Involvement of Opioid Receptors in the Lipid Rescue of Bupivacaine-Induced Cardiotoxicity

Abstract

BACKGROUND: Lipid emulsion (LE) has been successfully used for resuscitation of local anesthetic cardiotoxicity caused by bupivacaine overdose. Opioid receptors have been shown to play a key role in cardio protection. We explored whether this rescue action of LE is mediated through opioid receptors. METHODS: Asystole was induced by bupivacaine (10 mg/kg over 20 seconds, IV) in young male Sprague-Dawley rats, and resuscitation with LE (intralipid 20%; 5 mL/kg bolus and 0.5 mL/kg/min maintenance) was started immediately. The rats were pretreated 2 minutes before inducing asystole with nonselective opioid receptor antagonists such as naloxone and naloxone methiodide, as well as highly selective opioid receptor antagonists for subtype κ, δ, and µ or phosphate buffer solution as a control. Heart rates and ejection fractions were measured using echocardiography. RESULTS: LE rescue of bupivacaine cardiotoxicity was prevented by high-dose (1 mg/kg) naloxone but not by lower doses of naloxone (1, 5, and 10 µg/kg), by naloxone methiodide (which does not cross the blood-brain barrier), and by a selective δ- and κ-opioid receptor antagonists at a higher (10 mg/kg) dose. Successful LE rescue was not affected by highly selective µ-opioid receptor antagonists. δ-Opioid receptor antagonist (10 mg/kg) pretreatment also resulted in reduced phosphorylation level of cardiac glycogen synthase kinase-3β in rats that were not resuscitated by LE compared with control. CONCLUSIONS: Our data highlight the involvement of peripheral δ- and κ-opioid receptors in the rescue action of LE.