.) showed a significant reduction in morphine-induced (5 mg/kg, i.p.) locomotor stimulation when tested 29 h after ibogaine administration. Furthermore, this effect was apparent over a range of ibogaine (5-60 mg/kg, i.p.) and morphine test (2.5-5 mg/kg, i.p.) dosages. Doses of ibogaine (5 and 10 mg/kg, i.p.) which alone were inactive inhibited morphine-induced locomotor activity when rats had been pretreated with morphine. These results, showing that morphine pre-exposure affects ibogaine activity, suggest that variable histories of opioid exposure might account for individual differences in the efficacy of ibogaine to inhibit opioid addiction.

Interactions between iboga agents and methamphetamine sensitization: studies of locomotion and stereotypy in rats

“…An early study demonstrated that IBO produced differential effects on the expression of amphetamine-induced locomotion, depending on the previous amphetamine history of the animal; IBO increased the acute locomotor response to amphetamine but attenuated the locomotor response to amphetamine in chronic amphetamine-treated male rats (Blackburn and Szumlinski 1997). As this finding was consistent with an IBO-induced decrease in morphine-induced locomotion in rats with prior morphine history (Pearl et al 1995), it was postulated that IBO pretreatment reversed or reset the neuroadaptations underlying the expression of behavioral enhancement produced by the chronic administration of drugs of abuse (Blackburn and Szumlinski 1997). However, a recent study demonstrated that IBO enhances the expression of cocaine-induced locomotor sensitization (Szumlinski et al 1999a) and this reflects a shift in the inverted U-shaped dose-effect curve for cocaineinduced locomotion to the left of vehicle (VEH) controls (Szumlinski et al 1999b).…”

Effect of Iboga Alkaloids on µ-Opioid Receptor-Coupled G Protein Activation

“…Ibogaine and noribogaine diminish tolerance in morphine-tolerant mice [33,35,36], and dose-dependently potentiate the antinociceptive effect of morphine in morphine-tolerant but not in morphine-naïve mice [35]. Ibogaine has relatively selective effects on dopamine efflux in the nucleus accumbens [92] and locomotor activity [93,94] in morphine-tolerant versus non-tolerant rats. Ibogaine’s clinical effect of opioid detoxification without causing opioid overdose in non-tolerant individuals also suggests selectivity for neuroadaptations associated with prior exposure.…”

Sex Differences in Ibogaine Antagonism of Morphine-induced Locomotor Activity and in Ibogaine Brain Levels and Metabolism

“…The mechanism of action of ibogaine has yet to be determined. Based on studies of ibogaine affinity, ibogaine's mechanism may involve the kappa opioid receptor (3,18.22,24) the NMDA subtype of glutamate receptor (8,17,19,20,21,24), or the serotonin transporter (16,24). A metabolite of ibogaine, noribogaine (16), has also been shown to have affinity for these receptors (16,17,18).…”

“…Since noribogaine does not produce noticeable tremors in either sex, activity studies could be performed 1 h after its administration. Immediately following the morphine or saline challenge injection locomotor activity was monitored for 3 h. It should also be noted that ibogaine has previously been shown to not influence morphine metabolism (6), and morphine pretreatment has been shown to not influence ibogaine metabolism (19).…”