Dextromethorphan potentiates the antinociceptive effects of morphine and the delta-opioid agonist SNC80 in squirrel monkeys

Abstract

Dextromethorphan (DXM) is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist shown to prevent the development of tolerance to the antinociceptive effects of morphine in rodents. DXM also potentiates the antinociceptive effects of the mu-opioid receptor agonist morphine under some conditions; however, the effect of DXM in combination with opioids other than morphine has not been well characterized. This study determined the antinociceptive effects of DXM administered alone or in combination with morphine or the delta-opioid receptor (DOR) agonist SNC80 using a squirrel monkey titration procedure. In this procedure, shock (delivered to the tail) increases in intensity every 15 s (0.01-2.0 mA) in 30 increments. Five lever presses during any given 15-s shock period produces a 15-s shock-free period after which shock resumes at the next lower intensity. This assay provides a measure of antinociception that is separable from motor effects [response rate (RR)]. Morphine (0.3-3.0 mg/kg i.m.) and SNC80 (1.0-10 mg/kg i.m.), but not DXM (1.0-10 mg/kg i.m.) dose- and time-dependently increased the intensity below which monkeys (n = 4) maintained shock 50% of the time [median shock level (MSL)]. Doses of morphine and SNC80 that alone did not increase MSL were potentiated by DXM. Importantly, these combinations did not significantly alter RR. These data support previous findings with other NMDA receptor antagonists and morphine using this procedure and also extend those findings to a DOR agonist