Opioid peptides were assayed by inhibition of 3H-naloxone and 3H-leu-enkephalin binding in brain homogenates and by depression of contractions of the guinea pig ileum and mouse vas deferens. We conclude that the opioid peptidergic system has agonists of different characteristics which interact with more than one type of receptor.

Endogenous opioid peptides: multiple agonists and receptors

In the guinea pig ileum myenteric plexus--longitudinal muscle preparation, dynorphin-(1--13) and the prototypical kappa agonist ethylketocyclazocine had equally poor sensitivity to naloxone antagonism and showed selective cross protection in receptor inactivation experiments with the alkylating antagonist beta-chlornaltrexamine. In binding assays with membranes from guinea pig brain, ethylketocyclazocine and dynorphin-(1--13) amide were more potent in displacing tritium-labeled ethylketocyclazocine than in displacing typical mu and delta opioid receptor ligands. In the two preparations studied, the dynorphin receptor appears to be the same as the kappa opioid receptor.

http://science.sciencemag.org/content/sci/215/4531/413.full.pdf

Dynorphin is a specific endogenous ligand of the kappa opioid receptor.

The kappa opioid agonists are analgesics that seem to be free of undesired morphine-like effects. Their dysphoric actions observed with the kappa agonist cyclazocine are thought to be mediated by an action at sigma-phencyclidine receptors. The benzomorphan kappa agonist MR 2033 is inactive at sigma-phencyclidine receptors. In male subjects, the opiate-active (-)-isomer, but not the (+)-isomer, elicited dose-dependent dysphoric and psychotomimetic effects that were antagonized by naloxone. Thus, kappa opiate receptors seem to mediate psychotomimetic effects. In view of the euphorigenic properties of mu agonists, our results imply the existence of opposed opioid systems affecting emotional and perceptual experiences.

https://science.sciencemag.org/content/sci/233/4765/774.full.pdf

Psychotomimesis mediated by kappa opiate receptors.

Facing the rapidly spreading novel coronavirus disease (COVID-19), evidence to inform decision-making at both the clinical and policy-making level is highly needed. Based on the results of a study by Petrilli et al, we have developed a calculator using patient data at admission to predict the risk of critical illness (intensive care unit admission, use of mechanical ventilation, discharge to hospice, or death). 
We report a retrospective validation of the risk calculator on 145 consecutive patients admitted with COVID-19 to a single hospital in Israel. Of the 18 patients with critical illness, 17 were correctly identified by the model(sensitivity: 94.4%, 95% CI, 72.7% to 99.9%; specificity: 81.9%, 95% CI, 74.1% to 88.2%). Of the 127 patients with non-critical illness, 104 were correctly identified. This, despite considerable differences between the original and validation study populations. 
Our results show that data from published knowledge can be used to provide reliable, patient level, automated risk assessment, potentially reducing the cognitive burden on physicians and helping policy makers better prepare for future needs.

https://pharmrev.aspetjournals.org/content/pharmrev/48/4/567.full.pdf

International Union of Pharmacology. XII. Classification of opioid receptors

Four groups of narcotic analgesic drugs have been assessed for their opiate activities by using three binding assays and three pharmacological bioassays. In the binding assays, their inhibition constants (K
I, nM) were determined against the binding of the μ-ligand, [3H]-[d-Ala

 2
 ,MePhe

 4
 , Gly-ol5]enkephalin, of the δ-ligand, [3H]-[d-Ala

 2
 ,d-Leu
5]enkephalin and of the ϰ-ligand, [3H]-(±)-ethylketazocine after suppression of μ- and δ-binding by 100 nM of the unlabelled μ-ligand and 100 nM of the unlabelled δ-ligand. The pharmacological agonist or antagonist activities were assayed on the guinea-pig ileum, mouse vas deferens and rat vas deferens. The first group of compounds were pure agonists in all three pharmacological bioassays. The majority of the compounds showed preference to μ-binding but phenazocine and particularly etorphine had also high affinities to the δ- and ϰ-binding sites. The second group consisted of N-allyl and N-cyclopropylmethyl homologues of the morphine, 3-hydroxymorphinan and normetazocine series which had agonist and antagonist activities in the guinea-pig ileum and mouse vas deferens but were pure antagonists in the rat vas deferens. In the binding assays, μ-binding and ϰ-binding were prominent. The third group was made up by the ketazocine-like compounds which in the guinea-pig ileum and mouse vas deferens were pure agonists and in the rat vas deferens pure antagonists. The binding spectrum showed particularly high binding to the ϰ-binding site. The fourth group was the antagonists which were devoid of agonist activity with the exception of diprenorphine and Mr 2266 which had retained some agonism. The binding spectrum showed considerable variation, naloxone in low concentration being a selective μ-antagonist, Mr 2266 having high affinities to the μ- and ϰ-binding sites and diprenorphine having considerable affinities to the μ-, δ- and ϰ-binding sites. Since each of the four groups of compounds, whether pure agonists, agonist-antagonists, ketazocine-like drugs or pure antagonists, shows independent varittions in the affinities to the μ- and ϰ-binding sites, their different pharmacological behaviour cannot be solely due to difference in the binding spectra.

