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      What Is the Main Reason for Reduction in Duration of Action of Local Anesthetics Used for Spinal Anesthesia in Opium Addicted Patients?

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      , MD 1 , , MD 2
      Addiction & Health
      Kerman University of Medical Sciences

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          Abstract

          Dear editor According to recent studies, in opioid abusers, compared with non-addicts, spinal anesthesia with local anesthetics has been accompanied with shorter duration of action and lower level of sensory block.1-4 Thus, it seems that chronic opiate abuse can produce tolerance, or probably, cross-tolerance to analgesic effects of local anesthetics. As yet, no clear explanation has been presented for this tolerance. Local anesthetics produce their analgesic effects through connection to voltage-gated sodium channels.5 Opiate analgesia is attributed to µ receptors.6 Apparently, there is no similarity between opiate or local anesthetic receptors. This can explain addicts’ tolerance to local anesthetics. Opiates cause respiratory depression.7 Therefore, they cause mild respiratory acidosis in opioid abusers. Plasma acidosis can lead to diffusion of H+ to cerebrospinal fluid. Acidosis reduces the lipophilicity, and hence, efficiency of local anesthetics. Based on the abovementioned issues, perhaps occurrence of unexpected phenomenon, such as reduction of sodium channels, following chronic addiction to opiates results in tolerance to intrathecal local anesthesia. Moreover, secondary acidosis in cerebrospinal fluid following chronic addiction to opiate may be the cause of reduction in the efficacy of intrathecal local anesthesia. Therefore, we recommend these topics for future studies.

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          Voltage-gated sodium channels and pain pathways.

          Acute, inflammatory, and neuropathic pain can all be attenuated or abolished by local treatment with sodium channel blockers such as lidocaine. The peripheral input that drives pain perception thus depends on the presence of functional voltage-gated sodium channels. Remarkably, two voltage-gated sodium channel genes (Nav1.8 and Nav1.9) are expressed selectively in damage-sensing peripheral neurons, while a third channel (Nav1.7) is found predominantly in sensory and sympathetic neurons. An embryonic channel (Nav1.3) is also upregulated in damaged peripheral nerves and associated with increased electrical excitability in neuropathic pain states. A combination of antisense and knock-out studies support a specialized role for these sodium channels in pain pathways, and pharmacological studies with conotoxins suggest that isotype-specific antagonists should be feasible. Taken together, these data suggest that isotype-specific sodium channel blockers could be useful analgesics.
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            Heterodimerization of mu and delta opioid receptors: A role in opiate synergy.

            Opiate analgesics are widely used in the treatment of severe pain. Because of their importance in therapy, different strategies have been considered for making opiates more effective while curbing their liability to be abused. Although most opiates exert their analgesic effects primarily via mu opioid receptors, a number of studies have shown that delta receptor-selective drugs can enhance their potency. The molecular basis for these findings has not been elucidated previously. In the present study, we examined whether heterodimerization of mu and delta receptors could account for the cross-modulation previously observed between these two receptors. We find that co-expression of mu and delta receptors in heterologous cells followed by selective immunoprecipitation results in the isolation of mu-delta heterodimers. Treatment of these cells with extremely low doses of certain delta-selective ligands results in a significant increase in the binding of a mu receptor agonist. Similarly, treatment with mu-selective ligands results in a significant increase in the binding of a delta receptor agonist. This robust increase is also seen in SKNSH cells that endogenously express both mu and delta receptors. Furthermore, we find that a delta receptor antagonist enhances both the potency and efficacy of the mu receptor signaling; likewise a mu antagonist enhances the potency and efficacy of the delta receptor signaling. A combination of agonists (mu and delta receptor selective) also synergistically binds and potentiates signaling by activating the mu-delta heterodimer. Taken together, these studies show that heterodimers exhibit distinct ligand binding and signaling characteristics. These findings have important clinical ramifications and may provide new foundations for more effective therapies.
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              Differential roles of opioid receptors in respiration, respiratory disease, and opiate-induced respiratory depression.

              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)
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                Author and article information

                Journal
                Addict Health
                Addict Health
                AHJ
                Addiction & Health
                Kerman University of Medical Sciences
                2008-4633
                2008-8469
                Summer-Autumn 2015
                : 7
                : 3-4
                : 198
                Affiliations
                [1 ]Assistant Professor, Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
                [2 ]Assistant Professor, Department of Anesthesiology, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
                Author notes
                Correspondence to: Amir Saber-Tanha MD, Email: amirsaber43@ 123456yahoo.com
                Article
                AHJ-07-198
                4741241
                26885357
                d63d5b67-7445-49e1-99e9-b925323e6f93
                © 2015 Kerman University of Medical Sciences

                This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.

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