These studies were undertaken to determine the effects of morphine and other opiate and opioid agonists on body temperature in the mouse. Mice were lightly restrained, and rectal temperatures were monitored after injection of opiate analgesics at each of three ambient temperatures. The drugs tested were pure agonists representing eight different chemical classes. At 20 degrees C, morphine, hydromorphone, levorphanol, oxymorphone, methadone, etonitazene, fentanyl, etorphine and meperidine produced hyperthermia in low doses and hypothermia as the doses were raised. Codeine produced only hypothermia at 20 degrees C in the doses studied. At 25 degrees C, the hypothermic responses were greatly reduced in magnitude, and most drugs produced biphasic or only hyperthermic responses. At 30 degrees C, dose-related hyperthermia was the usual response with the exception of meperidine which produced only hypothermia, although a temperature increase was observed after anileridine, a closely related phenylpiperidine. There is good correlation between the relative potencies of the agonists with respect to their hypothermic effects in mice and their relative potencies as analgesics in mice. The temperature effects of morphine are complex but appear to be characteristic of opiate agonists as a class. The magnitude and the direction of the temperature responses to opiates are dose-dependent and profoundly influenced by the environmental temperature.

The effects of morphine, meperidine, alphaprodine, and anileridine were studied alone and in the presence of 1 mg/kg of naloxone in rats on level pressing under a fixed-ratio 20-response schedule of food presentation and on tail-withdrawal latency from warm water (55 degrees C) as a measure of analgesia. All four narcotics decreased rates of lever pressing and increased tail-withdrawal latencies. Naloxone antagonized the effects of all four narcotics on tail-withdrawal, but did not antagonize the rate-decreasing effect of meperidine on lever pressing. Naloxone shifted the morphine dose-effect for lever-pressing by a factor of 4-8; the alphaprodine dose-effect curve by a factor of 4-8; and the anileridine dose-effect curve by a factor of 2. These results strengthen the interpretation that meperidine's effect on schedule-controlled responding is not mediated by a narcotic action whereas the analgesic effect is. The results also suggest that anileridine has significant non-narcotic actions like meperidine.

The ability of pentobarbital, diazepam, and chlorpromazine to attenuate the rate-decreasing effects of a high dose (10 or 30 mg/kg) of meperidine was tested in pigeons responding under a multiple fixed-ratio, fixed-interval schedule of food presentation. Pentobarbital (10 mg/kg) attenuated the meperidine-induced rate decreases, whereas diazepam (0.3--3 mg/kg) or chlorpromazine (3--30 mg/kg) did not reliably attenuate the response rate decreases. The combination of 10 mg/kg of pentobarbital and meperidine resulted in a marked disruption of the pattern of responding in the fixed-interval component of the multiple schedule. Pentobarbital (1, 3, 10, and 17.5 mg/kg) was also tested in combination with rate-decreasing doses of normeperidine (17.5 mg/kg), anileridine (10 mg/kg), alphaprodine (10 mg/kg), and fentanyl (0.3 mg/kg). Pentobarbital reliably attenuated the rate-decreasing effects of normeperidine, anileridine, and alphaprodine, but not the rate decreases induced by fentanyl.

The separate and combined analgesic effects of 10 mg of oral amphetamine sulfate and 25 mg of oral anileridine dihydrochloride were studied in 24 healthy, adult, male volunteers. Tolerance of progressively increasing pain produced by the Submaximum Effort Tourniquet Technique was tested four times in each subject: after amphetamine, after anileridine, after the combination, and after a matching placebo. Treatments were administered double blind and in counterbalanced order. Elapsed time to report of slight, moderately distressing, very distressing, and unbearable pain was recorded on each trial. The four oral treatments differed significantly for very distressing and for unbearable pain. At each of the three upper pain levels, the mean tolerance times for anileridine and amphetamine were similar; each was longer than placebo but shorter than the combination; and the effect of the combination was approximately the sum of the effects of the two components.

The acute administration of levorphanol, morphine, anileridine, methadone, cyclazocine and pentazocine was found to increase brain levels of 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MOPEG-SO4) in rats. Drug-induced increases in brain levels of this norepinephrine metabolite were dose-dependent and peak drug effects generally occurred 1 hr after intraperitoneal injection. Six to 8 hr after opiate agonist or partial agonist administration, MOEG-SO4 levels returned to control values or below. The narcotic effect appeared to be stereospecific, since high doses of d-methadone and dextrorphan produced either no change or only minimal increases in brain MOPEG-SO4 levels when compared with saline-treated controls. The relative potency of the analgesics tested in producing increases in brain MOPEG-SO4 levels appeared to correlate reasonably well with the ability of these drugs to produce other characteristic pharmacological effects. The drug-induced increases in brain MOPEG-SO4 levels were antagonized by naloxone. The rate of disappearance of MOPEG-SO4 from the brains of animals treated with pargyline was not decreased by the opiate agonists or partial agonists tested indicating that these drugs did not inhibit the acid transport process. These results indicate that the production of an increase in brain norepinephrine turnover is a specific component of the pharmacological actions of narcotic analgesics.