The binding spectrum of narcotic analgesic drugs with different agonist and antagonist properties

1 Four benzomorphans which have potent antinociceptive activity in the hot-plate and writhing tests in the mouse but do not suppress or precipitate withdrawal symptoms in the morphine-dependent monkey, have been examined for their pharmacological actions in the guinea-pig ileum and mouse vas deferens 2 In the guinea-pig ileum their agonist potencies are 15 to 400 times greater than that of normorphine of morphine whereas in the mouse vas deferens their potencies relative to morphine are 03 to 100 They exhibit no antagonist activity in either preparation Benzomorphans which substitute for morphine in the morphine-dependent monkey do not show such differences between their relative potencies in the guinea-pig ileum and mouse vas diferens 3 The relative potencies of the four benzomorphans to inhibit stereospecific [3H]-dihydromorphine binding by membrane fragments from rat brain, are more closely related to their relative agonist potencies in the mouse vas deferens than to those found in the guinea-pig ileum 4 In order to antagonize the agonist actions of these benzomorphans, naloxone is required in concentrations which are 3 to 7 times higher than those needed for the antagonism of normorphine or morphine or of benzomorphans which suppress abstinence in morphine-dependent monkeys 5 It may be possible to use the three assays, namely, ratio of relative agonist potency in mouse vas deferens to that in guinea-pig ileum, ratio of relative agonist potency to relative affinity to opiate receptors and the concentration of nalozone required for antagonism, for the prediction of the potential of new compounds to produce physical dependence

Assessment in the guinea-pig ileum and mouse vas deferens of benzomorphans which have strong antinociceptive activity but do not substitute for morphine in the dependent monkey

DINGELL, J. V., SULSER, F. & GILLETTE, J. R. (1964). J. Pharmac. exp. Ther., 143,14-22. HAMMER, W. M. & BRODIE, B. B. (1967). Zbid., 157, 503-508. HAMMER, W. M. & SJOQUIST, F. (1967). Life Sci., 6, 1895-1903. HAMMER, W. M., MARTENS, . & SJOQVIST, F.(1969). JORI, A. & BERNARDI, D. (1968). J. Pharm. Phnrmac., 20,955-956. JORI, A., BERNARDI, D., MUSCETTOLA, G. & GARATTINI, S. (1971). JORI, A., BERNARDI, D., PUGLIATI, C. & GARATTINI, S. (1970). Biochem. Pharmac., 18, 2135-2143.

Agonist and antagonist potencies of isomeric 2,3-dimethyl-3-aryl-piperidines.

Introduction: The COVID-19 pandemic has had wide economic, social, and health impacts, and has disproportionately affected individuals who were already vulnerable. Individuals who use opioids have dealt with evolving public health measures and disruptions while also dealing with the ongoing opioid epidemic. Opioid-related mortalities in Canada increased throughout the COVID-19 pandemic, but it is unclear to what extent public health measures and the progression of the pandemic contributed to opioid-related harms. Methods: To address this gap, we used emergency room (ER) visits recorded in the National Ambulatory Care Reporting System (NACRS) between 1 April 2017, and 31 December 2021, to investigate trends of opioid-related harms throughout the pandemic. This study also included semi-structured interviews with service providers in the field of opioid use treatment, to help contextualize the trends seen in ER visits and offer perspectives on how opioid use and services have changed throughout the COVID-19 pandemic. Results: Overall, the number of hospitalizations related to an opioid use disorder (OUD) decreased with progressing waves of the pandemic and with increasing severity of public health measures in Ontario. The rate of hospitalizations related to opioid poisonings (e.g., central nervous system and respiratory system depression caused by opioids) significantly increased with the progressing waves of the pandemic, as well as with increasing severity of public health measures in Ontario. Discussion: The increase in opioid-related poisonings is reflected in the existing literature whereas the decrease in OUDs is not. Moreover, the increase in opioid-related poisonings aligns with the observations of service providers, whereas the decrease in OUD contradicts the trends that service providers described. This discrepancy could be explained by factors identified by service providers, including the pressures on ERs during the pandemic, hesitancy to seek treatment, and drug toxicity.

/pdf/opioid-use-in-the-era-of-covid-19-a-multifaceted-study-of-1j5r2ur3.pdf

M. Hutchinson

Papers

Assessment in the guinea-pig ileum and mouse vas deferens of benzomorphans which have strong antinociceptive activity but do not substitute for morphine in the dependent monkey

Agonist and antagonist potencies of isomeric 2,3-dimethyl-3-aryl-piperidines.

Opioid use in the era of COVID-19: a multifaceted study of the opioid epidemic in Canada