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Session 2: Narcotic agents
Session 2: Narcotic Agents he session on narcotic agents went into great detail describing the classification of different narcotic agents T and their receptor sites, and gave some insight into the development of less toxic narcotic agents. The relative explosion of research on opioid systems in the past decade was described, including the discovery of endogenous opioid agents and elaboration and understanding of opioid receptors. [We hope a better understanding of the mechanism of action of narcotic analgesics will lead to the development of newer analgesic drugs that have therapeutic efficacy but do not cause the degree of respiratory depression and propensity for physical dependence seen with morphine and similar narcotic analgesics.] One of the most basic insights into opiate flmction is understanding the cellular effects produced by opiate agonist agents. Dr Way cites his own and other research elaborating the interaction between opiate agents and calcium in producing analgesia, tolerance, and physical dependence. Based on the actions of opiates on Ca + + disposition, an operational hypothesis may be developed to explain the development of tolerance, physical dependence, and abstinence to opioid substances. A discussion of the opiate receptors and their roles in producing different opiate effects was important in all four talks. It is now well recognized that at least three opiate receptors exist in the central nervous system and in peripheral tissues. The ~ (mu) receptor, the classic "morphine" receptor, mediates analgesia, euphoria, respiratory depression, and physical dependence mainly at supraspinal sites in the brain stem and limbic system. Naloxone is a potent antagonist of effects produced by & receptor agonist agents. The K (kappa) receptor also mediates analgesia and exists in high density in the spinal cord. K receptor agonists are thought to produce analgesia at a "spinal" level. Both ~ and K agonists can produce tolerance and physical dependence, but the abstinence syndromes will differ for different receptor agonists; there is no cross-tolerance for the most part. The ¢r (sigma) receptor, the third receptor site, has been associated with the psychotomimetic properties of the mixed agonist-antagonist analgesics. Dr Martin describes the existence of partial agonists and the concept of receptor dualism. A partial agonist agent is one that will produce, the desired effect at a particular receptor, but does not produce a maximal effect regardless of the dosage used. Receptor dualism means that "drugs can produce the same pharmacologic action through different mechanisms and by interaction with different receptors." Dr Martin describes the importance of these concepts in the search to produce agents that will effect analgesia without severe respiratory depression and physical dependence. 15:9 September 1986
Buprenorphine is one such agent that is a partial agonist at the ~ receptor Although buprenorphine produces significant analgesia, it has a very low potential for physical dependence in man. Endogenous opioid substances were first isolated little more than ten years ago, but much has been learned in that short period. Endogenous opioids are released in response to acupuncture, stress, electrical brain stimulation, and the administration of exogenous opioid analgesics. Endogenous opioids may have important effects on pain, mood, respiration, thermic responses, cardiovascular changes, intestinal activity, satiety, drinking behavior, and sexual behavior A number of animal and human studies have been published suggesting that endogenous opioids may have a detrimental effect in various shock states, stroke, and spinal cord injury. Way and Dewey describe the three endogenous opioid systems as endorphinergic, enkephalinergic, and dynorphinergic. Each system has its own specific precursor molecule, and each precursor is distributed differently in the brain and periphery These endogenous opioids can be released from many different stimuli. ~-endorphin is released from the pituitary and is a portion of the same precursor molecule from which ACTH is derived. Plasma levels of ~endorphin are synchronous with those of ACTH, and stimuli for ACTH release, such as stress, also release ~-endorphin. This finding led to the early studies on the effects of naloxone in reversing the effects of f~-endorphin in shock states. Dr Dewey describes his work in elucidating the mechanism of the antinociceptive action of morphine. He indicates that morphine administration will promote the release of ~-endorphin into the blood and enkephalin into the cerebrospinal fluid of animals. The antinociceptive action of morphine requires a patent humoral CSF pathway, while the neural spinal pathway need not be intact. Thus morphine appears to cause the supraspinal release of endogenous opioid substances, which then travel through the CSF to inhibit nociceptive reflexes in the lower spinal cord. A recent and interesting finding presented by Dr Dewey concerns endogenous opioids and sudden infant death syndrome (SIDS). Elevated levels of immunoreactive f~-endorphin have been found in siblings of patients with SIDS. A long-acting narcotic antagonist, naltrexone, is being used in studies of children at high risk for SIDS. Theoretically, high levels of CSF ~-endorphin could cause respiratory depression and predispose to the sleep apnea seen in SIDS. As research with opioid substances continues, several goals are especially important to the clinician. The most important is the development of the "ideal" narcotic analgesic, that is, one that is as effective in producing analgesia
Annals of Emergency Medicine
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as morphine, with no respiratory depressant or physical dependence properties. While such an ideal is unlikely to be realized, we already have seen the development of more effective analgesic agents without the addictive potential of morphine, the so-called agonist-antagonist narcotic agents. Our growing knowledge of opioid receptor function can only improve the likelihood of finding other agents with the "fight mix" of agonistic or antagonistic effects at the appropriate receptor sites to be closer to the "ideal" analgesic agent. The other broad goal is to define the role of endogenous opioids in various disease states, as well as their effects in producing analgesia. Even more ideal than the "perfect" nar-
54/1020
cotic would be a way of manipulating endogenous opioids so that exogenous narcotics would not have to be administered. Concerning the effects of endogenous opioids in disease states, further studies are needed to define the effectiveness of narcotic antagonists in reversing some of the detrimental effects attributed to endogenous opioids in stroke, spinal cord injury,, various shock states, and SIDS.