The effects of anileridine, alphaprodine and fentanyl were studied on responding by pigeons under a multiple fixed-ratio, fixed-interval schedule of food presentation. Generally, all three drugs produced dose-related decreases in responding under both components of the multiple schedule, but rate increases were observed after low doses of anileridine and alphaprodine in some birds. Naloxone (1 mg/kg) antagonized the rate-increasing and rate-decreasing effects of doses of anileridine and alphaprodine of 10 mg/kg or less, whereas the effects of higher doses were not antagonized by naloxone. Likewise, chronic methadone or morphine (120 mg/kg/day p.o.) dosing produced only a slight cross-tolerance to the rate-decreasing effects of anileridine and alphaprodine. In contrast, naloxone (0.01, 0.1 and 1 mg/kg) and chronic methadone or morphine administration shifted the dose-effect curve for fentanyl to the right, indicating narcotic antagonism and methadone and morphine-induced cross-tolerance. These data indicate that the rate-decreasing effects of anileridine and alphaprodine are related only slightly to narcotic effects, whereas the rate-decreasing effects of fentanyl are primarily narcotic effects.

The effects of meperidine, anileridine and a alphaprodine were studied in the squirrel monkey whose behavior was maintained under a 2.0-sec schedule of shock increment. Low doses of all three drugs had no effect, whereas higher doses decreased responding at the zero shock intensity. Slightly higher doses of meperidine and anileridine increased responding at the zero shock intensity and produced convulsions.

A sensitive and specific radioimmunoassay for normeperidine has been developed that can detect as little as 100 pg of this metabolite. In competitive binding experiments with [125I]O-tyramyl-normeperidinic acid and an antiserum produced in rabbits immunized with a bovine serum albumin-normeperidinic acid conjugate, meperidine is only 0.01% as effective an inhibitor as normeperidine. Therefore, normeperidine can be determined in physiological fluids and in tissue extracts when relatively large amounts of meperidine or other N-phenylpiperidine esters are present. High pressure liquid chromatography can be used to confirm the results obtained by radioimmunoassay during the in vitro N-dealkylations of meperidine and anileridine to normeperidine. The normeperidine isolated by high pressure liquid chromatography accounts for all of the inhibitory reactivity determined in the enzymatic digests by the radioimmunoassay. Kinetic parameters (Km and Vmax) can be determined for the N-dealkylation of meperidine and anileridine. The formation of normeperidine with time can be followed in rabbits injected with meperidine or anileridine. Plasma levels may also be determined when meperidine is administered as an obsteric analgesic.

To test the hypothesis that the hyperpyrexia produced by meperidine and detromethorphan in rabbits pretreated with a monoamine oxidase inhibitor is related to inhibition of neuronal uptake of serotonin (5-hydroxytryptamine (5-HT)), fluoxetine (Lilly 110140) was studied. This potent and specific 5-HT neuronal uptake blocker was administered to phenelzine-pretreated rabbits and found to produce a lethal hyperpyrexia in doses equal to or greater than 2.5 mg/kg. The order of potency in blocking 5-[14C]HT uptake into synaptosomes prepared from rabbits was: fluoxetine greater than meperidine = dextromethorphan = levorphanol greater than anileridine greater than alphaprodine greater than morphine. Since fluoxetine, meperidine, and dextromethorphan produce hyperpyrexia in phenelzine-pretreated rabbits, whereas anileridine, alphaprodine, and morphine do not, there appears to be some correlation between the hyperpyrexic response and inhibition of 5-HT uptake. The exception is levorphanol, which is not hyperpyrexic despite being equipotent with meperidine and dextromethorphan in inhibiting 5-HT uptake. The ineffectiveness of levorphanol in producing hyperpyrexia may be due to its marked depressant properties, since the addition of another depressant drug (pentobarbital) antagonized the hyperpyrexic effect of meperidine.

The analgesic potency of anileridine compared with pethidine was found to be 4:1 by measuring the effect on withdrawal movements resulting from pinching of the skin or surgery during N2O + O2 anaesthesia. The potency ratio was examined postoperatively as well. Sixty patients who had undergone upper abdominal surgery with standard anaesthesia were studied in a double-blind, between-patient two dose comparison. Each patient and an observer graded the degree of pain relief. Here again, anileridine proved 4 times as potent as pethidine. With higher doses the response to anileridine was of shorter duration than was the response to pethidine. Respiratory depression was very similar after equianalgesic doses. Blood pressure and pulse rate remained stable. The total incidence of side effects was higher after pethidine.