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Opiate drugs: ‘guilt by association’

Molecular Psychiatry volume 5, pages 122–123 (2000)Cite this article

That psychiatrists avoid opiate treatments for conditions other than opiate addiction is understandable given the threat of death by respiratory depression, the addictive potential of opiates as well as the discomfort of constipation and symptoms accompanying withdrawal. But it is unjust for the family of opioid drugs to be lumped together under the same scary cloud of side effects. The stereotypic view of the actions of opiate drugs is derived from drugs such as heroin, morphine and fentanyl, but in truth, the actions, as well as the cellular and behavioral adaptations to specific opioid drugs, differ markedly. For example etorphine, which is used in tranquilizer guns, is 100–1000 times the potency of morphine with a narrow therapeutic range and is a lethal inhibitor of respiration even at low doses. Etorphine has a lower propensity than morphine to induce tolerance and withdrawal1 and dihydroetorphine, a drug which has similar characteristics to etorphine, is used clinically as an analgesic in China. Buprenorphine, unlike etorphine, has minimal effects on respiration with a ‘ceiling effect’ such that even at high doses, lethality is not a concern unless used with other drugs.2 Buprenorphine is also a potent analgesic yet in many paradigms shows little tolerance and dependence.3 So what is the basis for the differences between these opiate drugs?

The primary site of action of opioid drugs is at opioid receptors of which there are three pharmacologically distinct types, the mu, delta and kappa receptors (for review see Massotte and Kieffer4). Every opioid drug has a unique profile with regard to receptor selectivity. Etorphine for example, has high affinity for all opioid receptors whereas buprenorphine favors mu and kappa receptors. Many of the clinically used opiates such as morphine, methadone and fentanyl, favor the mu receptor. In addition to receptor selectivity and pharmacodynamics, which govern the pattern of cells directly modulated by an opioid drug, a property of critical importance is the efficacy of a drug in activation of receptors. Not all opiate agonists are equally efficacious in triggering opioid receptors to activate G-proteins. Thus, at the mu receptor, it has been shown that etorphine is more efficacious at G-protein activation than morphine and fentanyl, which in turn are more efficacious than buprenorphine.5 So can efficacy for signaling, receptor selectivity and pharmacodynamics explain the differences between opiate drugs?

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  1. Department of Biobehavioral Sciences and Psychiatry, Neuropsychiatric Institute, University of California, Los Angeles, 90024, CA, USA

    C J Evans, G Monteillet-Agius, N Saliminejad & P A Zaki

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  1. C J Evans
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  2. G Monteillet-Agius
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  4. P A Zaki
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Correspondence to C J Evans.

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Evans, C., Monteillet-Agius, G., Saliminejad, N. et al. Opiate drugs: ‘guilt by association’. Mol Psychiatry 5, 122–123 (2000). https://doi.org/10.1038/sj.mp.4000739

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