Upregulation of Opioid Receptors

Abstract

It is well established that chronic exposure to opioid receptor antagonists can result in opioid receptor upregulation. The phenomenon of antagonist-induced receptor upregulation is not unique to the opioid system but is common to many receptor systems including adenergic, cholinergic, serotinergic, and dopaminergic receptors. Chronic administration of naloxone or naltrexone reliably produces increases in binding to opioid receptors both in vivo and in vitro. This receptor upregulation is associated with functional supersensitivity to subsequent agonist administration. Thus, the analgesic potency of morphine is increased following prior exposure to opioid receptor antagonists. The three opioid receptor types show different degrees of upregulation in response to in vivo antagonist administration, with $μ$ opioid receptors showing the largest increases in binding in response to any given dose of naloxone or naltrexone, followed by more modest increases in $δ$ and k receptors. Antagonist-induced receptor upregulation appears to vary between brain regions, and the reason for this is not clear. Although the first demonstration of antagonist-induced opioid receptor upregulation occurred more than 30 years ago, the mechanisms mediating this effect remained elusive for much of this time. Recent data have provided new insights into potential molecular mechanisms of opioid receptor upregulation. Data are presented that support the hypothesis that naloxone and nal-trexone are acting as pharmacological chaperones, stabilizing intracellular receptor protein molecules and facilitating their trafficking and insertion into the cell membrane. Finally, heterologous opioid receptor upregulation occurs in response to repeated exposure to cocaine and ethanol, and the resulting opioid receptor regulation may play an important role in craving and reinforcement induced by these agents. Given the multiple potential clinical uses of opioid receptor antagonists described in other chapters of this volume, opioid receptor upregulation and the accompanying functional supersensitivity that results from antagonist exposure needs to be further explored in the clinical setting.