Section Review Central & Peripheral Nervous Systems: Pharmacological Modulation of Opioid Tolerance

Abstract

Although tolerance to opioids probably involves a variety of mechanisms, in vivo studies suggest a prominent role for the NMDA/nitric oxide cascade. Administration of NMDA antagonists blocks the development of tolerance to morphine and the delta opioid [D-Pen², D-Pen⁵]enkephalin without interfering with their analgesic actions, indicating the dissociation of analgesia and tolerance. Similar effects are observed with competitive and noncompetitive antagonists, as well as agents modulating NMDA function through its glycine regulatory site. Inhibitors of nitric oxide synthase have similar actions, suggesting the presence of an NMDA/nitric oxide cascade. This conclusion is supported by the ability of L-arginine, the substrate for nitric oxide synthase, to enhance morphine tolerance by increasing the production of nitric oxide. Tolerance to kappa analgesic systems behaves differently. In most studies, neither kappa₁ nor kappa₃ opioid tolerance is influenced by these drugs. This ability to modulate opioid tolerance has important clinical implication, in addition to providing insights into the mechanisms of analgesia and tolerance.