William G Barsan, MD Department of Emergency Medicine University of Cincinnati Cincinnati, Ohio
Annals of Emergency Medicine
15:9 September 1986
Buprenorphine is one such agent that is a partial agonist at the ~ receptor Although buprenorphine produces significant analgesia, it has a very low potential for physical dependence in man. Endogenous opioid substances were first isolated little more than ten years ago, but much has been learned in that short period. Endogenous opioids are released in response to acupuncture, stress, electrical brain stimulation, and the administration of exogenous opioid analgesics. Endogenous opioids may have important effects on pain, mood, respiration, thermic responses, cardiovascular changes, intestinal activity, satiety, drinking behavior, and sexual behavior A number of animal and human studies have been published suggesting that endogenous opioids may have a detrimental effect in various shock states, stroke, and spinal cord injury. Way and Dewey describe the three endogenous opioid systems as endorphinergic, enkephalinergic, and dynorphinergic. Each system has its own specific precursor molecule, and each precursor is distributed differently in the brain and periphery These endogenous opioids can be released from many different stimuli. ~-endorphin is released from the pituitary and is a portion of the same precursor molecule from which ACTH is derived. Plasma levels of ~endorphin are synchronous with those of ACTH, and stimuli for ACTH release, such as stress, also release ~-endorphin. This finding led to the early studies on the effects of naloxone in reversing the effects of f~-endorphin in shock states. Dr Dewey describes his work in elucidating the mechanism of the antinociceptive action of morphine. He indicates that morphine administration will promote the release of ~-endorphin into the blood and enkephalin into the cerebrospinal fluid of animals. The antinociceptive action of morphine requires a patent humoral CSF pathway, while the neural spinal pathway need not be intact. Thus morphine appears to cause the supraspinal release of endogenous opioid substances, which then travel through the CSF to inhibit nociceptive reflexes in the lower spinal cord. A recent and interesting finding presented by Dr Dewey concerns endogenous opioids and sudden infant death syndrome (SIDS). Elevated levels of immunoreactive f~-endorphin have been found in siblings of patients with SIDS. A long-acting narcotic antagonist, naltrexone, is being used in studies of children at high risk for SIDS. Theoretically, high levels of CSF ~-endorphin could cause respiratory depression and predispose to the sleep apnea seen in SIDS. As research with opioid substances continues, several goals are especially important to the clinician. The most important is the development of the "ideal" narcotic analgesic, that is, one that is as effective in producing analgesia
Annals of Emergency Medicine
1019/53
as morphine, with no respiratory depressant or physical dependence properties. While such an ideal is unlikely to be realized, we already have seen the development of more effective analgesic agents without the addictive potential of morphine, the so-called agonist-antagonist narcotic agents. Our growing knowledge of opioid receptor function can only improve the likelihood of finding other agents with the "fight mix" of agonistic or antagonistic effects at the appropriate receptor sites to be closer to the "ideal" analgesic agent. The other broad goal is to define the role of endogenous opioids in various disease states, as well as their effects in producing analgesia. Even more ideal than the "perfect" nar-
54/1020
cotic would be a way of manipulating endogenous opioids so that exogenous narcotics would not have to be administered. Concerning the effects of endogenous opioids in disease states, further studies are needed to define the effectiveness of narcotic antagonists in reversing some of the detrimental effects attributed to endogenous opioids in stroke, spinal cord injury,, various shock states, and SIDS.
William G Barsan, MD Department of Emergency Medicine University of Cincinnati Cincinnati, Ohio
Annals of Emergency Medicine
15:9 September 1986