Effects of naloxone on experimentally induced ischemic pain and on mood in human subjects.

Abstract

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...

Enhancement of a Nociceptive Reaction by Opioid Antagonists in Mice

“…In contrast to nociceptive /kg s.c. (log scale). Symresponses in animals, pain perception of humans is not influenced by naloxone (Sobky et al, 1976), a difference observed some time ago for morphine (Hardy, Wolf & Goodell, 1940;Beecher, 1957 on the skin of the tail (Berntson & Walker, 1977), Secondly, dextrallorphan to chemical stimulation of the peritoneum (Elliott et al, 1977) and to ischaemic pain (Grevert & Goldstein, 1977a). However, deep nociception was used in a study where naloxone was effective on the analgesia produced by central stimulation in the cat (Oliveras et al, 1977).…”

“…(1976) found naloxone ineffective, whereas King, Hughey, Massareno, Codd & Byrne (1977) and Berntson & Walker (1977) reported a decrease in reaction time induced by naloxone. However, naloxone does not affect other nociceptive reactions such as escape from foot-shock in trained rats (Goldstein, Pryor, Otis & Larsen, 1976), escape from tail-pinch (Berntson & Walker, 1977), writhing in mice (Elliott, Spieghler & Navarro, 1976) or pain rating in humans (Sobky, Dostrovsky & Wall, 1976;Grevert & Goldstein, 1977a).…”

Thrills in response to music and other stimuli

“…As shown by Fisher (1978, p. 100), the null hypothesis in this case-that naloxone had no effect in any subject-can be rejected at p < .01. We have shown elsewhere that double-blind injections of naloxone can not be distinguished from saline by any interoceptive cues (Grevert & Goldstein, 1977. Further experiments of this kind are in progress.…”

Nociceptive flexion reflex and pain rating responses during endogenous opiate blockade with naltrexone in healthy young adults

“…Early studies by Buchsbaum and colleagues demonstrated naloxone-related hyperalgesia (Buchsbaum et al 1977;Davis et al 1978;Buchsbaum et al 1983), although these effects were limited to specific individuals (e.g., "pain insensitive" participants) or conditions (e.g., prolonged or intense stimulation). Other studies have reported that naloxone has no effect on forearm ischemic pain (Grevert and Goldstein 1977;Grevert et al 1983a;Grevert et al 1983b;Posner and Burke 1985), cold pressor pain (Grevert and Goldstein 1978;McCubbin and Bruehl 1994), or electrocutaneous pain in response to stimulation applied to the finger (Bromm et al 1983), forearm (El-Sobky et al 1976), ear (Stacher et al 1988), or teeth (Ernst et al 1986). Finally, a few studies have suggested that, in some cases, opioid antagonists may actually inhibit pain (Volavka et al 1979;Tassorelli et al 1995;Janssen and Arntz 1997).…”

“…Numerous studies show that naloxone and naltrexone increase nociceptive responding across diverse noxious stimuli for a variety of species, including mice (Jacob et al 1974;Grevert and Goldstein 1977;Jacob and Ramabadran 1977), rats (Jacob et al 1974;Walker et al 1977;Woolf 1980), cats (Goldfarb and Hu 1976;Bell and Martin 1977;Willer et al 1982a), dogs (Jacob and Michaud 1976), and rabbits (Catley et al 1983).…”