FACTORS AFFECTING RESTRAINT STRESS-INDUCED POTENTIATION OF MORPHINE ANALGESIA

The analgesic effect of opioid drugs is potentiated in rats exposed to restraint stress as compared to unstressed rats. The purpose of the present study was to quantify how the following factors affect morphine-induced analgesia: habituation to restraint versus exposure to restraint for the first time, restraint stress duration, and interval from restraint to analgesic testing. Expts. 1 and 2 generated dose- and time course curves for morphine in rats exposed to one of 3 treatments: no restraint stress (NS), first exposure to 1 to 6 h of restraint (FS), or 5 days of restraint habituation followed by 1 or 6 h of restraint on the test day (HAB). Analgesia was measured by the tail-flick assay. Rats subjected to 1 h of restraint displayed dose- and time-dependent potentiation of morphine-induced antinociception compared to unstressed rats. Given 4.0 mg/kg morphine, FS-treated subjects showed 1.4- and 2.7-fold more potentiation of analgesia than HAB- and NS-treated rats, respectively. Rats restrained for 6 h prior to testing showed significant dose effect for morphine but failed to reveal significant treatment effects. Thus, increasing the duration of restraint from 1 to 6 h attenuated morphine antinociception in FS- and HAB-treated subjects to the level of NS subjects. In Expt. 3, several groups of rats underwent a single 1-h session of restraint at various time intervals prior to injection with morphine (4.0 mg/kg) and tail-flick testing. An unstressed group also receiving morphine served as control. Rats restrained at 0.5, 24, 48 and 168 h prior to testing showed significant potentiation of morphine-induced antinociception, with peak potentiation (twice the level of antinociception) occurring at 24 h after restraint. Thus, previous exposure to restraint, the duration of restraint, and interval between restraint and analgesia testing affect the degree to which stress modifies morphine-induced analgesia.