Evidence for a peripheral mechanism in cardiac opioid withdrawal

Studies involving heart catecholaminergic systems in morphine-dependent rat s have not established whether the adaptive changes observed in the heart d uring morphine withdrawal are mediated peripherally or centrally. In this s tudy, naloxone (Nx), naloxone methiodide (NxM) and N-methyl levallorphan (N ML), quaternary derivatives of Nx and levallorphan, respectively, that do n ot cross the blood-brain barrier, were administered to morphine-dependent r ats and catecholamines and their metabolites determined in the right ventri cle. Rats were made dependent on morphine by implantation of morphine pelle ts for 7 days. On day 8 animals received s.c. injections of saline, Nx (1 m g/kg), NxM (5 mg/kg) or NML (5 mg/kg) and were decapitated 30 min later. No radrenaline (NA) and its metabolites normetanephrine (NMN) and 3-methoxy4-h ydroxyphenylethyleneglycol (MHPG) and dopamine (DA) and its metabolite 3,4- dihydroxyphenylacetic acid (DOPAQ were determined by high-performance liqui d chromatography with electrochemical detection. After NxM or NML administr ation to morphine -dependent rats there was a pronounced increase in NMN an d DOPAC levels, as well as in NA and DA turnovers (as estimated by NMN/NA a nd DOPAC/DA ratios, respectively) in the right ventricle. Similarly, giving Nx to morphine-dependent rats increased NMN and DOPAC levels and NA and DA turnovers. In addition, in the paraventricular nucleus of the hypothalamus (PVN) NA and DA turnover, measured as the MHPG/NA or DOPAC/DA ratios, incr eased after Nx administration but not after NxM or NML. These results suggest that the changes in cardiac sympathetic activity obse rved during morphine withdrawal are due to intrinsic mechanisms outside the central nervous system. These data may be important for understanding the adaptive changes induced in the heart in subjects dependent on opioids.