National High Blood Pressure Education Program.

On the specificity of naloxone as an opiate antagonist.

Update on bispectral index monitoring.

In summary, these findings indicate the importance of designing future experiments that delineate between opioid and nonopioid forms of respiratory disease and dysfunction, and the need to identify means of diagnosing them in order to achieve successful recovery. Apparently there is great diversity between animal species in terms of contributions of endogenous opioids to tonic control of ventilation, and future work should strive to identify which species is most appropriate as a model of human ventilatory control and disease. Certain opioid receptor types appear to be linked to independent respiratory functions. For instance, mu receptors in the brain stem produce strong inhibitory actions on respiratory parameters, including RR, VT, VE, and CO2 sensitivity. These effects have been observed in vivo and by electrophysiologic recordings in vitro. Delta receptors may also exert some inhibitory effect on respiration, especially in the NTS. In the CNS, the ventral surfaces of the medulla and pons, especially the NTS and NA, seem to be important sites for opioid-induced inhibition of respiration, whereas the spinal cord probably is not involved in opioid-mediated ventilatory depression. Kappa receptors appear to be devoid of respiratory depressant activity, whereas sigma receptors may stimulate some ventilatory parameters. Morphine and similar pure mu agonists, such as fentanyl and oxymorphine, probably produce their analgesic and respiratory depressant effects through stimulation of mu receptors. Mixed agonists/antagonists that have mu antagonist (or partial agonist) activity plus kappa agonist and/or sigma agonist activity show a ceiling effect for respiratory depression. Future tests need to determine which opioid receptor may be responsible for the ceiling effect. In addition, the effects of mu, delta, kappa, and sigma selective agonists on hypoxic drive should also be determined, as a drug that stimulates hypoxic sensitivity in the face of hypercapnic depression may produce less overall respiratory depression due to counteractive effects. In the future, clinically optimal opiates should have more specificity of action than those available now. This may be achieved by creating drugs selective for single receptors or by creating drugs with desirable combinations of receptor selectivities. The combinations of mixed agonists/antagonists with pure mu agonists currently in use today are promising, as they provide analgesia with reduced respiratory depression. In the early days of opiate research and development, combination drug regimens were thoroughly tested to determine the "ideal ratios" that would retain analgesic properties but not the other undesirable effects such as respiratory depression (196).(ABSTRACT TRUNCATED AT 400 WORDS)

Differential Roles of Opioid Receptors in Respiration, Respiratory Disease, and Opiate-induced Respiratory Depression

ENDOGENOUS opiate-like substances (endorphins) have been isolated from the brain in a variety of species, including man1,2. Furthermore, there is recent evidence that the brain possesses an analgesia-producing system. The distribution of endorphins is consistent and overlaps significantly with central nervous system sites such as the midbrain periaqueductal grey which produce analgesia when activated by electrical stimulation or opiate microinjection3–5. This raises the possibility that the analgesia is mediated by endorphin release. At present very little is known about the factors which trigger endorphin release. One obvious possibility is that the pain suppression system is activated by noxious stimuli. In fact, it has been observed that noxious stimuli delivered at one region of the body reduce the reported intensity of a distant noxious stimulus6. Furthermore, studies of the component neurones of this analgesia-producing system are consistent with the idea that it is activated by noxious stimuli7,8. If the action of the analgesia-producing system is mediated by endogenous morphine-like compounds, then disruption of this system by naloxone, a pure opiate antogonist, would be expected, to increase the perceived intensity of a maintained noxious stimulus. Some animal studies report no effect of naloxone alone on baseline pain thresholds9,10; in other studies, however, a shortening of latencies on hot-plate and tail-flick tests has been observed11,12. In humans, pain thresholds are unaffected by naloxone alone13,14. However, reversal of analgesia produced by electrical stimulation15,16 or by acupuncture17 has been reported. In 1965 Lasagna commented on the “curious hyper-algesic effect” of naloxone in patients with postoperative pain18. These observations suggested that clinical pain might provide a more appropriate model to study the action of endorphins. We demonstrate here that following the extraction of impacted wisdom teeth, naloxone causes a significantly greater increase in reported pain intensity than placebo, an observation consistent with the suggested participation of endorphins in an intrinsic pain suppression system.

The narcotic antagonist naloxone enhances clinical pain

Nitrous oxide produced a dose-related "analgesia" in mice (median effective dose, 55 percent). The analgesia was evaluated by means of a phenylquinone writhing test. Narcotic antagonists or chronic morphinization reduced nitrous oxide analgesia. Either nitrous oxide releases an endogenous analgesic or narcotic antagonists have analgesic antagonist properties heretofore unappreciated.

https://science.sciencemag.org/content/sci/194/4268/967.full.pdf

AD Finck

Papers

Nitrous oxide "analgesia": resemblance to opiate action