Abstract
Methadone is used as a substitution drug for the treatment of opioid dependence and chronic pain. Despite its widespread use and availability, there is a serious concern with respect to the relative safety of methadone. The purpose of this study was to characterize how acute methadone overdose affects the cognitive and motor performance of naïve healthy rats. The methadone overdose was induced by administering an acute toxic dose of methadone (15 mg/kg; ip; the equivalent dose of 80% of LD50) to adolescent rats. Resuscitation using a ventilator pump along with a single dose of naloxone (2 mg/kg; ip) was administered following the occurrence of apnea. The animals which were successfully resuscitated divided randomly into three apnea groups that evaluated either on day 1, 5, or 10 post-resuscitation (M/N-Day 1, M/N-Day 5, and M/N-Day 10 groups) in the Y-maze and novel object memory recognition tasks as well as pole and rotarod tests. The data revealed that a single toxic dose of methadone had an adverse effect on spontaneous behavior. In addition, Recognition memory impairment was observed in the M/N-Day 1, 5, and 10 groups after methadone-induced apnea. Further, descending time in the M/N-Day 5 group increased significantly in comparison with its respective Saline control group. The overall results indicate that acute methadone-overdose-induced apnea produced delay-dependent cognitive and motor impairment. We suggest that methadone poisoning should be considered as a possible cause of delayed neurological disorders, which might be transient, in some types of memory or motor performance in naïve healthy rats.
Highlights
Methadone is a long-acting, synthetic mu-opioid agonist having multiple actions and pharmacologic properties that are similar to morphine (Barbosa Neto et al, 2015)
One-way analysis of variance (ANOVA) followed by Newman–Keuls post hoc analysis revealed no significant reduction in the number of total arm entries in the M/N-Sedate, as well as M/N-Day 1 and Day 10 groups, methadone or naloxone groups when compared with the Saline group [F(6,47) = 2.232, P < 0.05] but not for the M/N-Day 5 groups which showed significant reduction as compared with the Saline group
One-way ANOVA followed by Newman–Keuls post hoc test exhibited that administration of an acute toxic dose of methadone (15 mg/kg; i.p.) with subsequent naloxone (2 mg/kg; i.p.) administration in sedation state (M/N-Sedate group), three M/N-treated groups, as well as methadone and naloxone groups did not have attenuating effects on short-term memory when compared to the Saline group [F(6,46) = 3.871, P = 0.0010], while this parameter shown significant reduction in the M/N-Day 5 groups as compared with the Saline group
Summary
Methadone is a long-acting, synthetic mu-opioid agonist having multiple actions and pharmacologic properties that are similar to morphine (Barbosa Neto et al, 2015). Like other opioids such as buprenorphine, fentanyl, morphine, and oxycodone, methadone is used to alleviate severe pain (Argoff and Silvershein, 2009). Despite its considerable therapeutic applications, acute methadone intoxication may lead to morbidity and death (Shields et al, 2007; Soltaninejad et al, 2014). Acute poisoning with methadone continues to occur after therapeutic, recreational or accidental use (Jones et al, 2012). In Iran, opium was the drug of choice in 50% of all drug abuse from 2006 to 2009, but the prevalence of methadone toxicity has increased significantly from 2.26% in 2006 to 24.72% in 2011 (Hassanian-Moghaddam et al, 2014)
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