Pharmacological Diversity in Opioid Analgesics: Lessons From Clinically Useful Drugs

Acevedo‐Canabal, Agnes; Pantouli, Fani; Ravichandran, Akshaya; Rullo, Laura; Bohn, Laura M.

doi:10.1016/b978-0-12-820472-6.00188-2

Cited by 3 publications

(3 citation statements)

References 146 publications

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“…One exception may be buprenorphine, which has antagonistic properties in the presence of other opioid agonists such as fentanyl and morphine, depending on the response and the system [ 30 ]. For example, buprenorphine produces a bell-shaped antinociceptive response in mice [ 31 , 32 ]; however, buprenorphine also has multiple receptor targets, and it becomes difficult to fully explain these effects by actions of the MOR alone [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…When combined with morphine, SR-17108 decreases the level of morphine-stimulated hyperactivity in a dose-dependent manner ( Figure 4 and Figure 5 ). We hypothesize that this interaction may be due to SR-17018 promoting differential downstream signaling that does not result in the same behavioral output as that mediated by morphine [ 33 ]. SR-17018 was recently shown to be capable of binding within the orthosteric pocket [ 36 ] of MOR by cryo-electron microscopy studies.…”

Section: Discussionmentioning

confidence: 99%

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Hyperactivity in Mice Induced by Opioid Agonists with Partial Intrinsic Efficacy and Biased Agonism Administered Alone and in Combination with Morphine

Acevedo-Canabal,

Grim,

Schmid

et al. 2023

Biomolecules

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Opioid analgesics such as morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Herein, we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using 35S-GTPγS binding assays. While all of the agonists act as partial agonists for stimulating G protein coupling in striatum, morphine, fentanyl, and oliceridine are fully efficacious in stimulating locomotor activity; meanwhile, the noncompetitive biased agonists SR-17018 and SR-15099 produce submaximal hyperactivity. Moreover, the combination of SR-17018 and morphine attenuates hyperactivity while antinociceptive efficacy is increased. The combination of oliceridine with morphine increases hyperactivity, which is maintained over time. These findings provide evidence that noncompetitive agonists at MOR can be used to suppress morphine-induced hyperactivity while enhancing antinociceptive efficacy; moreover, they demonstrate that intrinsic efficacy measured at the receptor level is not directly proportional to drug efficacy in the locomotor activity assay.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hyperactivity in Mice Induced by Opioid Agonists with Partial Intrinsic Efficacy and Biased Agonism Administered Alone and in Combination with Morphine

Acevedo-Canabal,

Grim,

Schmid

et al. 2023

Biomolecules

View full text Add to dashboard Cite

show abstract

“…For example, buprenorphine produces a bell-shaped antinociceptive response in mice [26,27]. ; however, buprenorphine also has multiple receptor targets and it becomes difficult to fully explain these effects by actions at the MOR alone [28].…”

Section: Discussionmentioning

confidence: 99%

Hyperactivity in mice induced by opioid agonists with partial intrinsic efficacy and biased agonism; alone and in combination with morphine

Acevedo-Canabal,

Grim,

Schmid

et al. 2023

Preprint

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Opioid analgesics like morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Here we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using35S-GTPγS binding assays. While all of the agonists act as partial agonists for stimulating G protein coupling in striatum, morphine, fentanyl and oliceridine are fully efficacious in stimulating locomotor activity; meanwhile, the noncompetitive biased agonists, SR-17018 and SR-15099 produce submaximal hyperactivity. Moreover, the combination of SR-17018 and morphine attenuates hyperactivity while antinociceptive efficacy is increased. The combination of oliceridine with morphine increases hyperactivity which is maintained over time. These findings provide evidence that noncompetitive agonists at MOR can be used to suppress morphine-induced hyperactivity while enhancing antinociceptive efficacy; moreover, they demonstrate that intrinsic efficacy measured at the receptor level is not directly proportional to drug efficacy in the locomotor activity assay.

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Opioid system and related ligands: from the past to future perspectives

Rullo,

Morosini,

Lacorte

et al. 2024

J Anesth Analg Crit Care

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Chronic pain is a pathological condition affecting about 30% of population. It represents a relevant social-health issue worldwide, and it is considered a significant source of human suffering and disability, strongly affecting patients’ quality of life. Despite several pharmacological strategies to guarantee an adequate pain management have been proposed over the years, opioids still represent one of the primary choices for treating moderate-to-severe pain in both cancer and non-cancer patients. However, chronic use of opioids often leads to numerous side effects, including respiratory depression, constipation, analgesic tolerance, and opioid-induced hyperalgesia (OIH), which can strongly limit their use. Given the fundamental role of opioid system in pain relief, this review provides a general overview about the main actors (endogenous opioid peptides and receptors) involved in its modulation. Furthermore, this review explores the action and the limitations of conventional clinically used opioids and describes the efficacy and safety profile of some promising analgesic compounds. A deeper understanding of the molecular mechanisms behind both analgesic effects and adverse events could advance knowledge in this field, thus improving chronic pain treatment.

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Pharmacological Diversity in Opioid Analgesics: Lessons From Clinically Useful Drugs

Cited by 3 publications

References 146 publications

Hyperactivity in Mice Induced by Opioid Agonists with Partial Intrinsic Efficacy and Biased Agonism Administered Alone and in Combination with Morphine

Hyperactivity in Mice Induced by Opioid Agonists with Partial Intrinsic Efficacy and Biased Agonism Administered Alone and in Combination with Morphine

Hyperactivity in mice induced by opioid agonists with partial intrinsic efficacy and biased agonism; alone and in combination with morphine

Opioid system and related ligands: from the past to future perspectives

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