Modulation of opioid analgesia by agmatine

Abstract

Administered alone, agmatine at doses of 0.1 or 10 mg/kg is without effect in the mouse tailflick assay. However, agmatine enhances morphine analgesia in a dose-dependent manner, shifting morphine's ED 50 over 5-fold. A far greater effect is observed when morphine is given intrathecally (9-fold shift) than after intracerebroventricular administration (2-fold). In contrast to the potentiation of morphine analgesia, agmatine (10 mg/kg) has no effect on morphine's inhibition of gastrointestinal transit. δ-Opioid receptor-mediated analgesia also is potentiated by agmatine, but κ 1-receptor-mediated (U50,488H; trans-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetemide) and κ 3-opioid receptor-mediated (naloxone benzoylhydrazone) analgesia is not significantly enhanced by any dose of agmatine tested in this acute model. In chronic studies, agmatine at a low dose (0.1 mg/kg) which does not affect morphine analgesia acutely prevents tolerance following chronic morphine dosing for 10 days. A higher agmatine dose (10 mg/kg) has a similar effect. Agmatine also blocks tolerance to the δ-opioid receptor ligand [ d-Pen 2, d-Pen 5]enkephalin given intrathecally, but not to the κ 3-opioid receptor agonist naloxone benzoylhydrazone. Despite its inactivity on κ 1-opioid analgesia in the acute model, agmatine prevents κ 1-opioid receptor-mediated tolerance. These studies demonstrate the dramatic interactions between agmatine and opioid analgesia and tolerance.