Thirty subjects were given a placebo (intravenous saline), which was described as a known pain killer, once a week for 3 consecutive weeks. Experimental ischemic arm pain was produced prior to the placebo and again 1 h later. In a double blind procedure, half of the subjects received 10 mg of naloxone after placebo; the remaining subjects received naloxone vehicle. In addition to the placebo session, there were control and naloxone sessions each week to determine the normal changes in pain and the effect of naloxone on the pain, respectively, when no placebo was given. Significant placebo-induced analgesia was demonstrated, and a group of consistent placebo responders was identified. Although naloxone alone had no effect on the experimental pain, naloxone diminished the analgesic effectiveness of the placebo, suggesting that endogenous opioids are involved in producing placebo-induced analgesia.

In 30 human subjects, experimental pain was produced by either ischemia or cold-water immersion. In a double-blind procedure, intravenous doses of up to 10 milligrams of naloxone hydrochloride in saline were indistinguishable from similarly administered saline alone. There were no effects on subjective pain ratings, finger plethysmograph recordings, or responses to mood-state questionnaires. These laboratory procedures do not activate any functionally significant pain-attenuating or mood-altering effect of endorphins.

The hypothesis that painful stimuli activate the endogenous opioid (endorphin) system in humans was tested by examining the effect of the opiate antagonist naloxone on experimentally induced ischemic pain and on subjective mood ratings. Intravenous injections of saline or naloxone hydrochloride (2 and 10 mg) were administered under double-blind conditions to 12 subjects. Naloxone did not affect the pain ratings. However, a significant dose-related effect of naloxone on tension-anxiety was found, suggesting that the endorphins, like exogenously administered opiates, may have antianxiety properties.The discovery of endogenous substances with opioid activity (endorphins) in several species, including man (1-6), raises questions about what role these substances normally play. Since narcotic antagonists block and reverse the effects of opiates, the administration of these antagonists should similarly affect behavior mediated by endorphins. However, when administered to animals or humans who have not received an opiate, the "pure" antagonists, naloxone and naltrexone, appear to have no effect, suggesting that the endorphin system is not continuously active, but only activated in certain internal or environmental conditions. In both rats (7) and humans (8) naloxone diminishes analgesia produced by electric brain stimulation; however, it does not modify hypnotic analgesia in man (9). Naloxone does not alter threshold for escape from a noxious stimulus in trained rats (10), but it reduces the latency for escape behavior when mice or rats are exposed to a noxious stimulus for the first time (11, *).The purpose of the present study was to determine if painful stimuli activate the endorphin system in humans by examining the effect of naloxone on experimentally induced ischemic pain. In addition, recognizing the affective changes that result from administration of exogenous opiates, we hypothesized that naloxone would accentuate the stressful nature of the pain, resulting in a greater increase in anxiety, hostility, and depression than in the same situation without naloxone. METHODS Subjects. The subjects were six male and six female staff members who volunteered to participate in the study. The median age was 28 years. Informed consent was obtained.Drugs. Naloxone hydrochloride was dissolved in 0.9% saline solution at 2 and 10 mg/ml. At each session an intravenous injection of 1 ml of one of these solutions or of saline alone was administered at the rate of 1 ml/min. The sequence of drug administration was counterbalanced with the restriction that, as a precautionary measure, the 10 mg dose of naloxone was never administered first. Therefore, subjects were randomly assigned to one of the following sequences: saline, 2 mg naloxone, 10 mg paloxone; saline, 10 mg naloxone, 2 mg naloxone; 2 mg naloxone, saline, 10 mg naloxone; 2 mg naloxone, 10 mg naloxone, saline. Solutions were contained in identical vials coded by two-digit random numbers. They were prepared by a person who had no contact with the experiment. The exp...

The effect of naloxone on the latency of mice to enter a dark box was determined and the study of Jacob et al. (1974) on the effect of naloxone on hotplate behavior was replicated. Mice took significantly longer to enter a dark box after receiving 10 mg/kg of naloxone than did the saline controls. With the hot-plate technique, at all doses (0.1, 0.3, 1, 3, and 10 mg/kg) except the lowest (0.03 mg/kg), naloxone-treated mice jumped from the hot plate significantly sooner than did the saline controls. No effect of naloxone on paw-lick latency was found. All the data confirm the findings of Jacob et al. (1974). The hotplate results suggest that prolonged exposure to a noxious stimulus may be necessary to activate the endorphin system.